2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Memory-Disorders

Postmortem studies have suggested that β-amyloid (Aβ) deposition was only weakly related to the degree of cognitive impairment in Alzheimer's disease (AD). The development of Aβ ligands for in vivo PET imaging has greatly facilitated the assessment of this question.. The objective of the present study was to provide an overview of our current knowledge regarding the relationship between Aβ deposition and episodic memory deficits in nondemented elderly and in patients with mild cognitive impairment or AD.. Information was obtained both from studies comparing memory performance in individuals with high Pittsburgh compound B (PiB) and those with low PiB and from studies performing correlation analyses between memory performance and PiB retention considered as a continuous variable.. Previous studies assessing the relationship between memory and global neocortical PiB reported conflicting findings, and overall suggest that this link is weak, probably indirect, and detectable only in early stages. Assessing the relationship with regional instead of global neocortical PiB, we found a specific relationship between episodic memory deficits and neocortical temporal PiB, independent from hippocampal atrophy, in the predementia stage of the disease.. There is a relationship between regional Aβ deposition and episodic memory deficits in the presymptomatic stage of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Brain; Humans; Magnetic Resonance Imaging; Memory Disorders; Positron-Emission Tomography; Thiazoles

[(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.. One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results.. [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients.. In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Brain; Carbon Radioisotopes; Dementia; Diagnosis, Differential; Disease Progression; Early Diagnosis; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Follow-Up Studies; France; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Memory Disorders; Middle Aged; Molecular Imaging; Outpatient Clinics, Hospital; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Sensitivity and Specificity; Thiazoles; Treatment Outcome

To determine whether vascular and neurodegenerative factors influence cognition before clinically relevant Alzheimer disease pathology, we analyzed MRI measures and amyloid imaging in an ethnoracially diverse cohort of cognitively normal individuals older than 60 years.. Participants (n = 154; mean age 74.15 ± 6.94; 50% female; 54% Caucasian, 22.1% Hispanic, 14.9% African American) were recruited from the University of California, Davis Alzheimer's Disease Research Center, who were cognitively normal at baseline, time of PET, and MRI, and received yearly cognitive assessment for 6.23 ± 4.16 years. Mixed model regression with random slope and intercept was calculated for episodic memory and executive function, adjusting for age, sex, education, and ethnicity.. Vascular burden score was associated with total white matter hyperintensity (WMH) volume (β, 0.171; 95% confidence interval [CI], 0.024-0.318). WMH volume was associated with low baseline executive function (-0.115; -0.226 to -0.003) and rate of change in memory (-0.029; -0.045 to -0.012). Hippocampal volume was associated with the rate of change in memory (0.040; 0.021-0.059) and executive function (0.024; 0.008-0.039). Continuous measures of amyloid status influenced change in memory (-0.026; -0.044 to -0.008) and executive function (-0.033; -0.046 to -0.021) independently of MRI measures.. Vascular brain injury and neurodegeneration are associated with baseline cognitive performance and the rate of longitudinal change independent of amyloid status among community-dwelling, ethnicity diverse cognitively normal individuals, supporting the role of vascular diseases as risk factors for later-life dementia.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cerebrovascular Disorders; Cognition; Cognitive Dysfunction; Disease Progression; Executive Function; Female; Hippocampus; Humans; Independent Living; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Neuropsychological Tests; Organ Size; Plaque, Amyloid; Positron-Emission Tomography; Thiazoles; White Matter

The prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers.. To compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia.. A longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment.. Biomarker groups included amyloid β negative (Aβ-)/neurodegeneration negative (ND-), amyloid β positive (Aβ+)/ND-, Aβ-/neurodegeneration positive (ND+), and Aβ+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education.. Of the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ-/ND-, 32 (18.3%) were Aβ+/ND-, 35 (20.0%) were Aβ-/ND+, and 66 (37.7%) were Aβ+/ND+. On all cognitive measures, the Aβ+/ND+ group showed the steepest decline. Compared with the Aβ-/ND- group, the amyloid deposition alone (Aβ+/ND-) group showed faster decline on tests of verbal and visual memory (-0.3513; 95% CI, -0.5269 to -0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (-0.1934; 95% CI, -0.3520 to -0.0348). The Aβ-/ND+ group showed faster visual memory decline than the Aβ-/ND- reference group (-0.3007; 95% CI, -0.4736 to -0.1279).. In the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ+/ND- and Aβ-/ND+ groups.

