alpha-synuclein and 2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole

Our aim was to assess whether in vivo11C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-β (Aβ) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative 11C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical 11C-PIB binding upon PET is unlikely.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Benzothiazoles; Brain; DNA-Binding Proteins; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Sequestosome-1 Protein; tau Proteins; Thiazoles

Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer's disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Apolipoproteins E; Brain; Cognitive Dysfunction; Cohort Studies; Cross-Sectional Studies; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Peptide Fragments; Positron-Emission Tomography; ROC Curve; Statistics, Nonparametric; tau Proteins; Thiazoles

The purpose of this study was to investigate the relationship between disruption of MRI-measured resting-state functional connectivity (rs-fcMRI) brain networks and CSF levels of potentially pathogenic proteins that reflect brain pathology in Parkinson disease (PD).. PD participants without dementia (n = 43) and age-matched controls (n = 22) had lumbar punctures to measure CSF protein levels, Pittsburgh compound B (PiB)-PET imaging, and rs-fcMRI while off medication. Imaging analyses focused on 5 major resting-state networks as well as the striatum.. Participants with PD had significantly reduced sensorimotor functional connectivity, which correlated with reduced CSF levels of α-synuclein. The PD group also had significantly stronger default mode network functional connectivity that did not correlate with CSF β-amyloid (Aβ)42 or PiB uptake. In contrast, default mode network functional connectivity in the control group did correlate with CSF Aβ42 levels. Functional connectivity was similar between groups in the dorsal attention, control, and salience networks.. These results suggest that abnormal α-synuclein accumulation, but not Aβ, contributes to the disruption of motor-related functional connectivity in PD. Furthermore, correlating CSF protein measures with the strength of resting-state networks provides a direct link between abnormal α-synuclein metabolism and disrupted brain function in PD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amyloid beta-Peptides; Aniline Compounds; Biomarkers; Brain; Brain Mapping; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Motor Activity; Neural Pathways; Parkinson Disease; Peptide Fragments; Positron-Emission Tomography; Radiopharmaceuticals; Rest; Severity of Illness Index; Spinal Puncture; Thiazoles

To investigate the specificity of in vivo amyloid imaging with [(11)C]-Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD).. We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death.. We observed elevated cortical uptake of [(11)C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Abeta plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden.. [(11)C]-Pittsburgh Compound B (PIB) PET is specific for fibrillar Abeta molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Abeta amyloid in the setting of alpha-synucleinopathy makes [(11)C]-PIB PET a valuable tool for prospectively evaluating how the presence of Abeta amyloid influences the clinical course of dementia in patients with Lewy body disorders.

Topics: alpha-Synuclein; Amyloid; Amyloid beta-Peptides; Aniline Compounds; Autopsy; Brain Mapping; Carbon Radioisotopes; Cerebral Cortex; Dementia; Female; Humans; Lewy Bodies; Male; Mental Status Schedule; Neurofibrillary Tangles; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Protein Binding; Severity of Illness Index; tau Proteins; Thiazoles

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

Amyloid containing deposits are a defining neuropathological feature of a wide range of dementias and movement disorders. The positron emission tomography tracer PIB (Pittsburgh Compound-B, 2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole) was developed to target senile plaques, an amyloid containing pathological hallmark of Alzheimer's disease, formed from the amyloid-beta peptide. Despite the fact that PIB was developed from the pan-amyloid staining dye thioflavin T, no detailed characterisation of its interaction with other amyloid structures has been reported. In this study, we demonstrate the presence of a high affinity binding site (K(d) approximately 4 nM) for benzothiazole derivatives, including [3H]-PIB, on alpha-synuclein (AS) filaments generated in vitro, and further characterise this binding site through the use of radioligand displacement assays employing 4-N-methylamino-4'-hydroxystilbene (SB13) (K(i) = 87 nM) and 2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) (K(i) = 210 nM). Despite the presence of a high-affinity binding site on AS filaments, no discernible interaction of [3H]-PIB was detected with amygdala sections from Parkinson's disease cases containing frequent AS-immunoreactive Lewy bodies and related neurities. These findings suggest that the density and/or accessibility of AS binding sites in vivo are significantly less than those associated with amyloid-beta peptide lesions. Lewy bodies pathology is therefore unlikely to contribute significantly to the retention of PIB in positron emission tomography imaging studies.

Topics: alpha-Synuclein; Amyloid; Aniline Compounds; Binding Sites; Brain; Humans; Lewy Bodies; 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