2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Lewy-Body-Disease

To review the rapidly expanding literature of amyloid PET imaging with particular attention to Pittsburgh compound-B (PIB) in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), fronto-temporal dementia (FTD), mild cognitive impairment (MCI) and cognitively normal volunteers.. Literature searches were performed using Medline up to February 2010. Individual articles were then examined for additional references not revealed by automated searches. This yielded 79 articles whose abstracts were read by the authors to select key papers.. Amyloid deposition assessed using PIB-PET is significantly elevated in AD and DLB compared to controls and those with FTD. In MCI, uptake is often intermediate between AD and normal ageing, and excessive amyloid burden in non-demented individuals with MCI are likely to represent high-risk cases. Amyloid deposition appears to be an early event, and as dementia progresses clinical decline seems to be more associated with neurodegeneration than amyloid burden.. PIB-PET imaging is a sensitive and specific marker for underlying Aβ amyloid deposition and represents an important investigative tool for examining the relationship between amyloid burden, clinical symptoms and structural and functional changes in dementia. Amyloid imaging may also be useful for selecting patients for anti-amyloid therapies. However, studies have identified PIB-positive cases in otherwise healthy older individuals (10-30%), limiting diagnostic specificity. Development of biomarkers for investigating other aspects of dementia pathology, i.e. soluble Aβ, tau, synuclein and brain inflammation would further inform our understanding and assist in studying disease-modifying and preventive treatments in dementia.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Cognition Disorders; Dementia; Frontotemporal Dementia; Humans; Image Processing, Computer-Assisted; Lewy Body Disease; 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

We report a patient presenting with clinical features of logopenic variant primary progressive aphasia (lvPPA) who was later diagnosed with probable dementia with Lewy bodies. LvPPA is a neurodegenerative disease that is characterized by anomia, word-finding difficulty, impaired comprehension, and phonological errors. The most common underlying pathology for lvPPA is Alzheimer's disease. However, our patient with clinical features of logopenic progressive aphasia was later diagnosed with probable dementia with Lewy bodies. This case demonstrates that lvPPA can also be an initial manifestation of a phenotype of dementia with Lewy bodies.

Topics: Aged; Aniline Compounds; Aphasia, Primary Progressive; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Positron-Emission Tomography; Thiazoles

To develop imaging biomarkers of diseases in the Lewy body spectrum and to validate these markers against postmortem neuropathologic findings.. Four cognitively normal participants with Parkinson disease (PD), 4 with PD with cognitive impairments, and 10 with dementia with Lewy bodies underwent amyloid imaging with [11C]Pittsburgh compound B (PiB) and dopamine transporter (DAT) imaging with [11C]Altropane. All 18 had annual neurologic examinations. All cognitively normal participants with PD developed cognitive impairment before death. Neuropathologic examinations assessed and scored Braak Lewy bodies, Thal distribution of amyloid, Consortium to Establish a Registry for Alzheimer's Disease neuritic amyloid plaques, Braak neurofibrillary tangles, and cerebral amyloid angiopathy, as well as total amyloid plaque burden in the superior frontal, superior parietal, occipital, and inferior temporal cortical regions. PET data were expressed as the standardized uptake value ratio with cerebellar reference. Analyses accounted for the interval between imaging and autopsy.. All 18 patients met neuropathologic criteria for Lewy body disease; the DAT concentration was low in each case. All patients with elevated [11C]PiB retention measured in a neocortical aggregate had β-amyloid deposits at autopsy. [11C]PiB retention significantly correlated with neuritic plaque burden and with total plaque burden. [11C]PiB retention also significantly correlated with the severity of both Braak stages of neurofibrillary tangle and Lewy body scores. Neuritic plaque burden was significantly associated with neurofibrillary tangle pathology.. Antemortem [11C]Altropane PET is a sensitive measure of substantia nigra degeneration. [11C]PiB scans accurately reflect cortical amyloid deposits seen at autopsy. These findings support the use of molecular imaging in the evaluation of patients with Lewy body diseases.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Brain; Cocaine; Contrast Media; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Thiazoles

