florbetapir-f-18 and Cognitive-Dysfunction

To determine the DTA of the. This review is current to May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches.. We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of. We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies.. We included three studies, two of which evaluated the progression from MCI to ADD, and one evaluated the progression from MCI to any form of dementia.Progression from MCI to ADD was evaluated in 448 participants. The studies reported data on 401 participants with 1.6 years of follow-up and in 47 participants with three years of follow-up. Sixty-one (15.2%) participants converted at 1.6 years follow-up; nine (19.1%) participants converted at three years of follow-up.Progression from MCI to any form of dementia was evaluated in five participants with 1.5 years of follow-up, with three (60%) participants converting to any form of dementia.There were concerns regarding applicability in the reference standard in all three studies. Regarding the domain of flow and timing, two studies were considered at high risk of bias. MCI to ADD;Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment (n = 47, 1 study).Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment by the standardised uptake value ratio (SUVR)(n = 401, 1 study). MCI to any form of dementia;Progression from MCI to any form of dementia in those with a follow-up between one to less than two years had a sensitivity of 67% (95% CI 9 to 99) and a specificity of 50% (95% CI 1 to 99) by visual assessment (n = 5, 1 study). MCI to any other forms of dementia (non-ADD);There was no information regarding the progression from MCI to any other form of dementia (non-ADD).. Although sensitivity was good in one included study, considering the poor specificity and the limited data available in the literature, we cannot recommend routine use of

Topics: Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Dementia; Diagnosis, Differential; Disease Progression; Early Diagnosis; Ethylene Glycols; Fluorine Radioisotopes; Humans; Positron-Emission Tomography; Sensitivity and Specificity

Abstract Recent advances have made possible the in vivo detection of beta-amyloid (Aβ) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Aβ among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Asymptomatic Diseases; Benzothiazoles; Brain; Carbon Radioisotopes; Cognitive Dysfunction; Dementia; Ethylene Glycols; Fluorine Radioisotopes; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

Donanemab (LY3002813) is an IgG1 antibody directed at an N‑terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques.. To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity.. Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study.. Patients recruited at clinical research sites in the United States and Japan.. 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia.. Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15).. Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity.. Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients).. Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Antibodies, Monoclonal; Cognitive Dysfunction; Drug-Related Side Effects and Adverse Reactions; Ethylene Glycols; Female; Humans; Japan; Male; Middle Aged; Patient Safety; Positron-Emission Tomography; United States

Although the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid (Aβ) pathway, the high prevalence of apolipoprotein E ε4 (APOE ε4) in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow Aβ accumulation.. To determine whether the ε2 allele is protective against Aβ accumulation in the presence of the ε4 allele and evaluate how age and the APOE genotype are associated with emerging Aβ accumulation and cognitive dysfunction.. This cross-sectional study used screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study (A4 Study) collected from April 2014 to December 2017 and analyzed from November 2019 to July 2020. Of the 6943 participants who were a part of the multicenter clinical trial screening visit, 4432 were adults without cognitive impairment aged 65 to 85 years who completed a fluorine 18-labeled (18F)-florbetapir positron emission tomography scan, had APOE genotype information, and had a Clinical Dementia Rating of 0. Participants who were taking a prescription Alzheimer medication or had a current serious or unstable illness that could interfere with the study were excluded.. Aβ pathology, measured by 18F-florbetapir positron emission tomography and cognition, measured by the Preclinical Alzheimer Cognitive Composite.. A total of 4432 participants were included (mean [SD] age, 71.3 [4.7] years; 2634 women [59.4%]), with a mean (SD) of 16.6 (2.8) years of education and 1512 (34.1%) with a positive Aβ level. APOE ε2 was associated with a reduction in both the overall (standardized uptake value ratio [SUVR], ε24, 1.11 [95% CI, 1.08-1.14]; ε34, 1.18 [95% CI, 1.17-1.19]) and the age-dependent level of Aβ in the presence of ε4, with Aβ levels in the APOE ε24 group (n = 115; ε24, 0.005 SUVR increase per year of age) increasing at less than half the rate with respect to increasing age compared with the APOE ε34 group (n = 1295; 0.012 SUVR increase per year of age; P = .04). The association between Aβ and decreasing Preclinical Alzheimer Cognitive Composite scores did not differ by APOE genotype, and the reduced performance on the Preclinical Alzheimer Cognitive Composite in APOE ε4 carriers compared with noncarriers was completely mediated by Aβ (unadjusted difference in composite scores between ε4 carriers and noncarriers = -0.084, P = .005; after adjusting for 18F-florbetapir = -0.006, P = .85; after adjusting for 18F-florbetapir and cardiovascular scores = -0.009, P = .78).. These findings suggest that the protective outcome of carrying an ε2 allele in the presence of an ε4 allele against Aβ accumulation is important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aβ clearance in ε4 carriers. Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia. This strategy could represent an early treatment option, as many ε4 carriers begin to accumulate Aβ in early middle age.

Topics: Age Factors; Aged; Aged, 80 and over; Alleles; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E2; Apolipoprotein E4; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography

The present study examined the predictive values of amyloid PET,

Topics: Aged; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Diagnosis, Differential; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Male; Positron-Emission Tomography; Predictive Value of Tests

In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation.. To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine.. A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome.. Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOEɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOEɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002).. Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Apolipoprotein E4; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Glycation End Products, Advanced; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; Thiamine; Treatment Outcome

Observational and interventional studies addressing the link between amyloid (Aβ) burden and cognitive decline are increasing, but a clear definition of amyloid positivity is still lacking. This may represent a great stake for therapeutic studies enrolling Aβ + patients only. The main objective of this study was to define a population with "equivocal" amyloid status, and evaluate their cognitive changes.. Sixty-five participants over 75 years old, from the Control group of the interventional MAPT study, at risk to develop Alzheimer's disease, were included. Participants were classified into three groups in terms of amyloid load: Aβ +, Aβ - and Equivocal participants (according to visual reading, global standardized uptake (SUVR) cut-offs, or a k-mean clustering method). The cognitive changes over time (memory, executive functions, attention and processing speed) of this Equivocal group were then compared to Aβ + and Aβ - participants.. When classified by visual read, Equivocal participants' memory scores were comparable to the Aβ- participants, and greater than in Aβ + participants over time. Secondary analyses, using SUVR cut-offs classification, showed different trajectories with Equivocal participants being comparable to the Aβ + participants, and lower than Aβ-, on executive performance over time.. This original work pointed out a population that may be of great interest for interventional studies, raising the question of how amyloid status should be defined and integrated in such studies. These findings should be replicated in future studies on larger datasets, to confirm what methodological approach would be the most suitable to highlight this specific neuroimaging entity.

Topics: Aged; Aging; Amyloid; Aniline Compounds; Brain; Cognition; Cognitive Dysfunction; Ethylene Glycols; Executive Function; Female; Follow-Up Studies; Humans; Male; Memory; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals

This study aimed to assess efficacy and limitations of regional cerebral blood flow imaging using single-photon emission computed tomography (rCBF-SPECT) in the diagnosis of Alzheimer's disease (AD) with amyloid-positron emission tomography (amyloid-PET). Thirteen patients, who underwent both rCBF-SPECT and amyloid-PET after clinical diagnosis of AD or mild cognitive impairment, were retrospectively identified. The rCBF-SPECTs were classified into 4 grades, from typical AD pattern to no AD pattern of hypoperfusion; amyloid-beta (Aβ) positivity was assessed by amyloid-PET. Four patients were categorized into a typical AD pattern on rCBF-SPECT, and all were Aβ+. The other 9 patients did not exhibit a typical AD pattern; however, 4 were Aβ+. The Mini-Mental State Examination score and Clinical Dementia Rating scale were not significantly different between Aβ+ and Aβ- patients. A typical AD pattern on rCBF-SPECT can reflect Aβ+; however, if not, rCBF-SPECT has a limitation to predict amyloid pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebrovascular Circulation; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Multimodal Imaging; Positron-Emission Tomography; Retrospective Studies; Tomography, Emission-Computed, Single-Photon

To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study.. Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months.. A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit.. Knowledge of the amyloid status affects the diagnosis and alters patient management.

Topics: Aged; Alzheimer Disease; Amyloid; Amyloidogenic Proteins; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Feedback; Female; Follow-Up Studies; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Prospective Studies

The purpose of this study was to evaluate the performance characteristics and safety of florbetapir ((I8)F) positron emission tomography (PET) in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and cognitively normal (CN) control patients from Japan.. Florbetapir ((I8)F) PET was obtained in 48 subjects (15 AD patients, 15 MCI patients, and 18 CNs) within a multicenter phase 2/3 study. Amyloid burden was assessed visually and classified as positive or negative for pathologic levels of amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVRs) were determined from the florbetapir ((I8)F) PET images. Safety was assessed by monitoring adverse events, vital signs, clinical laboratory assessments, and electrocardiograms. Demographic variables and cognitive scales were summarized by using descriptive statistics for each group. Fisher's exact test and one-way analysis of variance were used to compare amyloid positivity and mean SUVRs, respectively, between diagnostic groups.. Florbetapir ((I8)F) PET was rated visually amyloid positive in 80.0% of AD patients, 33.3% of MCI patients, and 16.7% of CNs. Mean SUVRs were highest in the AD group and lowest in the CN group for each brain region (P < 0.01) and globally (P < 0.05). Kappa statistics showed strong inter-reader agreement (Fleiss' kappa = 0.82) and individual reader's agreement with the majority of readers (kappa ranged from 0.79 to 1.0). Seventeen of the 48 subjects (35.4%) were Apolipoprotein E genotype ε4 positive, which included 10 subjects in the AD group and 7 subjects in the MCI group. A total of 6 subjects (5 of whom were in the CN group) had at least 1 treatment-emergent adverse event (TEAE).. These data indicate that amyloid positivity increased with diagnostic category (CN < MCI < AD) and are consistent with expected rates of amyloid positivity among individuals with clinical diagnoses of AD and MCI. In addition, these results were similar to those obtained in United States studies. Florbetapir ((18)F) was safe and well tolerated. The reliability of both qualitative and quantitative assessments of florbetapir ((18)F) in this study population provides support for potential use in clinical settings in Japan.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Case-Control Studies; Cognitive Dysfunction; Ethylene Glycols; Female; Healthy Volunteers; Humans; Japan; Male; Middle Aged; Positron-Emission Tomography; Safety

Positron emission tomography (PET) imaging of brain amyloid load has been suggested as a core biomarker for Alzheimer's disease (AD). The aim of this study was to test the feasibility of using PET imaging with (18)F-AV-45 (florbetapir) in a routine clinical environment to differentiate between patients with mild to moderate AD and mild cognitive impairment (MCI) from normal healthy controls (HC).. In this study, 46 subjects (20 men and 26 women, mean age of 69.0 ± 7.6 years), including 13 with AD, 12 with MCI and 21 HC subjects, were enrolled from three academic memory clinics. PET images were acquired over a 10-min period 50 min after injection of florbetapir (mean ± SD of radioactivity injected, 259 ± 57 MBq). PET images were assessed visually by two individuals blinded to any clinical information and quantitatively via the standard uptake value ratio (SUVr) in the specific regions of interest, which were defined in relation to the cerebellum as the reference region.. The mean values of SUVr were higher in AD patients (median 1.20, Q1-Q3 1.16-1.30) than in HC subjects (median 1.05, Q1-Q3 1.04-1.08; p = 0.0001) in the overall cortex and all cortical regions (precuneus, anterior and posterior cingulate, and frontal median, temporal, parietal and occipital cortex). The MCI subjects also showed a higher uptake of florbetapir in the posterior cingulate cortex (median 1.06, Q1-Q3 0.97-1.28) compared with HC subjects (median 0.95, Q1-Q3 0.82-1.02; p = 0.03). Qualitative visual assessment of the PET scans showed a sensitivity of 84.6% (95% CI 0.55-0.98) and a specificity of 38.1% (95% CI 0.18-0.62) for discriminating AD patients from HC subjects; however, the quantitative assessment of the global cortex SUVr showed a sensitivity of 92.3% and specificity of 90.5% with a cut-off value of 1.122 (area under the curve 0.894).. These preliminary results suggest that PET with florbetapir is a safe and suitable biomarker for AD that can be used routinely in a clinical environment. However, the low specificity of the visual PET scan assessment could be improved by the use of specific training and automatic or semiautomatic quantification tools.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Follow-Up Studies; Humans; Male; Positron-Emission Tomography

The role of cerebral blood flow (CBF) in the early stages of Alzheimer's disease is complex and largely unknown. We investigated cross-sectional and longitudinal associations between CBF, amyloid burden, and cognition, in cognitively normal individuals with subjective cognitive decline (SCD).. A low baseline R. Our results suggest that amyloid accumulation and decrease in rCBF are two parallel disease processes without a fixed order, both providing unique predictive information for cognitive decline and each process enhancing the other longitudinally.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Cerebrovascular Circulation; Cognition; Cognitive Dysfunction; Cross-Sectional Studies; Humans; Positron-Emission Tomography

This study longitudinally examined participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent a conversion in amyloid-beta (Aβ) status in comparison to a group of ADNI participants who did not show a change in amyloid status over the same follow-up period. Participants included 136 ADNI dementia-free participants with 2 florbetapir positron emission tomography (PET) scans. Of these participants, 68 showed amyloid conversion as measured on florbetapir PET, and the other 68 did not. Amyloid converters and non-converters were chosen to have representative demographic data (age, education, sex, diagnostic status, and race). The amyloid converter group showed increased prevalence of APOE ε4 (p < 0.001), greater annualized percent volume loss in selected magnetic resonance imaging (MRI) regions (p < 0.05), lower cerebrospinal fluid Aβ

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Humans; Positron-Emission Tomography

Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected.. We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates.. There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning.. Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications.. NCT02798185.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Chronic Traumatic Encephalopathy; Cognition; Cognitive Dysfunction; Football; Humans; Male; Neurodegenerative Diseases; Positron-Emission Tomography

Recent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer's disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored.. Participants with concurrent. In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals.. These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Demyelinating Diseases; Diffusion Tensor Imaging; Ethylene Glycols; Humans; Myelin Sheath; Positron-Emission Tomography; tau Proteins; White Matter

This study sought to identify a reference tissue-based quantification approach for improving the statistical power in detecting changes in brain glucose metabolism, amyloid, and tau deposition in Alzheimer's disease studies. A total of 794, 906, and 903 scans were included for

Topics: Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Carbolines; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Fluorodeoxyglucose F18; Glucose; Humans; Positron-Emission Tomography