Topics: Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Cognition Disorders; Female; Hippocampus; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Positron-Emission Tomography; Retrospective Studies; Thiazoles

Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of β-amyloid (Aβ). However, the accumulation of Aβ begins slowly, years before biomarkers become abnormal. We used longitudinal [

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Carbolines; Cerebral Cortex; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Reference Values; tau Proteins; Thiazoles

To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults.. Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET β-amyloid (Aβ) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Aβ burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Aβ. Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Aβ. These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain Mapping; Female; Fluorodeoxyglucose F18; Hippocampus; Humans; Limbic System; Male; Memory; Memory Disorders; Mental Status Schedule; Neuropsychological Tests; Parietal Lobe; Positron-Emission Tomography; Radiopharmaceuticals; Rest; Surveys and Questionnaires; Thiazoles

The aim of this article was to evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline.. We acquired positron emission tomography using F18 flortaucipir (tau), C11 Pittsburgh compound B (amyloid), and F18 fluorodeoxyglucose (FDG) in 90 clinically normal elderly of the Harvard Aging Brain Study.. Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with subthreshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD.. Our study identified a synergistic effect of amyloid and tau deposits and demonstrated, for the first time, in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was observed with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. Ann Neurol 2017;81:583-596.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Female; Fluorodeoxyglucose F18; Humans; Male; Memory Disorders; Palmitates; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; tau Proteins; Thiazoles; Thiones

Patients with Alzheimer's disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion 'Quergold') powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion ('Mashiro' white onion) powder. These results indicate that quercetin might influence memory recall.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Animals; Antioxidants; Benzothiazoles; Conditioning, Psychological; Fear; Female; Humans; Iofetamine; Magnetic Resonance Imaging; Male; Memory Disorders; Mental Recall; Mental Status and Dementia Tests; Mice; Mice, Inbred C57BL; Neuropsychological Tests; Positron-Emission Tomography; Quercetin; Thiazoles

SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β =

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Cerebral Cortex; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Executive Function; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory Disorders; Positron-Emission Tomography; Stroke, Lacunar; Thiazoles

We investigated the extent to which decline in memory and working memory in beta-amyloid (Aβ) positive non-demented individuals was related to hippocampal atrophy and Aβ accumulation over 36 months. Cognitively normal older adults (CN) (n = 178) and adults with mild cognitive impairment (MCI) (n = 49) underwent positron emission tomography neuroimaging, magnetic resonance imaging, and cognitive assessments at baseline, 18- and 36-months. Relative to Aβ- CNs, Aβ+ CNs and Aβ+ MCIs showed greater rates of cognitive decline, Aβ accumulation, and hippocampal atrophy. Analysis of interrelationships between these Alzheimer's disease markers in Aβ+ CNs and MCIs indicated that rate of Aβ accumulation was associated with rate of hippocampal atrophy (β = -0.05, p = .037), which was in turn associated independently with rate of decline in memory (β = -0.03, p = .032). This suggests that Aβ accumulation precedes any neurodegeneration or clinical symptoms, and that the relationship between Aβ and cognitive decline is mediated by hippocampal atrophy.

