2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and dihydrotetrabenazine

Although most previous cognitive studies of β-amyloidopathy in PD focused on cortical plaque deposition, recent postmortem studies point to an important role of striatal β-amyloid plaque deposition. The aim of this study was to investigate the relative contributions of striatal and cortical β-amyloidopathy to cognitive impairment in PD.. Patients with PD (n = 62; age, 68.9 ± 6.4 years; H & Y stage: 2.7 ± 0.5; MoCA score: 25.2 ± 3.0) underwent [(11) C]Pittsburgh compound B β-amyloid, [(11) C]dihydrotetrabenazine monoaminergic, and [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase brain PET imaging and neuropsychological assessment. [(11) C]Pittsburgh compound B β-amyloid data from young to middle-aged healthy subjects were used to define elevated [(11) C]Pittsburgh compound B binding in patients.. Elevated cortical and striatal β-amyloid deposition were present in 37% and 16%, respectively, of this predominantly nondemented cohort of patients with PD. Increased striatal β-amyloid deposition occurred in half of all subjects with increased cortical β-amyloid deposition. In contrast, increased striatal β-amyloid deposition did not occur in the absence of increased cortical β-amyloid deposition. Analysis of covariance using global composite cognitive z scores as the outcome parameter showed significant regressor effects for combined striatal and cortical β-amyloidopathy (F = 4.18; P = 0.02) after adjusting for covariate effects of cortical cholinergic activity (F = 5.67; P = 0.02), caudate nucleus monoaminergic binding, duration of disease, and age (total model: F = 3.55; P = 0.0048). Post-hoc analysis showed significantly lower cognitive z score for combined striatal and cortical β-amyloidopathy, compared to cortical-only β-amyloidopathy and non-β-amyloidopathy subgroups.. The combined presence of striatal and cortical β-amyloidopathy is associated with greater cognitive impairment than cortical β-amyloidopathy alone in PD.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Analysis of Variance; Aniline Compounds; Carbon Isotopes; Cerebral Cortex; Cognition Disorders; Corpus Striatum; Cross-Sectional Studies; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Tetrabenazine; Thiazoles

Cholinergic denervation has been associated with falls and slower gait speed and β-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11) C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic "off" state. A subset of subjects (n = 61) underwent [(11) C]Pittsburgh compound-B β-amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal β-amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non-freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ(2)  = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ(2)  = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra-nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathological conditions studied. Extra-nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society.

Topics: Acetylcholinesterase; Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Benzothiazoles; Carbon Isotopes; Cross-Sectional Studies; Female; Freezing Reaction, Cataleptic; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Substantia Nigra; Tetrabenazine; Thiazoles; Vesicular Monoamine Transport Proteins

We evaluated PET-based classification of neurodegenerative pathology in mild cognitive impairment (MCI).. Our study was a cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based cognitive disorders clinic. We compared expert clinical consensus classification of MCI at entry and possible dementia at follow-up with molecular imaging-based classification using (11)C-dihydotetrabenazine PET measurement of striatal dopamine terminal integrity and (11)C-Pittsburgh compound B ((11)C-PiB) PET measurement of cerebral amyloid burden.. Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At a mean follow-up of 3 y, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition or nigrostriatal denervation was a strong predictor of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes.. Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful for identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.

Topics: Aged; Amyloid; Aniline Compounds; Benzothiazoles; Cognitive Dysfunction; Cohort Studies; Dopamine; Female; Follow-Up Studies; Humans; Male; Positron-Emission Tomography; Prognosis; Tetrabenazine; Thiazoles

Although motor impairments in Parkinson's disease (PD) are attributed to nigrostriatal dopaminergic denervation, postural instability and gait difficulty (PIGD) features are less responsive to dopaminergic medications. PIGD features are a risk factor also for the development of dementia in PD (PDD). These observations suggest that nondopaminergic mechanisms may contribute to axial motor impairments. The aim was to perform a correlative PET study to examine the relationship between neocortical β-amyloid deposition ([(11)C]-Pittsburgh Compound B), nigrostriatal dopaminergic denervation ([(11)C]-dihydrotetrabenazine), and PIGD feature severity in PD patients at risk for dementia. This was a cross-sectional study of 44 PD patients (11 female and 33 male; 69.5 ± 6.6 years of age; 7.0 ± 4.8 years motor disease duration; mean H & Y stage: 2.7 ± 0.5) who underwent PET, motor feature severity assessment using the Movement Disorder Society revised UPDRS, and the Dementia Rating Scale (DRS). Linear regression (R(2)(adj) = 0.147; F(4,39) = 2.85; P = 0.036) showed that increased PIGD feature severity was associated with increased neocortical [(11)C]-Pittsburgh Compound B binding (β = 0.346; t(39) = 2.13; P = 0.039) while controlling for striatal [(11)C]-dihydrotetrabenazine binding, age, and DRS total score. Increased neocortical β-amyloid deposition, even at low-range levels, is associated with higher PIGD feature severity in PD patients at risk for dementia. This finding may explain why the PIGD motor phenotype is a risk factor for the development of PDD.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Aniline Compounds; Carbon Isotopes; Cross-Sectional Studies; Dementia; Female; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Postural Balance; Psychiatric Status Rating Scales; Sensation Disorders; Severity of Illness Index; Tetrabenazine; Thiazoles

We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score≥18) underwent a conventional clinical evaluation followed by 11C-dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer's disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer's disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer's disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen's κ=0.39). Discordant classifications were least frequent in clinical consensus Alzheimer's disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia.

Topics: Amyloid; Analysis of Variance; Aniline Compounds; Benzothiazoles; Brain Mapping; Carbon Isotopes; Dementia; Dopamine; Humans; Neurologic Examination; Positron-Emission Tomography; Psychiatric Status Rating Scales; Tetrabenazine; Thiazoles