Amyloid positron emission tomography (PET) can reliably detect senile plaques and fluorinated ligands are approved for clinical use. However, the clinical impact of amyloid PET imaging is still under investigation. The aim of this study was to evaluate the diagnostic impact and clinical utility in patient management of amyloid PET using. Ninety-nine patients suspected of having AD underwent. Visual interpretation obtained 48 positive and 51 negative PET scans. The amyloid PET results changed the AD and non-AD diagnosis in 39 of 99 patients (39.3%). The change rates of 26 of the 54 patients (48.1%) with a pre-scan AD diagnosis were significantly higher than those of 13 of the 45 patients with a pre-scan non-AD diagnosis (χ. Amyloid PET using

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Humans; Positron-Emission Tomography

Recently, tau PET tracers have shown strong associations with clinical outcomes in individuals with cognitive impairment and cognitively unremarkable elderly individuals. flortaucipir PET scans to measure tau deposition in multiple brain areas as the disease progresses. This information needs to be summarized to evaluate disease severity and predict disease progression. We, therefore, sought to develop a machine learning-derived index, SPARE-Tau, which successfully detects pathology in the earliest disease stages and accurately predicts progression compared to a priori-based region of interest approaches (ROI).. 587 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort had flortaucipir scans, structural MRI scans, and an Aβ biomarker test (CSF or florbetapir PET) performed on the same visit. We derived the SPARE-Tau index in a subset of 367 participants. We evaluated associations with clinical measures for CSF p-tau, SPARE-MRI, and flortaucipir PET indices (SPARE-Tau, meta-temporal, and average Braak ROIs). Bootstrapped multivariate adaptive regression splines linear regression analyzed the association between the biomarkers and baseline ADAS-Cog13 scores. Bootstrapped multivariate linear regression models evaluated associations with clinical diagnosis. Cox-hazards and mixed-effects models investigated clinical progression and longitudinal ADAS-Cog13 changes. The Aβ positive cognitively unremarkable participants, not included in the SPARE-Tau training, served as an independent validation group.. Compared to CSF p-tau, meta-temporal, and averaged Braak tau PET ROIs, SPARE-Tau showed the strongest association with baseline ADAS-cog13 scores and diagnosis. SPARE-Tau also presented the strongest association with clinical progression in cognitively unremarkable participants and longitudinal ADAS-Cog13 changes. Results were confirmed in the Aβ+ cognitively unremarkable hold-out sample participants. CSF p-tau showed the weakest cross-sectional associations and longitudinal prediction.. Flortaucipir indices showed the strongest clinical association among the studied biomarkers (flortaucipir, florbetapir, structural MRI, and CSF p-tau) and were predictive in the preclinical disease stages. Among the flortaucipir indices, the machine-learning derived SPARE-Tau index was the most sensitive clinical progression biomarker. The combination of different biomarker modalities better predicted cognitive performance.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Humans; Machine Learning; Positron-Emission Tomography; tau Proteins

Visual reading of. The sagittal 2D-CNN classified the SCIENCe scans with the highest average accuracy of 99% ± 2 (SD), sensitivity of 97% ± 7 and specificity of 100%. The ADNI scans were classified with a 95% accuracy, 100% sensitivity and 92.3% specificity.. The 2D-CNN algorithm can classify Aß negative and positive

Topics: Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Humans; Neural Networks, Computer; Positron-Emission Tomography

Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects.. The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls.. AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes.. Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism.. Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Case-Control Studies; Cognitive Dysfunction; Endocytosis; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Immunity; Linear Models; Lipid Metabolism; Male; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Radiopharmaceuticals

Predicting the prognosis of mild cognitive impairment (MCI) has outstanding clinical value, and the hippocampal volume is a reliable imaging biomarker of AD diagnosis.. We aimed to longitudinally assess hippocampal sub-regional difference (volume and asymmetry) among progressive MCI (pMCI), stable MCI (sMCI) patients, and normal elderly.. We identified 29 pMCI, 52 sMCI, and 102 normal controls (NC) from the ADNI database. All participants underwent neuropsychological assessment and 3T MRI scans three times. The time interval between consecutive MRI sessions was about 1 year. Volumes of hippocampal subfield were measured by Freesurfer. Based on the analysis of variance, repeated measures analyses, and receiver operating characteristic curves, we compared cross-sectional and longitudinal alteration sub-regional volume and asymmetry index.. Compared to NC, both MCI groups showed significant atrophy in all subfields. At baseline, pMCI have a smaller volume than sMCI in the bilateral subiculum, molecular layer (ML), the molecular and granule cell layers of the dentate gyrus, cornu ammonis 4, and right tail. Furthermore, repeated measures analyses revealed that pMCI patients showed a faster volume loss than sMCI in bilateral subiculum and ML. After controlling for age, gender, and education, most results remained unchanged. However, none of the hippocampal sub-regional volumes performed better than the whole hippocampus in ROC analyses, and no asymmetric difference between pMCI and sMCI was found.. The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry may have smaller value in predicting the MCI prognosis.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Atrophy; CA1 Region, Hippocampal; CA2 Region, Hippocampal; CA3 Region, Hippocampal; Case-Control Studies; Cognitive Dysfunction; Dentate Gyrus; Disease Progression; Ethylene Glycols; Female; Hippocampus; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Organ Size; Positron-Emission Tomography; ROC Curve

To understand the time course of β-amyloid (Aβ) deposition in the brain, which is crucial for planning therapeutic trials of Aβ-lowering therapies in Alzheimer disease (AD).. Two samples of participants from the Alzheimer's Disease Neuroimaging Initiative were studied with [. The relationship between time and brain Aβ was sigmoidal, taking 6.4 years to transition from amyloid negative to positive and another 13.9 years to the onset of MCI. Aβ deposition rates began to slow only 3.8 years after reaching the positivity threshold. The incidence rate for scan positivity was 38/1,000 person-years, and factors associated with conversion were age, baseline FBP, and being a female. Lowering brain Aβ must be accomplished early in the evolution of AD. Transitions of PET scans from Aβ- to Aβ+ should be predictable, and it is reasonable to expect that lowering rates of Aβ even in early stages could produce clinically significant benefits.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Carbolines; Cognitive Dysfunction; Ethylene Glycols; Female; Follow-Up Studies; Heterozygote; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Positron-Emission Tomography; Sex Characteristics; tau Proteins

Early, accurate diagnosis of Alzheimer disease (AD) is essential but remains challenging. Neuropathological hallmarks of AD are β-amyloid neuritic plaques and tau protein neurofibrillary tangles. 18F-Florbetapir is one of several available PET tracers for imaging cortical fibrillary β-amyloid plaques. 18F-Flortaucipir PET was recently approved for evaluating the distribution and density of aggregated neurofibrillary tangles. We present cases of mild cognitive impairment or suspected AD to depict the nuances of flortaucipir distribution and scan interpretation as well as how combined information from amyloid and tau PET may help with differential diagnosis and prognosis.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Biomarkers; Carbolines; Cognitive Dysfunction; Ethylene Glycols; Humans; Male; Middle Aged; Positron-Emission Tomography

Elenbecestat, an oral BACE-1 inhibitor that has been shown to reduce Aβ levels in cerebrospinal fluid, was investigated in two global phase 3 studies in early AD. Here we report on differences observed in characteristics of APOE ε4 and amyloid positive subjects in the large screening cohort.. Screening was performed in 5 sequential tiers over a maximum of 80 days, as part of placebo controlled, double blind phase 3 studies.. Subjects were evaluated at sites in 7 regions (29 countries).. Overall, 9758 subjects were screened.. All screened subjects that were eligible received either placebo or 50 mg QID elenbecestat post randomisation.. Gender, disease staging, APOE ε4 status, amyloid status, amyloid positron emission tomography (PET) standard uptake value ratio (SUVr) and amyloid PET Centiloid (CL) values were determined for screened subjects; by country and region.. In this program, 44% of subjects were APOE ε4 positive. Frequency of females was similar in both APOE ε4 positive and negative groups. However, early mild AD subjects were slightly higher in the APOE ε4 positive group compared with the APOE ε4 negative group. 56% of subjects were amyloid positive. The mean age in the amyloid positive group was slightly higher than the amyloid negative group. The gender distribution was similar between amyloid groups. A lower number of mild cognitive impairment was observed in the amyloid positive group along with a higher number of early mild AD. APOE ε4 positive subjects were higher in amyloid positive group compared to the amyloid negative group. China had the lowest APOE ε4 and amyloid positivity rates with Western Europe and Oceania performing best. Subjects received florbetapir, florbetaben or flutemetamol amyloid PET tracer. Amyloid negative and positive subjects CL values were normally distributed around their respective means of 1.5 CL and 83 CL. However, there was an appreciable overlap in the 20-40 CL range.. In this large cohort of cognitively impaired subjects, subject demographics characteristics were comparable regardless of APOE genotype or amyloid positivity. APOE ε4 positivity and amyloid positivity varied by country and by geographical region.

Topics: Amyloid; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Genotype; Humans; Male; Positron-Emission Tomography

Identifying dynamic changes in biomarkers and clinical profiles is essential for understanding the progression of Alzheimer's disease (AD). The relevant studies have primarily relied on patients with autosomal dominant AD; however, relevant studies in sporadic AD are poorly understood. Here, we analyzed longitudinal data from 665 participants (mean follow-up 4.90 ± 2.83 years). By aligning normal cognition (CN) baseline with a clinical diagnosis of mild cognitive impairment (MCI) or AD, we studied the progression of AD using a linear mixed model to estimate the clinical and biomarker changes from stable CN to MCI to AD. The results showed that the trajectory of hippocampal volume and fluorodeoxyglucose (FDG) was consistent with the clinical measures in that they did not follow a hypothetical sigmoid curve but rather showed a slow change in the initial stage and accelerated changes in the later stage from MCI conversion to AD. Dramatic hippocampal atrophy and the ADAS13 increase were, respectively, 2.5 and 1 years earlier than the MCI onset. Besides, cognitively normal people with elevated and normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG. These results reveal that pre-MCI to pre-AD may be a better time window for future clinical trial design.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Linear Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Organ Size; Positron-Emission Tomography; Radiopharmaceuticals

To determine the association between occipital amyloid-PET uptake and neurocognitive performance in Alzheimer's disease (AD).. Fifty-eight participants with normal aged, mild cognitive impairment (MCI) due to AD and AD subjects who underwent F-18 florbetapir brain PET/CT scans were divided into four groups (A, normal; B, MCI; C, mild AD; and D, moderate/severe AD). Semiquantitative analyses of SUVR images were performed. The differences between groups and the correlations between florbetapir uptake and Thai Mental State Examination (TMSE) scores were determined. Significant differences were defined using a P < 0.001, uncorrected, or a P < 0.05, FWE for the voxel-based analyses with Statistical Parametric Mapping (SPM).. There was a slightly higher florbetapir uptake in the precuneus, parietal, and occipital association cortices in Group B > A. The occipital florbetapir uptake in Groups C and D was significantly higher than in Group A, in addition to the precuneus, anterior cingulate, posterior cingulate, temporoparietal, and frontal cortices. There was a strong negative correlation between TMSE scores and florbetapir uptake in the occipital lobe.. Occipital amyloid uptake is associated with clinically advanced AD, and is inversely correlated with neurocognitive performance and may be useful for evaluating AD severity.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Humans; Occipital Lobe; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography

Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology.. To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults.. In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021.. Self-reported daytime and nighttime sleep duration.. Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio.. Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aβ (F1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aβ (F1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aβ (F1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aβ (F1,2910 = 14.2; P = .001) in participants who tested Aβ negative.. In this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Geriatric Assessment; Humans; Male; Mental Status and Dementia Tests; Plaque, Amyloid; Positron-Emission Tomography; Sleep; Sleep Initiation and Maintenance Disorders

The aim of this study is to use 3D-SSP and a population-comparable normal database to investigate the associations between amyloid deposition detected by 18Fflorbetapir PET and neurocognitive performance of participants with mild cognitive impairment (MCI) and Alzheimer's disease (AD).. There was high agreement between the visual assessment results and the semiquantitative analysis (κ = 0.793 and 0.845). The stages of amyloid deposition were consistent with neurocognitive status across participants. Significantly higher SUVRs were found in AD than MCI and HC. Visual assessment and stage were not significantly correlated with TMSE scores. A significant negative correlation between the SUVRs and TMSE scores was partially demonstrated in MCI and AD, but not HC.. 3D-SSP analysis of

Topics: Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Humans; Positron-Emission Tomography

Histopathologic studies have demonstrated differential amyloid-β (Aβ) burden between cortical sulci and gyri in Alzheimer's disease (AD), with sulci having a greater Aβ burden.. To characterize Aβ deposition in the sulci and gyri of the cerebral cortex in vivo among subjects with normal cognition (NC), mild cognitive impairment (MCI), and AD, and to evaluate if these differences could improve discrimination between diagnostic groups.. T1-weighted 3T MR and florbetapir (amyloid) positron emission tomography (PET) data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). T1 images were segmented and the cortex was separated into sulci/gyri based on pial surface curvature measurements. T1 images were registered to PET images and regional standardized uptake value ratios (SUVr) were calculated. A linear mixed effects model was used to analyze the relationship between clinical variables and amyloid PET SUVr measurements in the sulci/gyri. Receiver operating characteristic (ROC) analysis was performed to define amyloid positivity. Logistic models were used to evaluate predictive performance of clinical diagnosis using amyloid PET SUVr measurements in sulci/gyri.. 719 subjects were included: 272 NC, 315 MCI, and 132 AD. Gyral and sulcal Aβ increased with worsening cognition, however there was a greater increase in gyral Aβ. Females had a greater gyral and sulcal Aβ burden. Focusing on sulcal and gyral Aβ did not improve predictive power for diagnostic groups.. While there were significant differences in Aβ deposition in cerebral sulci and gyri across the AD spectrum, these differences did not translate into improved prediction of diagnosis. Females were found to have greater gyral and sulcal Aβ burden.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cerebral Cortex; Cognitive Dysfunction; Ethylene Glycols; Female; Gray Matter; Humans; Male; Positron-Emission Tomography; Sex Factors