Objective Dementia with Lewy bodies (DLB) is a common type of neurodegenerative dementia. Molecular neuroimaging using dopamine transporter (DaT), Pittsburgh compound B (PIB), and fluorodeoxyglucose (FDG) positron emission tomography (PET) has advantages in detecting dopaminergic neuron loss, abnormal amyloid β-protein deposition, and glucose metabolism changes in patients with neurodegenerative disorders. However, the multi-modality molecular imaging features of patients with DLB have rarely been reported. Methods Five patients with a probable diagnosis of DLB were enrolled. PET/magnetic resonance imaging was performed with three tracers:

Topics: Aged; Aged, 80 and over; Aniline Compounds; Cocaine; Dopamine Plasma Membrane Transport Proteins; Female; Fluorodeoxyglucose F18; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Molecular Imaging; Multimodal Imaging; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

In subjects with amyloid deposition, striatal accumulation of. Seventy-three subjects who complained of cognitive disturbance underwent dynamic PiB-PET studies and showed positive PiB accumulation were retrospectively selected. These subjects included 34 AD, 26 mild cognitive impairment, 2 frontotemporal lobar degeneration, 2 Parkinson's disease, 5 dementia with Lewy bodies, and 4 undefined diagnosis patients. Individual BP. There were highly significant correlations between striatal and prefrontal BP. Our study demonstrated positive correlations in amyloid deposits between the striatum and other cortical areas with functional and anatomical links. The amyloid distribution in the brain is not random, but spreads following the functional and anatomical connections.

Topics: Aged; Alzheimer Disease; Amyloid; Aniline Compounds; Cerebral Cortex; Cognitive Dysfunction; Corpus Striatum; Female; Frontotemporal Lobar Degeneration; Humans; Lewy Body Disease; Male; Parkinson Disease; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies; Thiazoles

Patients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)-related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV-1451 uptake in patients with probable DLB, compared to AD, and its relationship to β-amyloid deposition on PET.. Consecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV-1451, and Pittsburgh compound-B (PiB) PET examinations. Age- and sex-matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas- and voxel-based analyses were performed.. The AD dementia group had significantly higher AV-1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV-1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006).. Medial temporal lobe AV-1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV-1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58-67.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Carbolines; Case-Control Studies; Cerebral Cortex; Female; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; tau Proteins; Thiazoles

Dementia with Lewy bodies (DLB) is the second most common subtype of degenerative dementia. To our knowledge, available information about the clinical features of DLB in China remains limited. Our study therefore aimed to address this issue. Thirty-seven Chinese patients with probable DLB were recruited for this study. All subjects underwent neuropsychological assessment by trained neurologists, as well as undergoing MRI, 11C-PIB PET scans for Aβ deposition and 18F-FDG PET scans for regional cerebral glucose metabolism. Our results showed that the gender ratio of patients was 16:21 (F:M). The mean age of onset was 69.5 ± 9.0 years and the mean age at diagnosis was 71.8 ± 9.1 years. At diagnosis, the prevalence of three core clinical features of DLB was: 64.9% for fluctuating cognition, 73.0% for visual hallucinations and 62.2% for parkinsonism. The result from 11C-PiB PET and 18F-FDG PET scans confirmed Aβ deposition in the cortex and demonstrated hypometabolism in the bilateral temporoparietooccipital region, the frontal lobe, the insular lobe, and the posterior cingulate, precuneus and caudate nuclei. Our study elucidated the clinical features of Chinese DLB patients, and will improve the understanding and the early diagnosis of DLB in Chinese patients.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Biological Transport; Brain; China; Female; Fluorodeoxyglucose F18; Glucose; Humans; Lewy Body Disease; Male; Middle Aged; Neuroimaging; Positron-Emission Tomography; Thiazoles