Topics: Aged; Aged, 80 and over; Aging; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Atrophy; Carbon Isotopes; Cognitive Dysfunction; Female; Hippocampus; Humans; Linear Models; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term; Middle Aged; Nerve Degeneration; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles; Time Factors

Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain Waves; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Polysomnography; Positron-Emission Tomography; Prefrontal Cortex; Recognition, Psychology; Sleep Stages; Sleep Wake Disorders; Thiazoles

Cognitive measures that are sensitive to biological markers of Alzheimer disease (AD) pathology are needed to (a) facilitate preclinical staging, (b) identify individuals who are at the highest risk for developing clinical symptoms, and (c) serve as endpoints for evaluating the efficacy of interventions. The present study assesses the utility of two cognitive composite scores of attentional control and episodic memory as markers for preclinical AD pathology in a group of cognitively normal older adults (N = 238), as part of the Adult Children Study. All participants were given a baseline cognitive assessment and follow-up assessments every 3 years over an 8-year period, as well as a lumbar puncture within 2 years of the initial assessment to collect cerebrospinal fluid (CSF) and amyloid tracer Pittsburgh compound-B scan for amyloid imaging. Results indicated that attentional control was correlated with levels of Aβ42 at the initial assessment whereas episodic memory was not. Longitudinally, individuals with high CSF tau exhibited a decline in both attention and episodic memory over the course of the study. These results indicate that measures of attentional control and episodic memory can be used to evaluate cognitive decline in preclinical AD and provide support that CSF tau may be a key mechanism driving longitudinal cognitive change.

Topics: Aged; Alzheimer Disease; Aniline Compounds; Attention Deficit Disorder with Hyperactivity; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Longitudinal Studies; Male; Memory Disorders; Memory, Episodic; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Predictive Value of Tests; Psychiatric Status Rating Scales; Thiazoles

It is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status.. From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden.. At P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners.. Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

Topics: Aged; Amyloid; Aniline Compounds; Apolipoprotein E4; Brain; Brain Mapping; Cognition Disorders; Female; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Observation; Positron-Emission Tomography; Prospective Studies; Thiazoles

Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB-positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Brain; Cerebrovascular Disorders; Cognition Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

High β-amyloid (Aβ) is associated with faster memory decline in healthy individuals and adults with mild cognitive impairment (MCI). However, longer prospective studies are required to determine if Aβ-related memory decline continues and whether it is associated with increased rate of disease progression.. Healthy controls (HCs; n = 177) and adults with MCI (n = 48) underwent neuroimaging for Aβ and cognitive assessment at baseline. Cognition was reassessed 18 and 36 months later.. Compared with low-Aβ HCs, high-Aβ HC and MCI groups showed moderate decline in episodic and working memory over 36 months. Those with MCI with low Aβ did not show any cognitive decline. Rates of disease progression were increased in the high-Aβ HC and MCI groups.. In healthy individuals, high Aβ likely indicates that Alzheimer's disease (AD)-related neurodegeneration has begun. Once commenced, the rate of decline in cognitive function remains constant across the preclinical and prodromal stages of AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cognition Disorders; Disease Progression; Female; Follow-Up Studies; Humans; Learning; Linear Models; Male; Memory Disorders; Memory, Short-Term; Neuropsychological Tests; Positron-Emission Tomography; Prodromal Symptoms; Psychiatric Status Rating Scales; Thiazoles

Two approaches are available for measuring Alzheimer's disease (AD) pathology in vivo. Biomarkers in cerebrospinal fluid (CSF) include amyloid-β1-42 (Aβ42) and tau. Furthermore, amyloid deposition can be visualized using positron emission tomography (PET) and [11C]Pittsburgh compound-B ([11C]PIB).. We investigated concordance between CSF biomarkers and [11C]PIB PET as markers for AD pathology in a memory clinic cohort.. We included 64 AD patients, 34 non-AD dementia patients, 22 patients with mild cognitive impairment (MCI), and 16 controls. [11C]PIB scans were visually rated as positive or negative. CSF biomarkers were considered abnormal based on Aβ42 alone (<550 ng/L), a more lenient Aβ42 cut-off (<640 ng/L) or a combination of both Aβ42 and tau ((373 + 0.82 tau)/Aβ42 > 1). Concordance between CSF biomarkers and [11C]PIB PET was determined.. Overall, concordance between [11C]PIB PET and CSF Aβ42 (<550 ng/L) was 84%. In discordant cases, [11C]PIB PET was more often AD-positive than Aβ42. When a more lenient Aβ42 cut-point (<640 ng/L) or a combination of Aβ42 and tau was used, concordance with [11C]PIB PET appeared to be even higher (90% and 89%). This difference is explained by a subgroup of mostly MCI and AD patients with Aβ42 levels just above cut-off. Now, in discordant cases, CSF was more often AD-positive than [11C]PIB PET.. Concordance between CSF Aβ42 and [11C]PIB PET was good in all diagnostic groups. Discordance was mostly seen in MCI and AD patients close to the cut-point. These results provide convergent validity for the use of both types of biomarkers as measures of AD pathology.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Cohort Studies; Female; Humans; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; tau Proteins; Thiazoles