Sporadic cerebral amyloid angiopathy shows progressive amyloid-β deposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex.. To investigate whether amyloid load and distribution, assessed by florbetapir positron emission tomography (PET), differs between patients with probable CAA-related intracerebral hemorrhage (CAA-ICH) and mild cognitive impairment due to Alzheimer's disease (MCI-AD).. We assessed [18F]florbetapir uptake in 15 patients with probable CAA-ICH and 20 patients with MCI-AD patients. Global and regional florbetapir retention were assessed using standard uptake values ratio (SUVr) in region-based and voxel-wise approaches. Visual reading of florbetapir scans was performed for all participants. Group comparisons were performed using univariate and multivariate analysis.. Global florbetapir retention was lower in patients with CAA-ICH than MCI-AD (median SUVr, 1.33 [1.21-1.41] versus 1.44 [1.35-1.66]; p = 0.032). In the region-based analysis, regional florbetapir distribution was similar between the two groups. There was a trend for an increased occipital/global ratio in CAA-ICH patients compared to MCI-AD (p = 0.060). In the voxel-wise approach, two clusters, one in parietal regions and the other in temporal regions, had higher uptake in MCI-AD relative to CAA patients.. Patients with CAA-ICH had a lower global florbetapir PET burden than patients with MCI-AD. Relative florbetapir retention in the posterior regions tended to be higher in CAA patients in region-based analysis but was not statistically different between groups. Investigation on differences in amyloid deposits distribution between groups required a fine-grained voxel-wise analysis. In future studies, selective amyloid tracers are needed to differentiate vascular from parenchymal amyloid.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Body Burden; Cerebral Amyloid Angiopathy; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Image Interpretation, Computer-Assisted; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals

Cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ42) reliably detects brain amyloidosis based on its high concordance with plaque burden at autopsy and with amyloid positron emission tomography (PET) ligand retention observed in several studies. Low CSF Aβ42 concentrations in normal aging and dementia are associated with the presence of fibrillary Aβ across brain regions detected by amyloid PET imaging.. An LC-MS/MS reference method for Aβ42, modified by adding Aβ40 and Aβ38 peptides to calibrators, was used to analyze 1445 CSF samples from ADNIGO/2 participants. Seventy runs were completed using 2 different lots of calibrators. For preparation of Aβ42 calibrators and controls spiking solution, reference Aβ42 standard with certified concentration was obtained from EC-JRC-IRMM (Belgium). Aβ40 and Aβ38 standards were purchased from rPeptide. Aβ42 calibrators' accuracy was established using CSF-based Aβ42 Certified Reference Materials (CRM).. CRM-adjusted Aβ42 calibrator concentrations were calculated using the regression equation Y (CRM-adjusted) = 0.89X (calibrators) + 32.6. Control samples and CSF pools yielded imprecision ranging from 6.5 to 10.2% (Aβ42) and 2.2 to 7.0% (Aβ40). None of the CSF pools showed statistically significant differences in Aβ42 concentrations across 2 different calibrator lots. Comparison of Aβ42 with Aβ42/Aβ40 showed that the ratio improved concordance with concurrent [18F]-florbetapir PET as a measure of fibrillar Aβ (n = 766) from 81 to 88%.. Long-term performance assessment substantiates our modified LC-MS/MS reference method for 3 Aβ peptides. The improved diagnostic performance of the CSF ratio Aβ42/Aβ40 suggests that Aβ42 and Aβ40 should be measured together and supports the need for an Aβ40 CRM.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Calibration; Case-Control Studies; Chromatography, Liquid; Cognitive Dysfunction; Ethylene Glycols; Humans; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Reference Standards; Reproducibility of Results; Tandem Mass Spectrometry

The causes of cognitive impairment among older HIV+ individuals may overlap with causes among elderly HIV seronegative (HIV-) individuals. The objective of this study was to determine if beta-amyloid (Aβ) deposition measured by [

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Biological Transport; Brain; Brain Mapping; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Fluorine Radioisotopes; HIV; HIV Infections; Humans; Male; Middle Aged; Positron-Emission Tomography; Severity of Illness Index

To clarify the preclinical stage of Alzheimer's disease by estimating when β-amyloid accumulation first becomes associated with changes in cognition.. Here we studied a large group (N = 4432) of cognitively unimpaired individuals who were screened for inclusion in the A4 trial (age 65-85) to assess the effect of subthreshold levels of β-amyloid on cognition and to identify which cognitive domains first become affected.. β-amyloid accumulation was linked to significant cognitive dysfunction in cognitively unimpaired participants with subthreshold levels of β-amyloid in multiple measures of memory (Logical Memory Delayed Recall, P = 0.03; Free and Cued Selective Reminding Test, P < 0.001), the Preclinical Alzheimer's Cognitive Composite (P = 0.01), and was marginally associated with decreased executive function (Digit Symbol Substitution, P = 0.07). Significantly, decreased cognitive scores were associated with suprathreshold levels of β-amyloid, across all measures (P < 0.05). The Free and Cued Selective Reminding Test, a list recall memory test, appeared most sensitive to β-amyloid -related decreases in average cognitive scores, outperforming all other cognitive domains, including the narrative recall memory test, Logical Memory.. Clinical trials for cognitively unimpaired β-amyloid-positive individuals will include a large number of individuals where mechanisms downstream from β-amyloid pathology are already activated. These findings have implications for primary and secondary prevention of Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Executive Function; Female; Humans; Male; Mental Recall; Positron-Emission Tomography; Prodromal Symptoms

Positron emission tomography (PET)-based staging of regional amyloid deposition has recently emerged as a promising tool for sensitive detection and stratification of pathology progression in Alzheimer's Disease (AD). Here we present an updated methodological framework for PET-based amyloid staging using region-specific amyloid-positivity thresholds and assess its longitudinal validity using serial PET acquisitions. We defined region-specific thresholds of amyloid-positivity based on Florbetapir-PET data of 13 young healthy individuals (age ≤ 45y), applied these thresholds to Florbetapir-PET data of 179 cognitively normal older individuals to estimate a regional amyloid staging model, and tested this model in a larger sample of patients with mild cognitive impairment (N = 403) and AD dementia (N = 85). 2-year follow-up Florbetapir-PET scans from a subset of this sample (N = 436) were used to assess the longitudinal validity of the cross-sectional model based on individual stage transitions and data-driven longitudinal trajectory modeling. Results show a remarkable congruence between cross-sectionally estimated and longitudinally modeled trajectories of amyloid accumulation, beginning in anterior temporal areas, followed by frontal and medial parietal areas, the remaining associative neocortex, and finally primary sensory-motor areas and subcortical regions. Over 98% of individual amyloid deposition profiles and longitudinal stage transitions adhered to this staging scheme of regional pathology progression, which was further supported by corresponding changes in cerebrospinal fluid biomarkers. In conclusion, we provide a methodological refinement and longitudinal validation of PET-based staging of regional amyloid accumulation, which may help improving early detection and in-vivo stratification of pathologic disease progression in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cerebral Cortex; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Ethylene Glycols; Female; Humans; Longitudinal Studies; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Reproducibility of Results

Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer's disease (AD).. To examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum.. We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity.. In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP.. The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Aniline Compounds; Brain; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Ethylene Glycols; Female; Glial Fibrillary Acidic Protein; Humans; Male; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer's disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms.. Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status.. We included 372 nondemented elderly from the Alzheimer's Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels.. Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOEɛ4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels.. Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.

Topics: Age Factors; Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Carbolines; Case-Control Studies; Cognitive Dysfunction; Contrast Media; Ethylene Glycols; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Organ Size; Peptide Fragments; Positron-Emission Tomography; tau Proteins

Topics: Aged; Aged, 80 and over; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Atherosclerosis; Atrial Fibrillation; Brain; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Echocardiography; Electrocardiography; Ethylene Glycols; Female; Heart Atria; Heart Diseases; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Positron-Emission Tomography; Risk Factors

Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase. This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed.. FDG standardized uptake value ratio, eAV45 (0-2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H. R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Cerebrovascular Circulation; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Male; Positron-Emission Tomography; Severity of Illness Index

Recent studies have found associations of increased brain amyloid beta (Aβ) accumulation and several abnormal sleep-wake patterns, including shorter latency and increased fragmentation in preclinical Alzheimer's disease (AD). There is little known about the relationship between sleep and tau. The objective of this study was to understand the associations of both tau and Aβ with early signs of sleep and night-time behavior changes in clinically normal elderly adults. Specifically, we have addressed the question of how informant-based subjective sleep reports are linked to regional [. Imaging and behavioral data from 35 subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative. The Neuropsychiatric Inventory Sleep (NPI-sleep) Questionnaire was used to assess the sleep and night-time behavior changes. Regional tau-positron emission tomography (PET) (entorhinal, brainstem) and Aβ-PET (posterior cingulate, precuneus, medial orbitofrontal) uptake values were calculated. A series of linear regression analyses were used to determine the combination of sleep symptoms that built the best models to predict each pathology.. Informant-based reports of abnormal night-time behavior (NPI questions k3, k5, and k8) were significantly associated with increased entorhinal tau and Aβ (all regions) accumulation. Interestingly, informant-based reports of sleep deficiencies without abnormal nigh-time activity (NPI questions k1, k2, and k6) were negatively associated with entorhinal tau burden.. Detection of abnormal night-time behaviors (wandering, pacing, other inappropriate activities) by family members indicates early signs of both AD pathologies and may encourage the affected individuals to seek help by health care providers for detailed cognitive/neurobehavioral assessments.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Behavioral Symptoms; Carbolines; Cognitive Dysfunction; Entorhinal Cortex; Ethylene Glycols; Female; Humans; Male; Neuroimaging; Positron-Emission Tomography; Sleep; Surveys and Questionnaires; tau Proteins; Time Factors

There is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer's disease (AD) and their pathological substrates.. To test the association between financial skills and cortical β-amyloid deposition in aging and subjects at risk for AD.. Cross-sectional analyses of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada.. Multicenter biomarker study.. 243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD).. 18F-Florbetapir brain PET scans to measure global cortical β-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual's financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0-74) with higher scores indicating better financial skill.. FCI-SF total score was significantly worse in MCI [Cohen's d= 0.9 (95%CI: 0.6-1.2)] and AD subjects [Cohen's d=3.1(CI: 2.5-3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical β-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen's f2=0.751(CI: 0.5-1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher β -amyloid PET SUVr was associated with longer task completion time [Cohen's f2=0.198(CI: 0.06-0.37)].. Using a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical β-amyloid deposition. In normal aging, β-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Brain; Canada; Case-Control Studies; Cerebral Cortex; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Ethylene Glycols; Female; Financial Management; Humans; Male; Positron-Emission Tomography; Prodromal Symptoms; Severity of Illness Index; United States

Amyloid beta (Aβ) plaques aggregation is considered as the "start" of the degenerative process that manifests years before the clinical symptoms appear in Alzheimer's Disease (AD). The aim of this study is to use back propagation neural networks (BPNNs) in 18F-florbetapir PET data for automated classification of four patient groups including AD, late mild cognitive impairment (LMCI), early mild cognitive impairment (EMCI), and significant memory concern (SMC), versus normal control (NC) for early AD detection. Five hundred images for AD, LMCI, EMCI, SMC, and NC, i.e., 100 images for each group, were used from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The results showed that the automated classification of NC/AD produced a high accuracy of 87.9%, while the results for the prodromal stages of the disease were 66.4%, 60.0%, and 52.9% for NC/LCMI, NC/EMCI and NC/SMC, respectively. The proposed method together with the image preparation steps can be used for early AD detection and classification with high accuracy using Aβ PET dataset.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Databases, Factual; Early Diagnosis; Ethylene Glycols; Female; Humans; Image Interpretation, Computer-Assisted; Male; Neural Networks, Computer; Neuroimaging; Positron-Emission Tomography

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Ethylene Glycols; Female; Humans; Longitudinal Studies; Magnetic Resonance Spectroscopy; Male; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Support Vector Machine

To identify potential predictors for outcome in individuals with mild cognitive impairment (MCI) who have reverted to normal cognition (NC).. We selected individuals with MCI, who reverted at follow-up to NC, with follow-up after reversion from Alzheimer's Disease Neuroimaging Initiative. Common clinical markers, Alzheimer disease (AD) biomarkers, and neurodegeneration imaging markers were used to compare MCI reverters based on subsequent clinical outcome (i.e., subsequent decline or stable reversion). For independent comparison, findings of the clinical Amsterdam Dementia Cohort are presented.. Seventy-seven (10%) out of 757 individuals with MCI reverted to NC and 61 of these individuals had follow-up data available. After 3.2 ± 2.2 years, 16 (24%) progressed to MCI, and 3 (5%) to dementia. Those who declined were older and had a higher amyloid PET burden and higher CSF tau levels.. In MCI reverters, abnormal biomarkers for AD pathology are associated with subsequent decline. AD biomarkers may aid in the prognosis of reverting MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Dementia; Disease Progression; Ethylene Glycols; Female; Humans; Male; Middle Aged; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Prognosis; Recurrence; Remission, Spontaneous; Risk Assessment; tau Proteins; Thiazoles

The link between brain amyloid-β (Aβ), metabolism, and dementia symptoms remains a pressing question in Alzheimer's disease. Here, using positron emission tomography ([

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Animals, Genetically Modified; Brain; Cognitive Dysfunction; Ethylene Glycols; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Neural Pathways; Neurofibrillary Tangles; Positron-Emission Tomography; Radiopharmaceuticals; Rats

We evaluated the associations of subjective (self-reported everyday cognition [ECog]) and objective cognitive measures with regional amyloid-β (Aβ) and tau accumulation in 86 clinically normal elderly subjects from the Alzheimer's Disease Neuroimaging Initiative. Regression analyses were conducted to identify whether individual ECog domains (Memory, Language, Organization, Planning, Visuospatial, and Divided Attention) were equally or differentially associated with regional [

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognitive Dysfunction; Ethylene Glycols; Fluorine Radioisotopes; Humans; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins

To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum.. We selected 839 β-amyloid (Aβ)-positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale-cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W scores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i.e., NC to MCI/AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF).. The median follow-up period was 24 months (interquartile range 6-42). Corrected for age, sex,. Among Aβ-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Case-Control Studies; Cognitive Dysfunction; Cognitive Reserve; Contrast Media; Disease Progression; Ethylene Glycols; Executive Function; Female; Gray Matter; Humans; Male; Memory; Middle Aged; Organ Size; Peptide Fragments; Thiazoles; White Matter