Effective therapies for dementia with Lewy bodies (DLB) and Parkinson's disease (PD) dementia will require accurate diagnosis and an understanding of the contribution of distinct molecular pathologies to these diseases. We seek to use imaging biomarkers to improve diagnostic accuracy and to clarify the contribution of molecular species to cognitive impairment in DLB and PD.. We have performed cross-sectional and prospective cohort studies in subjects with DLB, PD with normal cognition, PD with mild cognitive impairment and PD with dementia, contrasted with Alzheimer's disease (AD) and healthy control subjects (HCS). Subjects underwent formal neurological examination, detailed neuropsychological assessments, MRI and PET scans with the radioligands altropane (a dopamine transporter, DAT) and Pittsburgh compound B (PiB; β-amyloid). Putamen DAT concentrations were similar in DLB and PD and differentiated them from HCS and AD. Decreased caudate DAT concentration related to functional impairment in DLB but not PD. PiB uptake was greatest in DLB. However, cortical PiB retention was common in PD and predicted cognitive decline. PET imaging of tau aggregates holds promise both to clarify the contribution of tau to cognitive decline in these diseases and to differentiate DLB and PD from the parkinsonian tauopathies.. Together, DAT and amyloid PET imaging discriminate DLB from PD and from other disease groups and identify pathological processes that contribute to their course. Multimodal PET imaging has the potential to increase the diagnostic accuracy of DLB and PD in the clinic, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies.

Topics: Alzheimer Disease; Aniline Compounds; Brain; Carbolines; Cocaine; Cognitive Dysfunction; Cross-Sectional Studies; Diagnosis, Differential; Lewy Body Disease; Magnetic Resonance Imaging; Neuropsychological Tests; Parkinson Disease; Prospective Studies; Radionuclide Imaging; Radiopharmaceuticals; Survival Analysis; Thiazoles

This study investigated the improvement in the accuracy of diagnosis of dementia subtypes among Chinese dementia patients who underwent [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG PET) with or without carbon 11-labelled Pittsburgh compound B ((11)C-PIB).. This case series was performed in the Memory Clinic at Queen Mary Hospital, Hong Kong. We reviewed 109 subjects (56.9% were female) who received PET with or without (11)C-PIB between January 2007 and December 2014. Data including age, sex, education level, Mini-Mental State Examination score, Clinical Dementia Rating scale score, neuroimaging report, and pre-/post-imaging clinical diagnoses were collected from medical records. The agreement between the initial and post-PET with or without (11)C-PIB dementia diagnosis was analysed by the Cohen's kappa statistics.. The overall accuracy of initial clinical diagnosis of dementia subtype was 63.7%, and diagnosis was subsequently changed in 36.3% of subjects following PET with or without (11)C-PIB. The rate of accurate initial clinical diagnosis (compared with the final post-imaging diagnosis) was 81.5%, 44.4%, 14.3%, 28.6%, 55.6% and 0% for Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, other dementia, and mixed dementia, respectively. The agreement between the initial and final post-imaging dementia subtype diagnosis was only fair, with a Cohen's kappa of 0.25 (95% confidence interval, 0.05-0.45). For the 21 subjects who underwent (11)C-PIB PET imaging, 19% (n=4) of those with Alzheimer's disease (PIB positive) were initially diagnosed with non-Alzheimer's disease dementia.. In this study, PET with or without (11)C-PIB brain imaging helped improve the accuracy of diagnosis of dementia subtype in 36% of our patients with underlying Alzheimer's disease, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain; Dementia; Female; Fluorodeoxyglucose F18; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies; Thiazoles

The causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown.. To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function.. This cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET).. Imaging with fluorine 18-labeled AV-1451 ([18F]AV-1451) (formerly known as [18F]T807), [11C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale.. Main outcomes were differentiation of diagnostic groups on the basis of [18F]AV-1451 binding, the association of [18F]AV-1451 binding with [11C]PiB binding, and the association of [18F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [11C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function.. In patients with DLB, cortical [18F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [18F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [18F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [11C]PiB retention. For DLB and PD-impaired patients, greater [18F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.. Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support a role for tau copathology in the Lewy body diseases.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Carbolines; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Parkinson Disease; Positron-Emission Tomography; tau Proteins; Thiazoles