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of β amyloid (Aβ) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aβ levels have focused primarily on plasma Aβ(1-40) and not on the more pathogenic Aβ(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aβ levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aβ(1-40) and Aβ(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aβ(1-40); beta=0.208, P=0.017; Aβ(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Cognitive Dysfunction; Cohort Studies; Gonadotropins; Humans; Linear Models; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Psychiatric Status Rating Scales; Risk Factors; Statistics, Nonparametric; Testosterone; Thiazoles

The clinical role of amyloid brain positron emission tomographic imaging in the diagnosis of Alzheimer disease is currently being formulated. The specificity of a positive amyloid scan is a matter of contention.. An 83-year-old Canadian man presented with a 5-year history of predominantly short-term memory loss and functional impairment. Clinical evaluation revealed significant, gradually progressive short-term memory loss in the absence of any history of strokes or other neuropsychiatric symptoms. The patient met clinical criteria for probable Alzheimer disease but had a higher than expected burden of white matter disease on magnetic resonance imaging. A positron emission tomographic Pittsburgh Compound B scan was highly positive in typical Alzheimer disease distribution. The patient died of an intracerebral hemorrhage 6 months after the assessment. Autopsy revealed cerebral amyloid angiopathy in the complete absence of amyloid plaques or neurofibrillary tangles.. This patient demonstrates that a positive Pittsburgh Compound B scan in a patient with clinical dementia meeting criteria for probable Alzheimer disease is not proof of an Alzheimer disease pathophysiological process. A positive Pittsburgh Compound B scan in typical Alzheimer disease distribution in a patient with dementia can be secondary to cerebral amyloid angiopathy alone.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Cerebral Hemorrhage; Diagnosis, Differential; Fatal Outcome; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Positron-Emission Tomography; Sensitivity and Specificity; Thiazoles

High levels of amyloid-β (Aβ) have been associated with greater rates of decline in episodic memory over 18 months in healthy older adults. Serial assessments over shorter time intervals may facilitate earlier detection of Aβ-related memory decline in healthy older adults. In forty-four healthy older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Rate of Change Sub-Study, we compared rates of change in cognition over six months in healthy older adults with high and low levels of Aβ. High Aβ was associated with greater decline in episodic memory measures over 6 months in healthy older adults.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Australia; Female; Humans; Male; Memory Disorders; Memory, Episodic; Neuropsychological Tests; Positron-Emission Tomography; Prospective Studies; Thiazoles

The relationship between β-amyloid deposition and memory deficits in early Alzheimer's disease is unresolved, as past studies show conflicting findings. The present study aims to determine the relative contribution of regional β-amyloid deposition, hippocampal atrophy and white matter integrity to episodic memory deficits in non-demented older individuals harbouring one of the characteristic hallmarks of Alzheimer's disease, i.e. with β-amyloid pathology. Understanding these relationships is critical for effective therapeutic development. Brain magnetic resonance imaging and [(11)C]Pittsburgh Compound B-positron emission tomography scans were obtained in 136 non-demented individuals aged over 60 years, including 93 healthy elderly and 43 patients with mild cognitive impairment. Voxel-based correlations were computed between a memory composite score and grey matter volume, white matter volume and β-amyloid deposition imaging datasets. Hierarchical linear regression analyses were then performed using values extracted in regions of most significant correlations to determine the relative contribution of each modality to memory deficits. All analyses were conducted pooling all groups together as well as within separate subgroups of cognitively normal elderly, patients with mild cognitive impairment and individuals with high versus low neocortical β-amyloid. Brain areas of highest correlation with episodic memory deficits were the hippocampi for grey matter volume, the perforant path for white matter volume and the temporal neocortex for β-amyloid deposition. When considering these three variables together, only hippocampal volume and temporal β-amyloid deposition provided independent contributions to memory deficits. In contrast to global β-amyloid deposition, temporal β-amyloid deposition was still related to memory independently from hippocampal atrophy within subgroups of cognitively normal elderly, patients with mild cognitive impairment or cases with high neocortical β-amyloid. In the pre-dementia stage of Alzheimer's disease, subtle episodic memory impairment is related to β-amyloid deposition, especially in the temporal neocortex, and independently from hippocampal atrophy, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Brain Mapping; Carbon Radioisotopes; Cognition Disorders; Female; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Memory Disorders; Middle Aged; Positron-Emission Tomography; Regression Analysis; Thiazoles