Sleep changes have been associated with increased risks of developing cognitive disturbances and Alzheimer's disease (AD). A bidirectional relation is underlined between amyloid-beta (Aß) and sleep disruptions. The sleep profile in participants at risk to develop AD is not fully deciphered. We aim to investigate sleep-wake changes with objective sleep measurements in elderly participants without cognitive impairment depending on their brain amyloid status, positive (Aß+) or negative (Aß-) based on standard absorption ratios (SUVr) positron emission tomography-florbetapir imaging.. Sixty-eight participants without cognitive impairment who have accepted to be involved in the sleep ancillary study from the InveStIGation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT-pre AD) cohort, aiming to record sleep profile based on the analyses of an ambulatory accelerometer-based assessment (seven consecutive 24-hour periods). Neuropsychological tests were performed and sleep parameters have been individualized by actigraph. Participants also underwent a magnetic resonance imaging scan to assess their hippocampal volume. Based on SUVr PET-florbetapir imaging, two groups Aß+ and Aß- were compared.. Participants were divided into two groups: Aß+ (n = 24) and Aß- (n = 44). Except for the SUVr, the two subgroups were comparable. When looking to sleep parameters, increased sleep latency, sleep fragmentation (wake after sleep onset [WASO] score and awakenings) and worst sleep efficiency were associated with cortical brain amyloid load.. Actigraphic sleep parameters were associated with cortical brain amyloid load in participants at risk to develop AD. The detection of sleep abnormalities in those participants may be of interest to propose some preventive strategies.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Brain; Cognitive Dysfunction; Cohort Studies; Ethylene Glycols; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Sleep

To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline.. In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect.. Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures.. A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Asymptomatic Diseases; Benzothiazoles; Brain; Cognitive Dysfunction; Contrast Media; Disease Progression; Ethylene Glycols; Female; Humans; Male; Mental Recall; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; Time Factors; Trail Making Test

18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 18F-florbetapir PET are approved neuroimaging biomarkers for the Alzheimer's disease (AD) and mild cognitive impairment (MCI).. This study aims to compare the efficacy of 18F-FDG and 18F-florbetapir PET at evaluating the cognitive performance of patients with AD, MCI, and normal controls (NC).. 63 subjects (36 male/27 female, mean age = 68.3) including 19 AD, 23 MCI, and 21 NC underwent 18F-FDG and 18F-florbetapir PET imaging. A global quantification approach was applied on supra-tentorial, frontal, parieto-occipital, temporal, and cerebellar brain regions by calculating the global SUVmean ratios (GSUVr) as the weighted average of all regional SUVmean. 18F-FDG and 18F-florbetapir GSUVr of each region were subsequently correlated with the Mini-Mental State Examination (MMSE).. Subjects were studied in five categories as NC, MCI patients, AD patients, MCI and AD patients grouped together (MCI/AD), and a group including all the subjects (NC/MCI/AD). Both 18F-FDG and 18F-florbetapir could successfully detect subjects with dementia (p < 0.001). Studied in all regions and groups, the correlation analysis of 18F-FDG GSUVr with MMSE scores was significant in more regions and groups compared to that of 18F-florbetapir. We also demonstrated that the correlation of 18F-FDG GSUVr with MMSE is stronger than that of 18F-florbetapir in the supra-tentorial and temporal regions.. This study reveals how 18F-FDG-PET global quantification is a superior indicator of cognitive performance in AD and MCI patients compared to 18F-florbetapir PET. Accordingly, we still recommend 18F-FDG-PET over amyloid imaging in the evaluation for AD and MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals

To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification.. The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB.. A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees).. Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Prospective Studies; Sensitivity and Specificity; Supervised Machine Learning

Body weight loss in late-life is known to occur at a very early stage of Alzheimer's disease (AD). Apolipoprotein E4 (ApoE4) represents a major genetic risk factor for AD and is linked to an increased cortical amyloid-β (Aβ) accumulation. Since the relationship between body weight, ApoE4, and AD pathology is poorly investigated, we aimed to evaluate whether ApoE4 allelic status modifies the association of body mass index (BMI) with markers of AD pathology. A total of 368 Aβ-positive cognitively healthy or mild cognitive impaired subjects had undergone [18F]-AV45-PET, [18F]-FDG-PET, and T1w-MRI examinations. Composite cortical [18F]-AV45 uptake and [18F]-FDG uptake in posterior cingulate cortex were calculated as surrogates of cortical Aβ load and glucose metabolism, respectively. Multiple linear regressions were performed to assess the relationships between these PET biomarkers with BMI, present cognitive performance, and cognitive changes over time. Multivariate analysis of covariance was conducted to test for statistical differences between ApoE4/BMI categories on the PET markers and cognitive scores. In carriers of the ApoE4 allele only, BMI was inversely associated with cortical amlyoid load (β= -0.193, p < 0.005) and recent cognitive decline (β= -0.209, p < 0.05), and positively associated with cortical glucose metabolism in an AD-vulnerable region (β= 0.145, p < 0.05). ApoE4/BMI category analyses demonstrated lower Aβ load, higher posterior cingulate glucose metabolism, improved cognitive performance, and lower progression of cognitive decline in obese ApoE4 carriers. The effect of ApoE4 in promoting the accumulation of cortical amyoid, which may itself be a driver for weight loss, may be moderated by altering leptin signaling in the hypothalamus.

Topics: Adaptor Proteins, Signal Transducing; Aged; Amyloid; Aniline Compounds; Apolipoprotein E4; Body Mass Index; Brain; Cognition; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Glucose; Heterozygote; Humans; Male; Neurodegenerative Diseases; Positron-Emission Tomography; Radiopharmaceuticals; Repressor Proteins; Weight Loss; Zebrafish Proteins

There is increasing evidence showing that the accumulation of the amyloid-β (Aβ) peptide into extracellular plaques is a central event in Alzheimer's disease (AD). These abnormalities can be detected as lowered levels of Aβ42 in the cerebrospinal fluid (CSF) and are followed by increased amyloid burden on positron emission tomography (PET) several years before the onset of dementia. The aim of this study was to assess amyloid network topology in nondemented individuals with early stage Aβ accumulation, defined as abnormal CSF Aβ42 levels and normal Florbetapir PET (CSF+/PET-), and more advanced Aβ accumulation, defined as both abnormal CSF Aβ42 and Florbetapir PET (CSF+/PET+). The amyloid networks were built using correlations in the mean 18F-florbetapir PET values between 72 brain regions and analyzed using graph theory analyses. Our findings showed an association between early amyloid stages and increased covariance as well as shorter paths between several brain areas that overlapped with the default-mode network (DMN). Moreover, we found that individuals with more advanced amyloid accumulation showed more widespread changes in brain regions both within and outside the DMN. These findings suggest that amyloid network topology could potentially be used to assess disease progression in the predementia stages of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Brain Mapping; Cognitive Dysfunction; Diagnostic Self Evaluation; Disease Progression; Ethylene Glycols; Female; Humans; Male; Memory Disorders; Middle Aged; Neural Pathways; Positron-Emission Tomography; Prodromal Symptoms; Radiopharmaceuticals; Severity of Illness Index

Cognitive impairment resembling Alzheimer's disease is common in survivors of critical illness. We hypothesized that Intensive Care Unit (ICU) survivors with cognitive impairment would have significant amyloid and designed a pilot study to explore this relationship.. A pilot, case series of a convenience sample of 14 adult medical and surgical ICU survivors, in a clinical neuroradiology clinic. Patients underwent cognitive testing at 3months, 1year, 4years, and 6years after hospital discharge with the Repeatable Battery for the Assessment of Neuropsychological Status. They received a single PET scan using amyloid PET imaging (florbetapir F18) 2 to 4years after their ICU stay.. Amyloid (defined as a Standard Uptake Value ratio or SUVr >1.10) was present in 2 of 14 (14%) individuals, both of whom demonstrated significant cognitive impairment yet no consistent decline over time. Of the 6 impaired patients (RBANS<78), 4 (66.7%) were amyloid negative.. It is feasible to assess ICU survivors with amyloid imaging. In this small sample, most patients with cognitive impairment were negative on amyloid PET imaging, which raises the possibility that ICU survivors may experience a unique form of dementia not driven by an amyloid related mechanism.

Topics: Adult; Aged; Amyloid; Aniline Compounds; Cognitive Dysfunction; Critical Illness; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Neuropsychological Tests; Pilot Projects; Positron-Emission Tomography; Survivors

Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.. Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype.. The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls.. In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Brain; Cardiac Surgical Procedures; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Positron-Emission Tomography; Postoperative Complications; Prospective Studies

To evaluate the clinical and imaging characteristics of patients with visually equivocal amyloid PET images, patients from the Alzheimer's Disease Neuroimaging Initiative cohort who had fluorine-18-florbetapir PET scans both at baseline and 24 months were selected. Five nuclear medicine physicians visually assessed the PET images and classified them as either positive or negative. Images not reaching a majority agreement were classified as equivocal. Among a total of 379 patients, the number of patients in each fluorine-18-florbetapir PET negative/equivocal/positive categories was 218 (57.5%), 32 (8.4%), and 129 (34.0%). Eight to 9% of patients with normal cognition (N=12/141), mild cognitive impairment (N=20/214), and no Alzheimer's disease (N=0/24) showed equivocal PET finding for each. In negative/equivocal/positive groups, positive cerebrospinal fluid Aβ1-42 was observed in 25.7, 81.5, and 98.3%, respectively. Baseline standardized uptake value ratios of fluorine-18-florbetapir PET were 0.75±0.05, 0.86±0.09, and 1.01±0.09, respectively [F(2, 376)=603.547; P<0.001]. After 24 months of follow-up, the standardized uptake value ratios increased by 0.81±2.62, 2.81±2.90, and 2.17±3.66%, respectively [F(2, 376)=7.905, P<0.05 vs. the negative group]. Among mild cognitive impairment patients, the equivocal group showed a more rapid decline in glucose metabolism than the negative group [5.52±5.36 vs. 0.67±4.45; F(2, 122)=9.028, P<0.01]. 8.4% of the patients in this study showed a visually equivocal result of amyloid PET. These patients showed a moderate amount of amyloid accumulation and a rapid rate of accumulation.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Cohort Studies; Ethylene Glycols; Female; Humans; Male; Neuropsychological Tests; Observer Variation; Peptide Fragments; Positron-Emission Tomography

Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects was performed using baseline 18F-florbetapir and 18F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Brain Mapping; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Male; Positron-Emission Tomography; Prognosis; Prospective Studies; Radiopharmaceuticals; Sensitivity and Specificity

To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.. We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [. We found that participants with impaired awareness had lower [. Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Topics: Aged; Agnosia; Amyloid; Aniline Compounds; Apolipoprotein E4; Biomarkers; Brain; Cognitive Dysfunction; Dementia; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Male; Prognosis; Radiopharmaceuticals

For effective treatment of Alzheimer's disease (AD), it is important to identify subjects who are most likely to exhibit rapid cognitive decline. We aimed to develop an automatic image interpretation system based on a deep convolutional neural network (CNN) which can accurately predict future cognitive decline in mild cognitive impairment (MCI) patients using flurodeoxyglucose and florbetapir positron emission tomography (PET). PET images of 139 patients with AD, 171 patients with MCI and 182 normal subjects obtained from Alzheimer's Disease Neuroimaging Initiative database were used. Deep CNN was trained using 3-dimensional PET volumes of AD and normal controls as inputs. Manually defined image feature extraction such as quantification using predefined region-of-interests was unnecessary for our approach. Furthermore, it used minimally processed images without spatial normalization which has been commonly used in conventional quantitative analyses. Cognitive outcome of MCI subjects was predicted using this network. The prediction accuracy of the conversion of mild cognitive impairment to AD was compared with the conventional feature-based quantification approach. Accuracy of prediction (84.2%) for conversion to AD in MCI patients outperformed conventional feature-based quantification approaches. ROC analyses revealed that performance of CNN-based approach was significantly higher than that of the conventional quantification methods (p < 0.05). Output scores of the network were strongly correlated with the longitudinal change in cognitive measurements (p < 0.05). These results show the feasibility of deep learning as a practical tool for developing predictive neuroimaging biomarker.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Image Interpretation, Computer-Assisted; Imaging, Three-Dimensional; Male; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Sensitivity and Specificity; Support Vector Machine

Suspected non-Alzheimer's pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect "active" neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional 'hippocampal volume' only (SNAP/L-) versus both cross-sectional and longitudinal 'hippocampal atrophy rate' (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI).. 276 MCI patients from ADNI-GO/2 were designated amyloid "positive" (A+) or "negative" (A-) based on their florbetapir scan and neurodegeneration 'positive' or 'negative' based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate.. 74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L- and the A- CN group. SNAP/L- had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition.. Using a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests

Patients with late-life depression may be at the preclinical stage of dementia. However, the neurodegenerative processes in late-life depression are poorly understood. This study aimed to investigate the distribution patterns of amyloid pathology and neurodegeneration in a depressive population without dementia.. Most of the control subjects (81.8%) were biomarker-negative, in contrast to the MCI MDD patients (37.5%). A relatively high proportion of the MCI MDD patients (12.5%) exhibited both amyloid positivity and hippocampal atrophy as compared to the control subjects (4.5%) and non-MCI patients (5.1%). However, a considerable proportion of the MCI MDD patients (29.2%) were categorized into the group with hippocampal atrophy alone, and negative amyloid deposition, as compared to the control subjects (0%) and non-MCI patients (5.1%).. This study highlights the expected heterogeneity of the processes of neurodegeneration in MDD patients. The diverse neurodegenerative processes may have important etiologic and therapeutic implications regarding neurodegenerative pathophysiology in late-life depression.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Aniline Compounds; Atrophy; Biomarkers; Brain Diseases; Cognitive Dysfunction; Depressive Disorder, Major; Ethylene Glycols; Female; Hippocampus; Humans; Male; Middle Aged; Neurodegenerative Diseases; Positron-Emission Tomography; Radiopharmaceuticals; Temporal Lobe

Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Topics: Aged; Alzheimer Disease; Amyloid; Amyloidosis; Aniline Compounds; Atrophy; Cognition; Cognitive Dysfunction; Depression; Ethylene Glycols; Female; Follow-Up Studies; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Organ Size; Positron-Emission Tomography; Radiopharmaceuticals; Selective Serotonin Reuptake Inhibitors; Superior Sagittal Sinus; Treatment Outcome