There is evidence that some cases of patients with dementia with Lewy bodies (DLB) can demonstrate Alzheimer disease (AD) like reduced glucose metabolism without amyloid deposition. The aim of this study was to clarify whether regional hypometabolism is related to amyloid deposits in the DLB brain and measure the degree of regional hypometabolism.. Ten consecutive subjects with DLB and 10 AD patients who underwent both Pittsburgh compound B (PiB)-PET and (18)F-fluoro-2-deoxyglucose (FDG)-PET were included in this study. Regional standardized uptake value ratio (SUVR)s normalised to cerebellar cortices were calculated in the FDG- and PiB-PET images.. All AD patients and five DLB patients showed amyloid deposits (PiB positive). In the DLB group the parietotemporal and occipital metabolism were significantly lower than those in the AD group but there was no difference between the posterior cingulate hypometabolism between DLB and AD groups. There were no differences in regional glucose metabolism between PiB positive and negative DLB patients.. In the DLB brain, it is suggested that decreased regional glucose metabolism is unrelated to amyloid deposits, although the hypometabolic area overlaps with the AD hypometabolic area and the degree of parietotemporal and occipital hypometabolism in DLB brain is much larger than that in AD brain.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Aniline Compounds; Benzothiazoles; Brain; Brain Mapping; Female; Fluorodeoxyglucose F18; Glucose; Humans; Lewy Body Disease; Male; Radionuclide Imaging; Radiopharmaceuticals; Thiazoles

Apolipoprotein E ε4 allele (APOE ε4) increases the apolipoprotein E (apoE) protein levels in Alzheimer's disease (AD) cerebrospinal fluid (CSF). Thus, we hypothesized that apoE levels were also associated with the APOE genotype, and amyloid-β (Aβ)-associated clinical, functional, and imaging parameters in patients with Lewy body-associated disorders (LBD). Indeed, similar to AD, patients with LBD displayed high CSF apoE levels (greatest in patients with dementia with LBD), and this was linked to APOE ε4. High CSF apoE protein correlated positively with CSF soluble amyloid precursor protein, total tau, and cortical and striatal Pittsburgh compound B retention; and correlated negatively with CSF Aβ42, cognitive tests scores, and glucose uptake ratio in the temporal and parietal cortices. APOE ε4-triggered accumulation of apoE in CSF is related to Aβ-associated clinical and functional imaging parameters in LBD. Accordingly, therapeutic strategies aimed at reducing apoE levels in the brain should be explored not only in AD but also in LBD, particularly when accompanied with dementia.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Apolipoproteins E; Biomarkers; Brain; Carbon Radioisotopes; Cohort Studies; Female; Fluorodeoxyglucose F18; Glucose; Humans; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)-like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini-Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [(11)C]Pittsburgh Compound B to measure brain amyloid deposition as well as three-dimensional T1-weighted MRI. Gray-matter volumes (GMVs) were estimated by voxel-based morphometry. Volumes-of-interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid-positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid-negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid-positive DLB/PDD and AD groups and by 10% in the amyloid-negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD-like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD-like atrophy in DLB/PDD patients with amyloid deposition.

Topics: Aged; Aging; Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Atrophy; Benzothiazoles; Dementia; Female; Humans; Image Processing, Computer-Assisted; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

The association between ante mortem [(11)C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with Lewy bodies (DLB). A 76 year old man presenting with a clinical diagnosis of DLB had undergone PiB-positron emission tomography (PET), (18)F FDG-PET and magnetic resonance imaging (MRI) 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ density and PiB retention in the 17 corresponding ROIs (r = 0.899; p < 0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques, whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r = 0.13; p = 0.66); nor between NFT density and PiB retention (r = -0.36; p = 0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Carbon Radioisotopes; Fatal Outcome; Humans; Lewy Body Disease; Male; Neocortex; Peptidylprolyl Isomerase; Phenanthrolines; Positron-Emission Tomography; Thiazoles

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the (11)C-Pittsburgh Compound-B (PiB) retention and regional hypometabolism on positron emission tomography (PET) and regional cortical atrophy on magnetic resonance imaging (MRI) are complementary in characterizing patients with DLB and differentiating them from AD. We studied age-, gender-, and education-matched patients with a clinical diagnosis of DLB (n = 21), AD (n = 21), and cognitively normal subjects (n = 42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic = 0.98). Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that magnetic resonance imaging and PiB positron emission tomography contribute to characterizing the distinct pathological mechanisms in patients with AD compared with DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Aniline Compounds; Brain Mapping; Case-Control Studies; Female; Fluorodeoxyglucose F18; Humans; Imaging, Three-Dimensional; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Occipital Lobe; Positron-Emission Tomography; ROC Curve; Statistics, Nonparametric; Thiazoles