Cerebral amyloid beta (Aβ) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Aβ-related memory impairment in CN. We studied 45 CN subjects (mean age=71.7 ± 8.8) with Clinical Dementia Rating (CDR) scores=0 and MMSE ≥ 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Aβ deposition in frontal (R(2)=0.29, β=-2.2, p=0.02) and PPCLP cortices (R(2)=0.26, β=-2.4, p=0.05). In contrast, neither FN-O nor the SRT were significantly related to Aβ deposition. Performance on a demanding test of face-name associative memory was related to Aβ burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Aβ-related impairment.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Association Learning; Cerebral Cortex; Cognition; Face; Female; Humans; Male; Memory Disorders; Positron-Emission Tomography; Reference Values; Retention, Psychology; Thiazoles; Verbal Learning

Oligomeric amyloid β (Aβ) is currently considered to induce Alzheimer's disease (AD). We examined 2 patients with familial AD who possessed the Osaka (E693Δ) mutation in amyloid precursor protein. To the best of our knowledge, these patients are the first AD cases presumably affected with Aβ oligomers in the absence of senile plaques, and they support the Aβ oligomer hypothesis.. We evaluated the clinical course, neuropsychological data, cerebrospinal fluid biomarker levels, magnetic resonance imaging (MRI) scans, fluorodeoxyglucose-positron emission tomography (PET) scans, and Pittsburgh compound B (PiB)-PET images of these patients.. In the early stages, these patients developed memory disturbances in a similar rate to patients with sporadic AD. Despite their memory disturbances, both patients showed only limited brain atrophy on MRI and little amyloid accumulation on PiB-PET. Subsequent to the development of memory disturbances, both patients suffered from motor dysfunction, probably due to cerebellar ataxia, and, within a few years, the patients fell into an apallic state.. Familial AD patients with Osaka (E693Δ) mutation show severe dementia, cerebellar ataxia, and gait disturbances.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Apolipoproteins E; Atrophy; Benzothiazoles; Brain; Cerebellar Ataxia; Cognition; Disease Progression; Female; Fluorodeoxyglucose F18; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Memory Disorders; Middle Aged; Mutation; Neuropsychological Tests; Pedigree; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

The aim of this study was to evaluate the visual assessment of positron emission tomography images of N-[methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) in a patient population with mild to moderate memory impairment or dementia.. We compared the visual ratings of two readers using kappa statistics and correlated the results of visual and quantitative region of interest (ROI) analyses. The one reader had good experience in evaluating PIB images and the other had little previous experience. The sensitivity and specificity of the visual assessment was determined using quantitative data from 18 healthy controls previously examined: [11C]PIB uptake was considered as abnormal if it was more than 2 SD above the mean of the healthy subjects.. The evaluation of visual classification as "normal" or "abnormal" showed good interobserver agreement (kappa = 0.90). There was a clear correlation between visual and quantitative analysis (r = 0.47-0.79, p < 0.001). The most difficult visually assessed brain area was the putamen (kappa = 0.11; correlation with quantitative analysis: reader A r = 0.22; reader B r = 0.60).. Our study shows that visual evaluation of [(11)C]PIB images conforms with quantitative analyses also in a clinical patient population supporting the feasibility of visual evaluation in clinical settings.