Previous publications indicate that Alzheimer's Disease (AD) related cortical atrophy may develop in asymmetric patterns, with accentuation of the left hemisphere. Since fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide a sensitive and specific marker of neurodegenerative disease progression, we sought to investigate the longitudinal pattern of rCMRgl in amyloid-positive persons with mild cognitive impairment (MCI) and dementia, hypothesizing asymmetric declines of cerebral glucose metabolism.. Using florbetapir PET and cerebrospinal fluid (CSF) measures to define amyloid-β (Aβ) positivity, 40 Aβ negative (Aβ-) cognitively unimpaired controls (CU; 76 ± 5y), 76 Aβ positive (Aβ+) persons with MCI (76 ± 7y) and 51 Aβ + persons with probable AD dementia (75 ± 7y) from the AD Neuroimaging Initiative (ADNI) were included in this study with baseline and 2-year follow-up FDG PET scans. The degree of lateralization of longitudinal rCMRgl declines in subjects with Aβ + MCI and AD in comparison with Aβ- CU were statistically quantified via bootstrapped lateralization indices [(LI); range - 1 (right) to 1 (left)].. Compared to Aβ- CU, Aβ + MCI patients showed marked left hemispheric lateralization (LI: 0.78). In contrast, modest right hemispheric lateralization (LI: -0.33) of rCMRgl declines was found in Aβ + persons with probable AD dementia. Additional comparisons of Aβ + groups (i.e. MCI and probable AD dementia) consequently indicated right hemispheric lateralization (LI: -0.79) of stronger rCMRgl declines in dementia stages of AD. For all comparisons, voxel-based analyses confirmed significant (pFWE<0.05) declines of rCMRgl within AD-typical brain regions. Analyses of cognitive data yielded predominant decline of memory functions in both MCI and dementia stages of AD.. These data indicate that in early stages, AD may be characterized by a more lateralized pattern of left hemispheric rCMRgl declines. However, metabolic differences between hemispheres appear to diminish with further progression of the disease.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Follow-Up Studies; Glucose; Humans; Longitudinal Studies; Male; Positron-Emission Tomography

The objective of this study was to examine the distribution and severity of tau-PET binding in cognitively normal adults with preclinical Alzheimer's disease as determined by positive beta-amyloid PET.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Middle Aged; Parietal Lobe; Positron-Emission Tomography; Prodromal Symptoms; tau Proteins; Temporal Lobe

The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer's disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown.. We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis.. The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in serial brain 18F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients.. Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from -2.62% to -16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively.. The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Aspartic Acid; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Family Health; Female; Follow-Up Studies; Histidine; Humans; Male; Middle Aged; Positron-Emission Tomography; Taiwan

This study examined a longitudinal trajectory of β-amyloid (Aβ) accumulation at the predementia stage of Alzheimer's disease in the context of clinical trials.. Analyzed were baseline (BL) and 2 years' follow-up 18F-florbetapir positron emission tomography data of 246 Aβ-positive subjects with normal cognition and mild cognitive impairment. We studied the relationship between annual accumulation rates of 18F-florbetapir and BL standard uptake value ratios in whole gray matter (SUVR. Subjects with BL SUVR. There are global and regional variations in annual accumulation rate at the predementia stage of Alzheimer's disease. When taken into account, the sample size in anti-amyloid trials can be substantially reduced. Critically, treated and placebo groups should be matched for BL SUVR

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Clinical Trials as Topic; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Follow-Up Studies; Humans; Male; Models, Theoretical; Neuroprotective Agents; Positron-Emission Tomography; Prodromal Symptoms; Radiopharmaceuticals; Sample Size; Superior Sagittal Sinus

Peripheral biomarkers that identify individuals at risk of developing Alzheimer's disease (AD) or predicting high amyloid beta (Aβ) brain burden would be highly valuable. To facilitate clinical trials of disease-modifying therapies, plasma concentrations of Aβ species are good candidates for peripheral AD biomarkers, but studies to date have generated conflicting results.. The Fundació ACE Healthy Brain Initiative (FACEHBI) study uses a convenience sample of 200 individuals diagnosed with subjective cognitive decline (SCD) at the Fundació ACE (Barcelona, Spain) who underwent amyloid florbetaben(. Brain and plasma Aβ levels are partially correlated in individuals diagnosed with SCD. Aβ plasma measurements, particularly the TP42/40 ratio, could generate a new recruitment strategy independent of the APOE genotype that would improve identification of SCD subjects with brain amyloidosis and reduce the rate of screening failures in preclinical AD studies. Independent replication of these findings is warranted.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography

There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)-negative (Aβ-) suspected non-Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts.. To examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts.. A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ- and neurodegeneration-positive [Aβ-N+]) subtypes and their Aβ+N+ counterparts.. Participants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]).. The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were Aβ-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were Aβ+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their Aβ+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: Aβ-N+, 1.25 [0.11] vs Aβ+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ε4 (Aβ-N+, 18.7% vs Aβ+N+, 70.6%) and disproportionately high APOE ε2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (Aβ-N+, 6.5% vs Aβ+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their Aβ+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between Aβ-N+ and Aβ+N+ cases.. In MCI with SNAP, low APOE ε4 and high APOE ε2 carrier prevalence may account for differences in neurodegeneration patterns between Aβ-N+ and Aβ+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Biomarkers; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Neurodegenerative Diseases; Parietal Lobe; Positron-Emission Tomography; Temporal Lobe

Amyloid-positron emission tomography (PET) imaging of the brain detects elevated amyloid-beta (amyloid-β) neuritic plaques in vivo, which can be helpful in appropriately selected cases of mild cognitive impairment (MCI) and dementia, when Alzheimer's disease remains a possible etiology, after a comprehensive clinical evaluation. We reviewed cases of cognitively impaired patients who underwent amyloid-PET imaging because of diagnostic uncertainty. Pre- and post-PET elements of diagnosis and management were first compared, to assess impact of scan results on clinical decision-making, and then an analysis of those decisions was undertaken in appropriate clinical situations, to delineate the added value and limitations of amyloid-PET imaging. The potential benefits and limitations of this diagnostic tool are important to understand in an era when the utility of such scans in clinical practice is evolving.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Dementia; Ethylene Glycols; Female; Humans; Male; Middle Aged; Positron-Emission Tomography

Depressive symptoms are prevalent in patients with mild cognitive impairment (MCI) and are considered to be a risk factor for progression to dementia.. The purpose of this study was to evaluate whether depressive symptoms in MCI promote disease progression in a manner related to amyloid status, and to determine the relationship between depressive symptoms and longitudinal cerebral structural changes.. Baseline data for 336 patients with MCI (75 with depression and 261 without) from the Alzheimer's Disease Neuroimaging Initiative study were analyzed. All participants underwent comprehensive cognitive testing, volumetric magnetic resonance imaging (MRI), and [18F]AV45 positron emission tomography amyloid imaging. Depressive symptoms were measured using the Neuropsychiatric Inventory Questionnaire. A voxel-based morphometric analysis using volumetric brain MRI data was used to compare longitudinal structural changes related to depressive symptoms.. The conversion rate to dementia was different between patients with and without depression in amyloid-positive MCI (40.8% versus 19.7%, respectively; p = 0.006). Patients who were amyloid-positive at baseline also exhibited a greater degree of 2-year cognitive decline. Depression in amyloid-positive MCI was associated with longitudinal cortical atrophy in the left cingulate gyrus.. Our study indicates that the presence of depressive symptoms in patients with amyloid-positive MCI is associated with higher progression to dementia and longitudinal cortical atrophy.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Dementia; Depression; Disease Progression; Ethylene Glycols; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Surveys and Questionnaires

Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults.. To examine whether a continuous, dose-response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults.. This cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([18F]-florbetapir) at baseline and cognitive assessments at baseline and a 4-year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline.. Linear mixed models assessed the effect of increasing baseline amyloid over time (SUVR × time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein ε4, and the random effect of intercepts were included as covariates.. The mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR × time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle-aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein ε4 homozygotes.. These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization.

Topics: Adult; Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Humans; Longitudinal Studies; Male; Middle Aged; Positron-Emission Tomography

See Markus (doi:10.1093/awx161) for a scientific commentary on this article.Evidence for vascular contributions to Alzheimer's disease has been increasingly identified, with increased blood pressure and decreased cerebral blood flow both linked to in vivo biomarkers and clinical progression of Alzheimer's disease. We therefore hypothesized that an elevated ratio of blood pressure to cerebral blood flow, indicative of cerebrovascular resistance, would exhibit earlier and more widespread associations with Alzheimer's disease than cerebral blood flow alone. Further, we predicted that increased cerebrovascular resistance and amyloid retention would synergistically influence cognitive performance trajectories, independent of neuronal metabolism. Lastly, we anticipated associations between cerebrovascular resistance and later brain atrophy, prior to amyloid accumulation. To evaluate these hypotheses, we investigated associations between cerebrovascular resistance and amyloid retention, cognitive decline, and brain atrophy, controlling for neuronal metabolism. North American older adults (n = 232) underwent arterial spin labelling magnetic resonance imaging to measure regional cerebral blood flow in brain regions susceptible to ageing and Alzheimer's disease. An estimated cerebrovascular resistance index was then calculated as the ratio of mean arterial pressure to regional cerebral blood flow. Positron emission tomography with 18F-florbetapir and fludeoxyglucose was used to quantify amyloid retention and neuronal metabolism, respectively. Cognitive performance was evaluated via annual assessments of global cognition, memory, and executive function. Results indicated diminished inferior parietal and temporal cerebral blood flow for patients with Alzheimer's disease (n = 33) relative to both non-demented groups, but no cerebral blood flow differences between non-demented amyloid-positive (n = 87) and amyloid-negative (n = 112) cases. In contrast, the cerebrovascular resistance index was significantly elevated in amyloid-positive versus amyloid-negative cases, with additional elevation in patients with Alzheimer's disease. Furthermore, cerebrovascular resistance index group differences were of greater statistical effect size and encompassed a greater number of brain regions than those for cerebral blood flow alone. Cognitive decline over 2-year follow-up was accelerated by elevated baseline cerebrovascular resistance index, particularly for amyloid-positive indivi

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Atrophy; Blood Pressure; Brain; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Neurons; Neuropsychological Tests; Positron-Emission Tomography; Spin Labels; Vascular Resistance; White Matter

Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD).. In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD.. Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared.. Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group.. This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Aniline Compounds; Awareness; Brain; Brain Mapping; Cognitive Dysfunction; Ethylene Glycols; Female; Functional Laterality; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Psychiatric Status Rating Scales; Surveys and Questionnaires

To explore early autonomic cardiac changes in pre-clinical Alzheimer's disease (AD), we have evaluated electrocardiologic measures of vagal tone for 63 adults (ages 55-75) at rest, during cognitive testing, and then again at rest. All subjects had multiple risk factors for AD, and all completed amyloid PET scans (18F-Florbetapir) to determine amyloid positivity (Aβ+). No change in electrocardiographic measures were observed for Aβ+ participants under each testing condition, whereas Aβ-subjects showed an expected increase in vagal tone during the cognitive stress condition. These findings suggest an early relationship between cortical Aβ accumulation, a precursor to AD development, and autonomic cardiac function.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Disease Progression; Electroencephalography; Ethylene Glycols; Female; Heart Diseases; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Risk Factors

We previously found that subjects with amnestic mild cognitive impairment exhibit a pro-inflammatory immune profile in the cerebrospinal fluid similar to multiple sclerosis, a central nervous system autoimmune disease. We therefore hypothesized that early neuroinflammation would reflect increases in brain amyloid burden during amnestic mild cognitive impairment.. Cerebrospinal fluid and blood samples were collected from 24 participants with amnestic mild cognitive impairment (12 men, 12 women; 66 ± 6 years; 0.5 Clinical Dementia Rating) enrolled in the AETMCI study. Analyses of cerebrospinal fluid and blood included immune profiling by multi-parameter flow cytometry, genotyping for apolipoprotein (APO)ε, and quantification of cytokine and immunoglobin levels. Amyloid (A)β deposition was determined by. Soluble Aβ. Elevations in brain Aβ burden associate with a shift from T cells to memory B cells in the cerebrospinal fluid of subjects with amnestic mild cognitive impairment in this exploratory cohort. These data suggest the presence of cellular adaptive immune responses during Aβ accumulation, but further study needs to determine whether lymphocyte populations contribute to, or result from, Aβ dysregulation during memory decline on a larger cohort collected at multiple centers.. AETMCI NCT01146717.

Topics: Adaptive Immunity; Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain; Cognitive Dysfunction; Cytokines; Ethylene Glycols; Female; Flow Cytometry; Humans; Lymphocytes; Male; Middle Aged; Positron-Emission Tomography

Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1-42/Aβ1-40 ratio is used as compared to CSF Aβ1-42 levels alone.. In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting.. Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1-42, Aβ1-40, T-tau, P-tau181).. We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1-42/Aβ1-40 was applied compared to Aβ1-42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matterConclusions:The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1-42/Aβ1-40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Imaging, Three-Dimensional; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; tau Proteins

To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.. Multiregional analysis of florbetapir (. According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia.. The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cerebral Cortex; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Ethylene Glycols; Female; Humans; Male; Neostriatum; Peptide Fragments; Positron-Emission Tomography

To improve our understanding of early β-amyloid (Aβ) accumulation processes using florbetapir-PET scan in 20- to 60-year-old individuals.. Seventy-six cognitively normal individuals aged 20 to 60 years, 57 cognitively normal older individuals (61-84 years old), and 70 patients with mild cognitive impairment or probable Alzheimer disease (AD) underwent a florbetapir-PET scan. Images were spatially normalized and scaled using the whole cerebellum. The relationship with age was assessed on the mean neocortical standardized uptake value ratio (SUVR) and voxelwise in the younger group to assess early Aβ accumulation processes. To compare the topography of early-age-related vs AD-related changes, Aβ increase in patients vs cognitively normal older adults was also assessed.. A linear increase of Aβ deposition from 20 to 60 years old was found on the mean neocortical SUVR, and more specifically on the temporal neocortex. By contrast, increase in patients predominated in frontal and medial parietal areas. The temporal increase in healthy participants was still significant when including only the 20- to 50-year-old individuals and controlling for several possible methodologic confounds.. Florbetapir binding increases linearly from 20 to 60 years old in the temporal lobe. Pending replication, including with other PET tracers, this study suggests that the well-described medial frontal and parietal accumulation in late adulthood and AD might superimpose to a physiologic accumulation of Aβ, starting from young adulthood, in temporal lobes.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorine Radioisotopes; Healthy Volunteers; Humans; Male; Middle Aged; Neocortex; Positron-Emission Tomography; Temporal Lobe; Young Adult

Semi-quantitative image analysis methods in Alzheimer's Disease (AD) require normalization of positron emission tomography (PET) images. However, recent studies have found variabilities associated with reference region selection of amyloid PET images. Haralick features (HFs) generated from the Gray Level Co-occurrence Matrix (GLCM) quantify spatial characteristics of amyloid PET radiotracer uptake without the need for intensity normalization. The objective of this study is to calculate several HFs in different diagnostic groups and determine the group differences.. All image and metadata were acquired through the Alzheimer's Disease Neuroimaging Initiative database. Subjects were grouped in three ways: by clinical diagnosis, by APOE e4 allele, and by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score. Several GLCM matrices were calculated for different direction and distances (1-4 mm) from multiple regions on PET images. The HFs, contrast, correlation, dissimilarity, energy, entropy, and homogeneity, were calculated from these GLCMs. Wilcoxon tests and Student. Preliminary results from statistical testing indicate that HFs were capable of distinguishing groups at baseline and follow-up (false discovery rate corrected. These results suggest that this technique could improve subject stratification in AD drug trials and help to evaluate the disease progression and treatment effects longitudinally without the disadvantages associated with intensity normalization.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Humans; Male; Pattern Recognition, Automated; Positron-Emission Tomography; ROC Curve; Severity of Illness Index