The noninvasive evaluation of nigrostriatal dopaminergic integrity by PET can provide useful information for the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).. To evaluate the diagnostic potential of imaging striatal monoaminergic terminal integrity with the novel vesicular monoamine transporter type 2 (VMAT2) radioligand [(18)F]AV-133 and PET to distinguish DLB from AD.. Fifty participants [9 DLB, 11 AD, 20 Parkinson's disease (PD) and 10 healthy age-matched control subjects (HC)] underwent [(18)F]AV-133 PET studies. Additionally, 20 participants underwent amyloid imaging PET scans with either [(11)C]PiB or (18)F-florbetaben. VMAT2 density was calculated through normalized tissue uptake value ratios (R(T)) at 120-140 min after injection using the primary visual or the cerebellar cortex as reference region. Comparison of the R(T) for [(18)F]AV-133 was done between the different clinical diagnostic groups.. Significantly lower striatal VMAT2 densities were observed in DLB and PD when compared to AD and HC, especially in the posterior putamen. In contrast to PD and DLB, no reductions were observed in AD patients when compared to HC.. [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. In contrast to amyloid imaging, VMAT2 imaging with [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in DLB patients, assisting in the differential diagnosis from AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amygdala; Aniline Compounds; Brain Mapping; Carbon Radioisotopes; Case-Control Studies; Corpus Striatum; Diagnosis, Differential; Female; Fluorine Radioisotopes; Humans; Lewy Body Disease; Male; Middle Aged; Positron-Emission Tomography; Tetrabenazine; Thiazoles; Vesicular Monoamine Transport Proteins

Many patients with PD develop PD with dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account, in part, for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases. Twenty-nine cognitively healthy PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD, and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and Pittsburgh compound B (PiB) imaging with PET. Apolipoprotein E (ApoE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference. PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the ApoE ε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition. DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD, or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Antiparkinson Agents; Apolipoprotein E3; Cognition; Cognitive Dysfunction; Female; Genotype; Humans; Levodopa; Lewy Body Disease; Male; Neurologic Examination; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Thiazoles

We previously found that some cases of clinically diagnosed Alzheimer's disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail.. Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, (123)I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM).. When examined by (123)I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus.. PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Case-Control Studies; Dementia; Female; Fluorodeoxyglucose F18; Humans; Iodine Radioisotopes; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Perfusion Imaging; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins; Thiazoles

Multiple Systems Atrophy (MSA) and Dementia with Lewy bodies (DLB) can present with both REM behavior disorder and severe autonomic dysfunction. In rare occasions, patients with MSA progress to cognitive impairment and even dementia. Positron emission topography (PET) imaging using both the amyloid ligand Pittsburgh Compound B (11C-PiB) and 18 flurodeoxyglucose (18F-FDG) was used to ascertain the presence of amyloid and pattern of glucose metabolic derangement in both disorders.. Patients diagnosed with probable DLB or MSA, with clinical symptoms of either REM Behavior Disorder (RBD), Parkinsonism, or dysautonomia were prospectively identified. All underwent both 11C-PiB and 18F-FDG PET imaging. Statistical comparison between DLB, MSA, and normal controls was performed.. Six patients, 3 with DLB, 2 with Parkinson predominant MSA (MSA-P), and 1 with cerebellar predominant MSA (MSA-C) were identified. Increased level of PiB retention was noted in all patients diagnosed with DLB, but was absent in MSA. In those with DLB, glucose hypometabolism corresponded with regions of amyloid presence, and included prefrontal, parietotemporal, occipital and primary visual cortex regions. MSA patients were distinguished by cerebellar glucose hypometabolism.. These findings emphasize the distinguishing characteristics between the alpha-synuclein related disorders of DLB and MSA. The absence of amyloid in the cases of MSA is a possible distinguishing characteristic of the disorder.