Topics: Aged; Aged, 80 and over; Aniline Compounds; Benzothiazoles; Cognition Disorders; Dementia; Female; Humans; Male; Memory Disorders; Middle Aged; Positron-Emission Tomography; Reference Standards; Thiazoles

New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers.. Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs).. Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions.. A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Biomarkers; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Fluorodeoxyglucose F18; Glucose; Humans; Image Interpretation, Computer-Assisted; Male; Memory Disorders; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

To determine whether amyloid deposition is associated with impaired neuropsychological (NP) performance and whether cognitive reserve (CR) modifies this association.. In 66 normal elderly controls and 17 patients with Alzheimer disease (AD), we related brain retention of Pittsburgh Compound B (PiB) to NP performance and evaluated the impact of CR using education and American National Adult Reading Test intelligence quotient as proposed proxies.. We found in the combined sample of subjects that PiB retention in the precuneus was inversely related to NP performance, especially in tests of memory function, but also in tests of working memory, semantic processing, language, and visuospatial perception. CR significantly modified the relationship, such that at progressively higher levels of CR, increased amyloid deposition was less or not at all associated with poorer neuropsychological performance. In a subsample of normal controls, both the main effect of amyloid deposition of worse memory performance and the interaction with CR were replicated using a particularly challenging memory test.. Amyloid deposition is associated with lower cognitive performance both in AD patients and in the normal elderly, but the association is modified by CR, suggesting that CR may be protective against amyloid-related cognitive impairment.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Aniline Compounds; Benzothiazoles; Cognition; Cognition Disorders; Disability Evaluation; Disease Progression; Female; Humans; Longitudinal Studies; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; Plaque, Amyloid; Positron-Emission Tomography; Predictive Value of Tests; Reference Values; Severity of Illness Index; Thiazoles

Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

Topics: Age Factors; Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Atrophy; Carbon Radioisotopes; Case-Control Studies; Educational Status; Female; Hippocampus; Humans; Linear Models; Magnetic Resonance Imaging; Male; Memory Disorders; Middle Aged; Multivariate Analysis; Organ Size; Positron-Emission Tomography; Psychiatric Status Rating Scales; Radiopharmaceuticals; Sex Factors; Thiazoles

A valid quantitative imaging method for the measurement of amyloid deposition in humans could improve Alzheimer's disease (AD) diagnosis and antiamyloid therapy assessment. Our group developed Pittsburgh Compound-B (PIB), an amyloid-binding radiotracer, for positron emission tomography (PET). The current study was aimed to further validate PIB PET through quantitative imaging (arterial input) and inclusion of subjects with mild cognitive impairment (MCI). Pittsburgh Compound-B studies were performed in five AD, five MCI, and five control subjects and five subjects were retested within 20 days. Magnetic resonance images were acquired for partial volume correction and region-of-interest definition (e.g., posterior cingulate: PCG; cerebellum: CER). Data were analyzed using compartmental and graphical approaches. Regional distribution volume (DV) values were normalized to the reference region (CER) to yield DV ratios (DVRs). Good agreement was observed between compartmental and Logan DVR values (e.g., PCG: r=0.89, slope=0.91); the Logan results were less variable. Nonspecific PIB retention was similar across subjects (n=15, Logan CER DV: 3.63+/-0.48). Greater retention was observed in AD cortical areas, relative to controls (P<0.05). The PIB retention in MCI subjects appeared either 'AD-like' or 'control-like'. The mean test/retest variation was approximately 6% in primary areas-of-interest. The Logan analysis was the method-of-choice for the PIB PET data as it proved stable, valid, and promising for future larger studies and voxel-based statistical analyses. This study also showed that it is feasible to perform quantitative PIB PET imaging studies that are needed to validate simpler methods for routine use across the AD disease spectrum.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Cerebellar Cortex; Female; Humans; Image Processing, Computer-Assisted; Kinetics; Male; Memory Disorders; Middle Aged; Positron-Emission Tomography; Protein Binding; Radiography; Thiazoles