Recent literature proposes that amyloid β (Aβ) and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia.. We stratified 314 mild cognitive impairment individuals using [. We found that the synergism between [. Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between Aβ and p-tau proteins.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Follow-Up Studies; Humans; Logistic Models; Male; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins

Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Brain Mapping; Cognitive Dysfunction; Ethylene Glycols; Famous Persons; Female; Humans; Judgment; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Personality; Positron-Emission Tomography; Radiopharmaceuticals; Recognition, Psychology; Self Concept

The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as 18F-T807) have made it possible to investigate the sequence of development of tau and amyloid-β in relationship to age, and to the development of cognitive impairment due to Alzheimer's disease. In this study, flortaucipir tau and florbetapir amyloid positron emission tomography were obtained for 217 subjects including 16 young and 58 older cognitively normal subjects, 95 subjects with mild cognitive impairment (Mini-Mental State Examination 24-30) and 48 subjects with clinically-defined possible or probable Alzheimer's disease (Mini-Mental State Examination >10). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Aβ+) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer's disease > mild cognitive impairment > older cognitively normal) and was significantly elevated for Aβ+ mild cognitive impairment and Alzheimer's disease subjects relative to the respective Aβ- subjects. In contrast, florbetapir Aβ- older cognitively normal subjects showed an increase in flortaucipir standard uptake value ratios in mesial temporal lobe regions (amygdala, hippocampus/choroid plexus region of interest) compared to younger cognitively normal subjects, but no increased standard uptake value ratios in neocortical regions. Analysis of covariance with planned contrasts showed no differences in regional or composite posterior neocortical flortaucipir standard uptake value ratio as a function of diagnostic group among Aβ- older cognitively normal or clinically diagnosed Alzheimer's disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Aβ+ subjects was reminiscent of the cross-sectional distribution of tau reported in post-mortem pathology studies, in that the most commonly affected regions were the inferior and lateral temporal lobes, the same regions where the first signs of increased retention appeared in Aβ+ cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Aβ+ subjects. Although high neocortical flortaucipir retention was consistently associated with an Aβ+ florbetapir positron emission tomography scan, not all Aβ+ subjects had elevated flortaucipir st

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Young Adult

Amyloid imaging is a tool that has recently become available to dementia specialists evaluating patients with possible Alzheimer's disease. Studies have assessed the impact of amyloid imaging on diagnostic and treatment decisions, but patient and family perspectives have received less attention.. To examine how amyloid imaging affects the diagnostic experience of patients and families, we interviewed members of 26 patient-caregiver dyads with whom a neurologist discussed the option of amyloid positron emission tomography.. Most participants who chose to undergo amyloid imaging would choose to do so again. Regardless of the scan outcome, patients and caregivers commonly expressed relief on learning the scan results. Some participants expressed expectations that were beyond scan capabilities.. Amyloid imaging may provide information that patients and their families find useful. Clinicians must set correct expectations and ensure that families understand the limitations of amyloid imaging.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Caregivers; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Interviews as Topic; Male; Memory Disorders; Mental Status and Dementia Tests; Middle Aged; Patient Satisfaction; Positron-Emission Tomography; Radiopharmaceuticals

Depressive symptoms are frequently seen in patients with dementia and mild cognitive impairment (MCI). Evidence suggests that there may be a link between current depressive symptoms and Alzheimer disease (AD)-associated pathological changes, such as an increase in cortical amyloid-β (Aβ). However, limited in vivo studies have explored the relationship between current depressive symptoms and cortical Aβ in patients with MCI and AD. Our study, using a large sample of 455 patients with MCI and 153 patients with AD from the Alzheimer's disease Neuroimaging Initiatives, investigated whether current depressive symptoms are related to cortical Aβ deposition. Depressive symptoms were assessed using the Geriatric Depression Scale and Neuropsychiatric Inventory-depression/dysphoria. Cortical Aβ was quantified using positron emission tomography with the Aβ probe(18)F-florbetapir (AV-45).(18)F-florbetapir standardized uptake value ratio (AV-45 SUVR) from the frontal, cingulate, parietal, and temporal regions was estimated. A global AV-45 SUVR, defined as the average of frontal, cingulate, precuneus, and parietal cortex, was also used. We observed that current depressive symptoms were not related to cortical Aβ, after controlling for potential confounds, including history of major depression. We also observed that there was no difference in cortical Aβ between matched participants with high and low depressive symptoms, as well as no difference between matched participants with the presence and absence of depressive symptoms. The association between depression and cortical Aβ deposition does not exist, but the relationship is highly influenced by stressful events in the past, such as previous depressive episodes, and complex interactions of different pathways underlying both depression and dementia.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Depression; Depressive Disorder, Major; Ethylene Glycols; Female; Humans; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography

To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care.. We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates.. HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status.. Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum.

Topics: Aged; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Biomarkers; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neuroimaging; Organ Size; Positron-Emission Tomography

The objective of this study was to evaluate the amyloid burden, as assessed by (18)F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients.. The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and (18)F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined.. Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative (18)F-florbetapir uptake in all cortical regions, and a significant difference in relative (18)F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects (P < 0.05) and HCs (P < 0.01). Voxel-wise analyses revealed significantly increased relative (18)F-florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas (P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score (r = -0.342, P = 0.010) and memory function (r = -0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity (β = -3.607, t = -2.874, P = 0.006).. We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the hypothesis that a higher amyloid burden is associated with a poorer memory performance. We also observed a high prevalence of MCI among elderly depressed patients, and depressed patients with MCI exhibited heterogeneously elevated (18)F-florbetapir retention as compared with depressed patients without MCI. The higher amyloid burden in the aMCI patients suggests that these patients may also be more likely to develop Alzheimer's disease than other patients diagnosed with major depression.

Topics: Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognitive Dysfunction; Depressive Disorder, Major; Ethylene Glycols; Female; Humans; Male; Middle Aged; Positron-Emission Tomography

Published appropriate use criteria (AUC) describe patients for whom amyloid positron emission tomography (PET) might be most useful. This study compared the impact of amyloid PET on diagnosis and management in subjects likely to either meet or not meet AUC.. Physicians provided a provisional diagnosis and management plan for patients presenting with cognitive decline before and after amyloid PET imaging with florbetapir F 18. Participants were classified as AUC-like or not, based on the prescan diagnosis and demographic features.. In all, 125 of 229 participants (55%) were classified as AUC-like. Sixty-two percent of the AUC-like subjects had a change in diagnosis after scanning compared with 45% of the non-AUC subjects (p = 0.011). Both groups demonstrated high rates of change in their management plans after scanning (88.0% for AUC-like cases, 85.6% for non-AUC cases).. The impact of amyloid imaging on diagnosis and planned management was maintained and, if anything, amplified in AUC-like patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals

Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation of amyloid-β (Aβ) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest (18)F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions.. We calculated the correlation between (18)F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Aβ1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique-the weighted two-point correlation function (wS2)-to capture potentially more subtle changes in Aβ-PET data.. Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Aβ1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Aβ1-42 levels across all time points and reference regions, including the cerebellar gray matter.. The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical (18)F-florbetapir uptake in longitudinal studies.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Longitudinal Studies; Male; Peptide Fragments; Positron-Emission Tomography; Reference Standards; Reproducibility of Results

This study aimed to investigate the independent and interactive influences of apolipoprotein E (APOE) ε4 and beta-amyloid (Aβ) on multiple cognitive domains in a large group of cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were included if clinical and cognitive assessments, amyloid imaging, and APOE genotype were all available from the Alzheimer's Disease Neuroimaging Initiative database (CN = 324, MCI = 502, AD = 182). Individuals with one or two copies of ε4 were designated as APOE ε4 carriers (ε4+); individuals with no ε4 were designated as APOE ε4 non-carriers (ε4-). Based on mean florbetapir standard uptake value ratios, participants were classified as Aβ burden-positive (Aβ+) or Aβ burden-negative (Aβ-). In MCI, APOE ε4 effects were predominantly observed on frontal executive function, with ε4+ participants exhibiting poorer performances; Aβ positivity had no influence on this effect. Aβ effects were observed on global cognition, memory, and visuospatial ability, with Aβ+ participants exhibiting poorer performances. Measures of frontal executive function were not influenced by Aβ. Interactive effects of APOE ε4+ and Aβ were observed on global cognition and verbal recognition memory. Aβ, not APOE ε4+, influenced clinical severity and functional status. The influences of APOE ε4+ and Aβ on cognitive function were minimal in CN and AD. In conclusion, we provide further evidence of both independent and interactive influences of APOE ε4+ and Aβ on cognitive function in MCI, with APOE ε4+ and Aβ showing dissociable effects on executive and non-executive functions, respectively.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Cognition; Cognitive Dysfunction; Databases, Factual; Demography; Ethylene Glycols; Female; Genotype; Humans; Male; Positron-Emission Tomography; Radiography

For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer's disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: Volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Predictive Value of Tests; Psychiatric Status Rating Scales; Sensitivity and Specificity

We investigated dual-phase (18)F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs).. A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase (18)F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion (18)F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid (18)F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and (18)F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses.. HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P < 0.0001). (18)F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and (18)F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when (18)F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced MCI.. Our results indicate that brain perfusion deficits and beta-amyloid deposition in AD follow different trajectories that can be successfully traced using dual-phase (18)F-AV-45 PET imaging.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biological Transport; Case-Control Studies; Cerebrovascular Circulation; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Positron-Emission Tomography

Magnet resonance image (MRI)-based segmentations are widely used for clinical brain research, especially in conjunction with positron-emission-tomography (PET). Although artifacts due to segmentation errors arise commonly, the impact of these artifacts on PET quantitation has not yet been investigated systematically. Therefore, the aim of this study was to assess the effect of segmentation errors on [(18)F]-AV45 and [(18)F]-FDG PET quantitation, with and without correction for partial volume effects (PVE).. 119 subjects with both [(18)F]-AV45, and [(18)F]-FDG PET as well as T1-weighted MRI at baseline and at two-year follow-up were selected from the ADNI cohort, and their MRI brain images were segmented using PMOD 3.5. MRIs with segmentation artifacts were masked with the corresponding [(18)F]-FDG PET standard-uptake-value (SUV) images to elucidate and quantify the impact of artifacts on PET analyses for six defined volumes-of-interest (VOI). Artifact volumes were calculated for each VOI, together with error-[%] and root-mean-square-errors (RMSE) in uncorrected and PVE corrected SUV results for the two PET tracers. We also assessed the bias in longitudinal PET data.. Artifacts occurred most frequently in the parietal cortex VOI. For [(18)F]-AV45 and [(18)F]-FDG PET, the percentage-errors were dependent on artifact volumes. PVEC SUVs were consequently more distorted than were their uncorrected counterparts. In static and longitudinal assessment, a small subgroup of subjects with large artifacts (≥1500 voxels; ≙5.06 cm³) accounted for much of the PET quantitation bias.. Large segmentation artifacts need to be detected and resolved as they considerably bias PET quantitation, especially when PVEC is applied to PET data.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Artifacts; Brain; Brain Mapping; Cognitive Dysfunction; Cohort Studies; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Positron-Emission Tomography

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

Topics: Aged; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Apolipoprotein E4; Cerebral Cortex; Cluster Analysis; Cognitive Dysfunction; Ethylene Glycols; False Positive Reactions; Female; Follow-Up Studies; Genotype; Humans; Longitudinal Studies; Male; Positron-Emission Tomography; Radiopharmaceuticals

To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders.. Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures.. LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain.. Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Brain; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Independent Living; Male; Middle Aged; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Prodromal Symptoms; Stress, Psychological

To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.. In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.. Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.. A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Biomarkers; Brain; Cognition; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mental Status Schedule; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; Regression Analysis

It is inconclusive as to whether benzodiazepines (BZDs) are related to cognitive deterioration in the elderly populations. Animal studies suggest that γ-aminobutyric acid A receptor agonists, such as BZDs, may prevent Aβ-neurotoxicity and reduce β-amyloid (Aβ). However, no studies have investigated the effects of BZD use on Aβ in humans.. This cross-sectional, prospective study using Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada on nondemented elderly adults between 55 and 90 years of age assessed cortical Aβ levels by positron emission tomography radiotracer F. Previous BZD users (N = 15) had lower cortical Aβ levels in frontal (F(1, 26) = 8.82, p = 0.006), cingulate (F(1, 26) = 8.58, p = 0.007), parietal (F(1, 26) = 7.31, p = 0.012), and temporal (F(1, 26) = 7.67, p = 0.010) regions compared with matched BZD nonusers (N = 15), after controlling for history of psychiatric disorders and antidepressant use. Also, no differences were found in global cognitive function and changes in cortical Aβ over 2 years between continuous BZD users (N = 15) andthe matched nonuser group (N = 15).. Previous BZD use was associated with lower cortical Aβ levels in nondemented elderly control subjects. Future studies with larger samples are required to replicate our findings.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Benzodiazepines; Case-Control Studies; Cerebral Cortex; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Fluorine Radioisotopes; Follow-Up Studies; Frontal Lobe; Gyrus Cinguli; Humans; Male; Neuropsychological Tests; Parietal Lobe; Pilot Projects; Positron-Emission Tomography; Prospective Studies; Regression Analysis; Risk Factors; Temporal Lobe

In recent years, increasing attention has been given to the identification of the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Brain neuroimaging techniques have been widely used to support the classification or prediction of MCI. The present study combined magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose PET (FDG-PET), and 18F-florbetapir PET (florbetapir-PET) to discriminate MCI converters (MCI-c, individuals with MCI who convert to AD) from MCI non-converters (MCI-nc, individuals with MCI who have not converted to AD in the follow-up period) based on the partial least squares (PLS) method. Two types of PLS models (informed PLS and agnostic PLS) were built based on 64 MCI-c and 65 MCI-nc from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The results showed that the three-modality informed PLS model achieved better classification accuracy of 81.40%, sensitivity of 79.69%, and specificity of 83.08% compared with the single-modality model, and the three-modality agnostic PLS model also achieved better classification compared with the two-modality model. Moreover, combining the three modalities with clinical test score (ADAS-cog), the agnostic PLS model (independent data: florbetapir-PET; dependent data: FDG-PET and MRI) achieved optimal accuracy of 86.05%, sensitivity of 81.25%, and specificity of 90.77%. In addition, the comparison of PLS, support vector machine (SVM), and random forest (RF) showed greater diagnostic power of PLS. These results suggested that our multimodal PLS model has the potential to discriminate MCI-c from the MCI-nc and may therefore be helpful in the early diagnosis of AD.