Topics: Aged; Amyloid; Aniline Compounds; Brain Mapping; Female; Fluorodeoxyglucose F18; Glucose; Humans; Lewy Body Disease; Male; Middle Aged; Multiple System Atrophy; Positron-Emission Tomography; Thiazoles; Tomography, X-Ray Computed

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-β does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-β may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Cognition Disorders; Diagnosis, Differential; Female; Humans; Lewy Bodies; Lewy Body Disease; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Severity of Illness Index; Statistics, Nonparametric; Thiazoles

About one fourth of Lewy body disease (LBD) patients show cortical beta-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with beta-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters. Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(-) according to cortical PIB uptake. PIB+ and PIB(-) patients were then compared according to demographic, clinical, biochemical and genetic parameters. None of the PDND, but four PDD and four DLB subjects were PIB+. In PIB+ subjects, ApoE4 prevalence was higher, CSF Abeta42 levels were lower and, among demented patients, PIB-binding was associated with a lower MMSE score. Motor symptoms were not associated with PIB binding. Thus, LBD patients with cortical beta-amyloid show characteristics usually observed in AD.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Apolipoprotein E4; Brain; Carbon Radioisotopes; Female; Humans; Lewy Body Disease; Likelihood Functions; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Positron-Emission Tomography; Regression Analysis; Sequence Analysis, DNA; Thiazoles

11C-Pittsburgh Compound B (11C-PiB) PET has demonstrated significantly higher PiB retention in the gray matter of Alzheimer disease (AD) patients than in healthy controls (HCs). PiB is similarly retained within the white matter of HC and AD brains. Although the specificity of PiB for Abeta plaques in gray matter has been well described, the nature of PiB binding to white matter remains unclear. In this study, we characterized the binding of PiB to human white matter homogenates.. In vitro binding studies were conducted using 3H-PiB (0.1-500 nM) and white matter brain homogenates (100 microg) from 3 AD patients and 3 HCs. Nonspecific binding was determined using PiB (1 microM). White matter from the same patients was also analyzed by immunofluorescence/immunohistochemistry (IF/IHC) microscopy and Western blotting for Abeta expression. White matter kinetics were also characterized in vivo through 11C-PiB PET studies in 27 HCs and 34 patients with dementia. IF/IHC experiments were conducted on 1 postmortem patient with dementia, to compare with the 11C-PiB distribution volume ratio data acquired 23 mo earlier.. In vitro saturation studies indicated that 3H-PiB binds nonspecifically to white matter brain homogenates. PiB fluorescence staining of AD and HC brain sections was consistent with absence of Abeta in IHC staining. Higher gray matter-to-white matter ratios were observed in IHC images than in 11C-PiB PET images.. These studies suggest that PiB binding to white matter is mainly nonsaturable and nonspecific and that PiB retention in the 11C-PiB PET studies is largely attributable to slower PiB white matter kinetics.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Brain; Carbon Radioisotopes; Case-Control Studies; Female; Humans; Immunohistochemistry; In Vitro Techniques; Lewy Body Disease; Male; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Thiazoles

Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).. To determine whether amyloid deposition, as assessed by PET imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.. Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.. Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.. Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that beta-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Brain; Cognition; Dementia; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Middle Aged; Movement; Neuropsychological Tests; Parkinson Disease; Positron-Emission Tomography; Thiazoles; Tissue Distribution

[(11)C]PIB ((11)C-6-OH benzothiazole) reflects the regional distribution of amyloid (beta-sheeted proteins) in patients with Alzheimer's disease (AD). Proteinaceous inclusions in Parkinson's disease with dementia (PDD), so-called Lewy bodies, also consist of fibrillar, misfolded proteins, chiefly alpha-synuclein. To test whether PDD subjects show specific amyloid binding in vivo and whether this could reflect fibrillar alpha-synuclein accumulation, we investigated 10 PDD subjects with [(11)C]PIB-PET. Radioligand binding was compared to that in 11 control and 6 AD subjects. Furthermore, postmortem sections of 4 patients with Parkinson's disease (PD), therefrom 2 with dementia (PDD), and of 6 controls were stained with PIB to evaluate the histological distribution of the fluorescent ligand in the brainstem. In PET, only 2 PDD patients displayed increased PIB binding to cortical amyloid comparable to AD patients. The other 8 patients showed control-like cortical findings but elevated PIB binding in the pons and mesencephalon. Fluorescence microscopy showed PIB binding to Lewy bodies and neuromelanin in the substantia nigra of PD and PDD brainstem sections, but not in controls. These data suggest that PIB-PET can be used to further differentiate PDD with respect to cortical amyloid. Furthermore, we provide evidence that--in addition to nonspecific binding--PIB uptake in the brainstem may also reflect PDD related amyloid.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Brain; Dementia; Diagnosis, Differential; Female; Humans; Lewy Body Disease; Male; Melanins; Microscopy, Fluorescence; Middle Aged; Neuropsychological Tests; Parkinson Disease; Protein Structure, Secondary; Radionuclide Imaging; Radiopharmaceuticals; Thiazoles