Topics: Aged; Aniline Compounds; Brain; Cognitive Dysfunction; Dermatitis, Allergic Contact; Discriminant Analysis; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Image Interpretation, Computer-Assisted; Least-Squares Analysis; Linear Models; Magnetic Resonance Imaging; Male; Methacrylates; Multimodal Imaging; Multivariate Analysis; Positron-Emission Tomography; Radiopharmaceuticals; ROC Curve; Support Vector Machine

Cerebral amyloidosis is a key abnormality in Alzheimer disease (AD) and can be detected in vivo with positron emission tomography (PET) ligands. Although amyloid PET has clearly demonstrated analytical validity, its clinical utility is debated.. To evaluate the incremental diagnostic value of amyloid PET with florbetapir F 18 in addition to the routine clinical diagnostic assessment of patients evaluated for cognitive impairment.. The Incremental Diagnostic Value of Amyloid PET With [18F]-Florbetapir (INDIA-FBP) Study is a multicenter study involving 18 AD evaluation units from eastern Lombardy, Northern Italy, 228 consecutive adults with cognitive impairment were evaluated for AD and other causes of cognitive decline, with a prescan diagnostic confidence of AD between 15% and 85%. Participants underwent routine clinical and instrumental diagnostic assessment. A prescan diagnosis was made, diagnostic confidence was estimated, and drug treatment was provided. At the time of this workup, an amyloid PET/computed tomographic scan was performed, and the result was communicated to physicians after workup completion. Physicians were asked to review the diagnosis, diagnostic confidence, and treatment after the scan. The study was conducted from August 5, 2013, to December 31, 2014.. Primary outcomes were prescan to postscan changes of diagnosis, diagnostic confidence, and treatment.. Of the 228 participants, 107 (46%) were male; mean (SD) age was 70.5 (7) years. Diagnostic change occurred in 46 patients (79%) having both a previous diagnosis of AD and an amyloid-negative scan (P < .001) and in 16 (53%) of those with non-AD diagnoses and an amyloid-positive scan (P < .001). Diagnostic confidence in AD diagnosis increased by 15.2% in amyloid-positive (P < .001; effect size Cohen d = 1.04) and decreased by 29.9% in amyloid-negative (P < .001; d = -1.19) scans. Acetylcholinesterase inhibitors and memantine hydrochloride were introduced in 61 (65.6%) patients with positive scan results who had not previously received those drugs, and the use of the drugs was discontinued in 6 (33.3%) patients with negative scan results who were receiving those drugs (P < .001).. Amyloid PET in addition to routine assessment in patients with cognitive impairment has a significant effect on diagnosis, diagnostic confidence, and drug treatment. The effect on health outcomes, such as morbidity and mortality, remains to be assessed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Positron-Emission Tomography; Predictive Value of Tests

We examined florbetapir positron emission tomography (PET) amyloid scans across stages of preclinical Alzheimer's disease (AD) in cortical, allocortical, and subcortical regions. Stages were characterized using empirically defined methods.. A total of 312 cognitively normal Alzheimer's Disease Neuroimaging Initiative participants completed a neuropsychological assessment and florbetapir PET scan. Participants were classified into stages of preclinical AD using (1) a novel approach based on the number of abnormal biomarkers/cognitive markers each individual possessed, and (2) National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria. Preclinical AD groups were compared to one another and to a mild cognitive impairment (MCI) sample on florbetapir standardized uptake value ratios (SUVRs) in cortical and allocortical/subcortical regions of interest (ROIs).. Amyloid deposition increased across stages of preclinical AD in all cortical ROIs, with SUVRs in the later stages reaching levels seen in MCI. Several subcortical areas showed a pattern of results similar to the cortical regions; however, SUVRs in the hippocampus, pallidum, and thalamus largely did not differ across stages of preclinical AD.. Substantial amyloid accumulation in cortical areas has already occurred before one meets criteria for a clinical diagnosis. Potential explanations for the unexpected pattern of results in some allocortical/subcortical ROIs include lack of correspondence between (1) cerebrospinal fluid and florbetapir PET measures of amyloid, or between (2) subcortical florbetapir PET SUVRs and underlying neuropathology. Findings support the utility of our novel method for staging preclinical AD. By combining imaging biomarkers with detailed cognitive assessment to better characterize preclinical AD, we can advance our understanding of who is at risk for future progression. (JINS, 2016, 22, 978-990).

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Prodromal Symptoms

We compared amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) in subjects clinically diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHC) in order to test how these imaging biomarkers represent cognitive decline in AD.. Fifteen OHC, 19 patients with MCI, and 19 patients with AD were examined by [(18)F]florbetapir PET to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI and the voxel-based specific regional analysis system for AD to calculate z-score as the degree of entorhinal cortex atrophy, and by mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive component--Japanese version (ADAS-Jcog) for cognitive functions.. Both cutoff values for measuring AD-like levels of amyloid (1.099 for SUVR) and entorhinal cortex atrophy (1.60 for z-score) were well differentially diagnosed and clinically defined AD from OHC (84.2% for SUVR and 86.7% for z-score). Subgroup analysis based on beta-amyloid positivity revealed that z-score significantly correlated with MMSE (r = -0.626, p < 0.01) and ADAS-Jcog (r = 0.691, p < 0.01) only among subjects with beta-amyloid.. This is the first study to compare [(18)F]florbetapir PET and MRI voxel-based analysis of entorhinal cortex atrophy for AD. Both [(18)F]florbetapir PET and MRI detected changes in AD compared with OHC. Considering that entorhinal cortex atrophy correlated well with cognitive decline only among subjects with beta-amyloid, [18F]florbetapir PET makes it possible to detect AD pathology in the early stage, whereas MRI morphometry for subjects with beta-amyloid provides a good biomarker to assess the severity of AD in the later stage.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Biomarkers; Brief Psychiatric Rating Scale; Case-Control Studies; Cognitive Dysfunction; Diagnosis, Differential; Entorhinal Cortex; Ethylene Glycols; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography

We examined patients with mild cognitive impairment (MCI) with a history of geriatric depression (GD) and healthy controls (HC) to evaluate the effect of beta-amyloid (Aβ) pathology on the pathology of GD by using [(18)F]florbetapir PET.. Thirty-three elderly patients (76.7 ± 4.2 years) and 22 healthy controls (HC; 72.0 ± 4.5 years, average ± SD) were examined by [(18)F]florbetapir positron emission tomography (PET) to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI to determine the degree of atrophy, by Mini-Mental State Examination for cognitive functions, and by Geriatric Depression Scale for the severity of depression, and by Clinical Dementia Rating for activity of daily living (ADL). The cut-off value of 1.08 for SUVR was defined as Aβ-positive.. Of the patients and HC, 39.4% and 27.3%, respectively, were beta-amyloid-positive. The onset age of GD was significantly correlated with SUVR (r = 0.44, p < 0.01). Compared to patients without Aβ (GD-Aβ), patients with Aβ (GD + Aβ) did not differ in terms of age, cognitive function, severity of depression and ADL, and brain atrophy. GD + Aβ had significantly older average ± SD age at onset of GD (73.6 ± 7.1 versus 58.7 ± 17.8, p < 0.01) and significantly shorter average ± SD time between onset of GD and PET scan day (3.1 ± 5.2 years versus 18.1 ± 18.6 years, p < 0.001) than GD-Aβ.. Our results showed that the rate of Aβ positivity was higher in late-onset GD and that onset-age was associated with SUVR, suggesting that the later the onset of GD, the more Aβ pathology affected its onset.

Topics: Age of Onset; Aged; Aged, 80 and over; Aniline Compounds; Case-Control Studies; Cognitive Dysfunction; Depressive Disorder; Ethylene Glycols; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Psychiatric Status Rating Scales

It is recognized that individuals with mild cognitive impairment (MCI) already demonstrate difficulty in aspects of daily functioning, which predicts disease progression. This study examined the relationship between self- versus informant-report of functional ability, and how those reports relate to objective disease measures across the disease spectrum (i.e. cognitively normal, MCI, Alzheimer's disease). A total of 1080 subjects with self- and/or informant-rated Everyday Cognition questionnaires were included. Objective measures included cognitive functioning, structural brain atrophy, cerebrospinal fluid abnormalities, and a marker of amyloid deposition using positron emission tomography with [18F]AV45 (florbetapir). Overall, informant-report was consistently more associated with objective markers of disease than self-report although self-reported functional status may still have some utility in early disease.

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Aniline Compounds; Apolipoprotein E4; Biomarkers; Brain; Cognition; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Self Report; Severity of Illness Index

Amyloid positron-emission-tomography (PET) offers an important research and diagnostic tool for investigating Alzheimer's disease (AD). The majority of amyloid PET studies have used the cerebellum as a reference region, and clinical studies have not accounted for atrophy-based partial volume effects (PVE). Longitudinal studies using cerebellum as reference tissue have revealed only small mean increases and high inter-subject variability in amyloid binding. We aimed to test the effects of different reference regions and PVE-correction (PVEC) on the discriminatory power and longitudinal performance of amyloid PET. We analyzed [(18)F]-AV45 PET and T1-weighted MRI data of 962 subjects at baseline and two-year follow-up data of 258 subjects. Cortical composite volume-of-interest (VOI) values (COMP) for tracer uptake were generated using either full brain atlas VOIs, gray matter segmented VOIs or gray matter segmented VOIs after VOI-based PVEC. Standard-uptake-value ratios (SUVR) were calculated by scaling the COMP values to uptake in cerebellum (SUVRCBL), brainstem (SUVRBST) or white matter (SUVRWM). Mean SUV, SUVR, and changes after PVEC were compared at baseline between diagnostic groups of healthy controls (HC; N=316), mild cognitive impairment (MCI; N=483) and AD (N=163). Receiver operating characteristics (ROC) were calculated for the discriminations between HC, MCI and AD, and expressed as area under the curve (AUC). Finally, the longitudinal [(18)F]-AV45-PET data were used to analyze the impact of quantitation procedures on apparent changes in amyloid load over time. Reference region SUV was most constant between diagnosis groups for the white matter. PVEC led to decreases of COMP-SUV in HC (-18%) and MCI (-10%), but increases in AD (+7%). Highest AUCs were found when using PVEC with white matter scaling for the contrast between HC/AD (0.907) or with brainstem scaling for the contrast between HC/MCI (0.658). Longitudinal increases were greatest in all diagnosis groups with application of PVEC, and inter-subject variability was lowest for the white matter reference. Thus, discriminatory power of [(18)F]-AV45-PET was improved by use of a VOI-based PVEC and white matter or brainstem rather than cerebellum reference region. Detection of longitudinal amyloid increases was optimized with PVEC and white matter reference tissue.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Positron-Emission Tomography; White Matter

The aim of this study is to compare regional cerebral metabolic rate of glucose metabolism and amyloid-β density in patients with Alzheimer disease (AD), mild cognitive impairment (MCI), and healthy elderly subjects.. Eighteen patients (including 6 AD, 5 amnestic MCI, and 7 controls) were enrolled at the University Hospital of Tours, France, and submitted to clinical, neuropsychological, and MRI examinations. PET images using F-florbetapir (266 MBq) and F-FDG (185 MBq) were acquired. SUV ratios in specific regions were defined using PMOD3.2 software.. The mean values of F-FDG SUV ratio were significantly lower in frontal, anterior cingulate, and temporal regions in MCI patients than in normal elderly (-15%, -22%, and -11%, respectively). Alzheimer disease patients showed global cerebral metabolic rate of glucose metabolism decrease, especially in parietal and precuneus regions (-15% and -13% compared with healthy control subjects). Only precuneus cortex showed an increased F-florbetapir uptake in AD. There was no other significant regional difference in the amyloid-β density.. In this study, we observed regional brain metabolic changes between MCI, AD, and controls, whereas only precuneus showed an increased amyloid-β density in AD. F-florbetapir PET analysis needs to be visual and global, whereas F-FDG analysis can be regional.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Case-Control Studies; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals

Amyloid load, as measured by florbetapir positron emission tomography (PET) standardized uptake value ratio (SUVr), has high specificity in the diagnosis of Alzheimer disease (AD). As the posterior cingulate cortex (PCC) represents densely amyloid-affected regions early in AD, we hypothesized that amyloid load within the key hubs of the default mode networks (DMN) may result in local or distant interconnected gray matter (GM) volume atrophy, thereby affecting cognitive performance. Thirty AD patients with a clinical dementia rating sum of box score ≤2 were enrolled and underwent cognitive evaluation, 3-dimensional T1-weighted imaging and florbetapir PET. Volumes of interest (VOIs) included the hippocampus, lateral temporal region, and key hubs of the DMN [anterior cingulate cortex (ACC), PCC, posterior parietal, and precuneus]. The SUVr was calculated by florbetapir standard uptake value (SUV) within the T1-weighted image segmented GM VOIs divided by the cerebellar GM SUV. Our results suggested inverse correlations between ACC (ρ = -0.444, P = 0.016) and PCC SUVr (ρ = -0.443, P = 0.016) with PCC GM volume. In stepwise regression, the orientation scores were associated with PCC SUVr (β = 2.584, P = 0.02) and posterior parietal volume (β = -0.446, P = 0.04), whereas the word recall score was related to hippocampal volume (β = -0.391, P = 0.04). After removing the patients with a hippocampal VOI below the lowest tertile and adjusting for age, an inverse correlation was found between hippocampal volume and SUVr in the ACC (partial σ = -0.639, P = 0.002), precuneus (partial σ = -0.692, P = 0.002), and lateral temporal SUVr (partial σ = -0.604, P = 0.005). Our results suggest that amyloid burden within the key DMN regions may contribute to local and distant GM atrophy, and that this may explain the cognitive scores.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorine Radioisotopes; Gray Matter; Hippocampus; Humans; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies

We evaluated the relationship between florbetapir-F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers.. Alzheimer's Disease Neuroimaging Initiative-Grand Opportunity and Alzheimer's Disease Neuroimaging Initiative 2 (GO/2) healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects with clinical measures and CSF collected ±90 days of FBP PET data were analyzed using correlation and logistic regression.. In HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Aβ1-42) and tau/Aβ1-42 ratios. Using logistic regression, Aβ1-42, total tau (t-tau), phosphorylated tau181P (p-tau), and FBP PET composite each differentiated HC versus AD. Aβ1-42 and t-tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p-tau added discriminative power to FBP PET when classifying HC versus AD.. Based on cross-sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Humans; Male; Middle Aged; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; Retrospective Studies; tau Proteins

Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging.. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake.. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively).. These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Cognitive Dysfunction; Cohort Studies; Ethylene Glycols; Europe; Female; Humans; Male; Middle Aged; Molecular Imaging; North America; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Sex Characteristics; Thiazoles

Selecting a set of relevant markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) has become a challenging task given the wealth of regional pathologic information that can be extracted from multimodal imaging data. Here, we used regularized regression approaches with an elastic net penalty for best subset selection of multiregional information from AV45-PET, FDG-PET and volumetric MRI data to predict conversion from MCI to AD. The study sample consisted of 127 MCI subjects from ADNI-2 who had a clinical follow-up between 6 and 31 months. Additional analyses assessed the effect of partial volume correction on predictive performance of AV45- and FDG-PET data. Predictor variables were highly collinear within and across imaging modalities. Penalized Cox regression yielded more parsimonious prediction models compared to unpenalized Cox regression. Within single modalities, time to conversion was best predicted by increased AV45-PET signal in posterior medial and lateral cortical regions, decreased FDG-PET signal in medial temporal and temporobasal regions, and reduced gray matter volume in medial, basal, and lateral temporal regions. Logistic regression models reached up to 72% cross-validated accuracy for prediction of conversion status, which was comparable to cross-validated accuracy of non-linear support vector machine classification. Regularized regression outperformed unpenalized stepwise regression when number of parameters approached or exceeded the number of training cases. Partial volume correction had a negative effect on the predictive performance of AV45-PET, but slightly improved the predictive value of FDG-PET data. Penalized regression yielded more parsimonious models than unpenalized stepwise regression for the integration of multiregional and multimodal imaging information. The advantage of penalized regression was particularly strong with a high number of collinear predictors.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Predictive Value of Tests; Prognosis

In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal co

Topics: Aged; Aniline Compounds; Atrophy; Brain; Case-Control Studies; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Glucose; Humans; Magnetic Resonance Imaging; Male; Neuroimaging; Plaque, Amyloid; Positron-Emission Tomography

Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Apolipoproteins E; Butyrylcholinesterase; Cerebral Cortex; Cognitive Dysfunction; Ethylene Glycols; Female; Functional Neuroimaging; Genome-Wide Association Study; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; White People

¹⁸F-florbetapir positron emission tomography (PET) imaging of the brain is now approved by the Food and Drug Administration (FDA) approved for estimation of β -amyloid neuritic plaque density when evaluating patients with cognitive impairment. However, its impact on clinical decision-making is not known. We present 11 cases (age range 67-84) of cognitively impaired subjects in whom clinician surveys were done before and after PET scanning to document the theoretical impact of amyloid imaging on the diagnosis and treatment plan of cognitively impaired subjects. Subjects have been clinically followed for about 5 months after the PET scan. Negative scans occurred in five cases, leading to a change in diagnosis for four patients and a change in treatment plan for two of these cases. Positive scans occurred in six cases, leading to a change in diagnosis for four patients and a change in treatment plan for three of these cases. Following the scan, only one case had indeterminate diagnosis. Our series suggests that both positive and negative florbetapir PET scans may enhance diagnostic certainty and impact clinical decision-making. Controlled longitudinal studies are needed to confirm our data and determine best practices.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cholinesterase Inhibitors; Cognitive Dysfunction; Diagnosis, Differential; Ethylene Glycols; Female; Frontotemporal Dementia; Humans; Male; Memory Disorders; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals

The literature suggests that a history of depression is associated with an increased risk of developing Alzheimer's disease (AD). The aim of this study was to examine brain amyloid accumulation in patients with lifetime major depression using (18)F-florbetapir (AV-45/Amyvid) PET imaging in comparison with that in nondepressed subjects.. The study groups comprised 25 depressed patients and 11 comparison subjects who did not meet the diagnostic criteria for AD or amnestic mild cognitive impairment. Vascular risk factors, homocysteine and apolipoprotein E (ApoE) genotype were also examined. The standard uptake value ratio (SUVR) of each volume of interest was analysed using whole the cerebellum as the reference region.. Patients with a lifetime history of major depression had higher (18)F-florbetapir SUVRs in the precuneus (1.06 ± 0.08 vs. 1.00 ± 0.06, p = 0.045) and parietal region (1.05 ± 0.08 vs. 0.98 ± 0.07, p = 0.038) than the comparison subjects. Voxel-wise analysis revealed a significantly increased SUVR in depressed patients in the frontal, parietal, temporal and occipital areas (p < 0.01). There were no significant associations between global (18)F-florbetapir SUVRs and prior depression episodes, age at onset of depression, or time since onset of first depression.. Increased (18)F-florbetapir binding values were found in patients with late-life major depression relative to comparison subjects in specific brain regions, despite no differences in age, sex, education, Mini Mental Status Examination score, vascular risk factor score, homocysteine and ApoE ε4 genotype between the two groups. A longitudinal follow-up study with a large sample size would be worthwhile.

Topics: Age of Onset; Aged; Alzheimer Disease; Aniline Compounds; Brain; Case-Control Studies; Cognitive Dysfunction; Depressive Disorder, Major; Ethylene Glycols; Female; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Risk Factors

Topics: Alzheimer Disease; Aniline Compounds; Brain; Cognitive Dysfunction; Depressive Disorder, Major; Ethylene Glycols; Female; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals

This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognitive Dysfunction; Disease Progression; Ethylene Glycols; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Nootropic Agents; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals

Mild cognitive impairment (MCI) is a heterogeneous group and certain MCI subsets eventually convert to dementia. Cerebrospinal fluid (CSF) biomarkers are known to predict this conversion. We sought evidence for the differences in white matter connectivity between early amnestic MCI (EMCI) subgroups according to a CSF phosphorylated tau181p/amyloid beta1-42 ratio of 0.10. From the Alzheimer's Disease Neuroimaging Initiative database, 16 high-ratio, 25 low-ratio EMCI patients, and 20 normal controls with diffusion tensor images and CSF profiles were included. Compared to the high-ratio group, radial diffusivity significantly increased in both sides of the corpus callosum and the superior and inferior longitudinal fasciculus in the low-ratio group. In widespread white matter skeleton regions, the low-ratio group showed significantly increased mean, axial, and radial diffusivity compared to normal controls. However, the high-ratio group showed no differences when compared to the normal group. In conclusion, our study revealed that there were significant differences in white matter connectivity between EMCI subgroups according to CSF phosphorylated tau181p/amyloid beta1-42 ratios.

Topics: Aged; Aniline Compounds; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Ethylene Glycols; Female; Humans; Male; Nerve Net; tau Proteins; White Matter

Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Canada; Cerebrovascular Circulation; Cognitive Dysfunction; Databases, Factual; Ethylene Glycols; Female; Humans; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Regional Blood Flow; Spin Labels; United States

Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein E ɛ4 (APOE ɛ4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ɛ4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ɛ4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Genotype; Humans; Image Processing, Computer-Assisted; Male; Positron-Emission Tomography; Radiopharmaceuticals

We examined agreement and disagreement between 2 biomarkers of β-amyloid (Aβ) deposition (amyloid positron emission tomography [PET] and cerebrospinal fluid [CSF] Aβ1-42 ) in normal aging and dementia in a large multicenter study.. Concurrently acquired florbetapir PET and CSF Aβ were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease participants (n = 374) from the Alzheimer's Disease Neuroimaging Initiative. We also compared Aβ measurements in a separate group with serial CSF measurements over 3.1 ± 0.8 years that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases.. Florbetapir and CSF Aβ were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the 2 discordant groups had different profiles: the florbetapir(+) /CSF Aβ(-) group was larger (n = 13) and was made up of only normal and early MCI subjects, whereas the florbetapir(-) /CSF Aβ(+) group was smaller (n = 7) and had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aβ trajectories and those actively transitioning from normal to abnormal, but the final CSF Aβ measurements were in good agreement with florbetapir cortical retention.. CSF and amyloid PET measurements of Aβ were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aβ regularly becomes abnormal prior to fibrillar Aβ accumulation early in the course of disease.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Ethylene Glycols; Female; Humans; Longitudinal Studies; Male; Peptide Fragments; Positron-Emission Tomography

Although it is well known that many clinical and genetic factors have been associated with beta-amyloid deposition, few studies have examined the interactions of such factors across different stages of Alzheimer's pathogenesis.. We used 18F-florbetapir F18 PET imaging to quantify neuritic beta-amyloid plaque density across four cortical regions in 602 elderly (55-94 years) subjects from the national ADNI biomarker study. The group comprised of 194 normal elderly, 212 early mild cognitive impairment [EMCI], 132 late mild cognitive impairment [LMCI], and 64 mild Alzheimer's (AD).. In a model incorporating multiple predictive factors, the effect of apolipoprotein E ε4 and diagnosis was significant on all four cortical regions. The highest signals were seen in cingulate followed by frontal and parietal with lowest signals in temporal lobe (p<0.0001). The effect of apolipoprotein E ε4 (Cohen's D 0.96) on beta-amyloid plaque density was approximately twice as large as the effect of a diagnosis of AD (Cohen's D 0.51) and thrice as large as the effect of a diagnosis of LMCI (Cohen's D 0.34) (p<0.0001). Surprisingly, ApoE ε4+ normal controls had greater mean plaque density across all cortical regions than ε4- EMCI and ε4- LMCI (p<0.0001, p=0.0009) and showed higher, though non-significant, mean value than ε4- AD patients (p<0.27). ApoE ε4+ EMCI and LMCI subjects had significantly greater mean plaque density across all cortical regions than ε4- AD patients (p<0.027, p<0.0001).. Neuritic amyloid plaque load across progressive clinical stages of AD varies strongly by ApoE4 genotype. These findings support the need for better pathology-based and supported diagnosis in routine practice. Our data also provides additional evidence for a temporal offset between amyloid deposition and clinically relevant symptoms.

Topics: Age Factors; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Apolipoprotein E4; Brain; Brain Mapping; Cognitive Dysfunction; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals

To inform whether the Alzheimer's Disease Neuroimaging Initiative (ADNI) should change its policy of not returning research results to ADNI participants, we surveyed investigators and research staff about disclosing ADNI biomarker information to research participants, with particular emphasis on amyloid imaging results.. In April 2012, just before Food and Drug Administration approval of the amyloid-binding radiotracer, florbetapir, all ADNI investigators and personnel were recruited to complete an anonymous online survey that contained fixed choice and free-text questions.. Although ADNI participants often requested amyloid imaging results (the proportions of investigators who reported requests from more than half of their participants with normal cognition or mild cognitive impairment were 20% and 22%, respectively), across all diagnostic groups, the majority of ADNI investigators (approximately 90%) did not return amyloid imaging results to ADNI participants. However, the majority of investigators reported that, if the Food and Drug Administration approved florbetapir, they would support the return of amyloid imaging results to participants with mild cognitive impairment and normal cognition, but they emphasized the need for guidance on how to provide these results to participants and for research to assess the value of returning results as well as how returning results will affect study validity and participant well-being.. A majority of ADNI investigators support returning amyloid imaging results to ADNI participants. The findings that they want guidance on how to do this and research on the impact of disclosure suggest how to develop and monitor a disclosure process.

Topics: Alzheimer Disease; Aniline Compounds; Attitude; Biomarkers; Brain; Cognitive Dysfunction; Educational Status; Ethylene Glycols; Female; Fluorine Radioisotopes; Health Surveys; Humans; Male; Neuroimaging; Radionuclide Imaging; Research Personnel; United States; United States Food and Drug Administration

Investigate apolipoprotein E ε4 (APOE4) gene and aging effects on florbetapir F18 positron emission tomography (PET) in normal aging and Alzheimer's disease (AD).. Florbetapir F18 PET images were analyzed from 245 participants, 18-92 years of age, from Avid Radiopharmaceutical's multicenter registered trials, including 86 younger healthy control volunteers (yHC), 61 older healthy control volunteers (oHC), 53 mild cognitive impairment (MCI) patients, and 45 AD dementia patients (DAT). Mean florbetapir standard uptake value ratios (SUVRs) were used to evaluate the effects of APOE4 carrier status, older age, and their interaction in each of these groups.. In comparison with non-carriers, the APOE4 carriers in each of the oHC, MCI, and DAT groups had higher mean cortical-to-cerebellar florbetapir SUVRs, patterns of florbetapir PET elevations characteristic of DAT, and a higher proportion meeting florbetapir PET positivity criteria. Only the oHC group had a significant association between mean cortical florbetapir SUVRs and age. In cognitively normal adults, without regards to APOE4 genotype, amyloid began to increase at age 58 (95% confidence interval [CI]: 52.3-63.7), with a predicted typical age of florbetapir positivity occurring around age 71 years. Presence of the APOE4 gene reduced the age of predicted florbetapir positivity in normal aging to around age 56 years, approximately 20 years younger than non-carriers.. Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positivity appears to begin near age 56 years in cognitively intact APOE4 carriers and age 76 years in APOE4 non-carriers.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Analysis of Variance; Aniline Compounds; Apolipoprotein E4; Brain; Brain Mapping; Cognitive Dysfunction; Ethylene Glycols; Humans; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Young Adult

Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.. A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ-) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.. In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating-sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ- subjects (p < 0.10).. Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition Disorders; Cognitive Dysfunction; Dementia; Ethylene Glycols; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Psychiatric Status Rating Scales; Psychomotor Performance; Radiopharmaceuticals; Risk

Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.. We examined associations between mean cortical florbetapir uptake, mean (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer's Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements.. Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.. Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.

Topics: Aged; Amyloid; Aniline Compounds; Body Burden; Cognition Disorders; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Ethylene Glycols; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography

Topics: Alzheimer Disease; Aniline Compounds; Benzothiazoles; Cerebral Cortex; Cognitive Dysfunction; Dementia; Ethylene Glycols; Female; Fluorine Radioisotopes; Humans; Male; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles

To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar β-amyloid (Aβ) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs).. Cerebral-to-whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable Aβ because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) ε4.. Multiple research imaging centers.. A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure Florbetapir-PET activity.. All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P < 1.0 × 10⁻⁷), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P < 1.0 × 10⁻⁷), and in percentage meeting SUVR criteria for the presence of any identifiable Aβ (85.3%, 46.6%, and 28.1%, respectively; P < 1.0 × 10⁻⁷). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P = .05). For the 54 OHCs with available APOE genotypes, APOE ε4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P = .048).. The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar Aβ burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Dementia; Ethylene Glycols; Fluorine Radioisotopes; Humans; Male; Middle Aged; Plaque, Amyloid; Positron-Emission Tomography; Young Adult