To determine the correspondence between uptake of Pittsburgh Compound B (PiB) in life and measures of beta-amyloid (Abeta) in postmortem tissue analysis. Patient A 76-year-old man with a clinical diagnosis of dementia with Lewy bodies underwent fluorodeoxyglucose (18)F and PiB positron emission tomographic brain scans. Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. Intervention Autopsy was performed 3 months after the PiB scan.. Autopsy confirmed the clinical diagnosis; in addition, there was severe cerebral amyloid angiopathy and only moderate numbers of parenchymal Abeta plaques. Biochemical measures revealed a positive correlation between Abeta levels and regional PiB binding.. This report confirms that PiB detects Abeta in the living patient and demonstrates that amyloid deposited as cerebral amyloid angiopathy can be the dominant source of signal.

Topics: Aged; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Brain; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Lewy Body Disease; Male; Positron-Emission Tomography; Radiopharmaceuticals; Thiazoles

To compare brain beta-amyloid (Abeta) burden measured with [(11)C]Pittsburgh Compound B (PIB) PET in normal aging, Alzheimer disease (AD), and other dementias.. Thirty-three subjects with dementia (17 AD, 10 dementia with Lewy bodies [DLB], 6 frontotemporal dementia [FTD]), 9 subjects with mild cognitive impairment (MCI), and 27 age-matched healthy control subjects (HCs) were studied. Abeta burden was quantified using PIB distribution volume ratio.. Cortical PIB binding was markedly elevated in every AD subject regardless of disease severity, generally lower and more variable in DLB, and absent in FTD, whereas subjects with MCI presented either an "AD-like" (60%) or normal pattern. Binding was greatest in the precuneus/posterior cingulate, frontal cortex, and caudate nuclei, followed by lateral temporal and parietal cortex. Six HCs (22%) showed cortical uptake despite normal neuropsychological scores. PIB binding did not correlate with dementia severity in AD or DLB but was higher in subjects with an APOE-epsilon4 allele. In DLB, binding correlated inversely with the interval from onset of cognitive impairment to diagnosis.. Pittsburgh Compound B PET findings match histopathologic reports of beta-amyloid (Abeta) distribution in aging and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in the course of neurodegeneration and to determine if Abeta deposition in nondemented subjects is preclinical AD are now feasible. Our findings also suggest that Abeta may influence the development of dementia with Lewy bodies, and therefore strategies to reduce Abeta may benefit this condition.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Apolipoproteins E; Brain Chemistry; Carbon Radioisotopes; Cognition Disorders; Dementia; Female; Gyrus Cinguli; Humans; Lewy Body Disease; Magnetic Resonance Imaging; Male; Middle Aged; Neocortex; Radionuclide Imaging; Radiopharmaceuticals; Thiazoles

Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of alpha-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Abeta plaques are also present in most DLB cases. The contribution of Abeta to the development of DLB is unclear. [11C]-Pittsburgh compound B ([11C]-PIB) is a thioflavin-T derivative that has allowed in vivo Abeta burden to be quantified using positron emission tomography (PET). [11C]-PIB PET studies have shown similar high cortical [11C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to alpha-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human alpha-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [3H]-PIB binds to alpha-synuclein fibrils but with lower affinity than that demonstrated/reported for Abeta(1-42) fibrils. Furthermore, [3H]-PIB was observed to bind to Abeta plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Abeta plaque-free ("pure DLB"). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Abeta plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [11C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [11C]-PIB PET studies is largely attributable to PIB binding to Abeta plaques and not Lewy bodies.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Aniline Compounds; Binding Sites; Cerebral Cortex; Humans; In Vitro Techniques; Lewy Bodies; Lewy Body Disease; Positron-Emission Tomography; Thiazoles