The 10‐year Landscape of United States‐Registered Parkinson Disease Clinical Trials: 2007–2016

BackgroundWe know little about how well the goals and results of clinical trials in Parkinson disease (PD) reflect the priorities of patients and the broader PD community.ObjectivesWe conducted a review of registered trials on clincialtrials.gov from 2007 to 2016 to explore whether PD trials have moved closer to the therapeutic priority goals articulated by the PD community.MethodsUsing the search terms: Parkinson, interventional trials, phase “0‐4,” we categorized therapeutic PD studies from clinicaltrials.gov between January 1, 2007 and December 31, 2016. Seven hundred and sixty‐six trials met the criteria for analysis. We explored temporal trends in the utilization of balance problems and falls; mood symptoms, including stress and anxiety; cognitive dysfunction, including dementia; and dyskinesias as primary outcomes. We analyzed trials where recruitment was listed as “completed” (n = 391) to explore publication rates.ResultsBalance problems and falls were listed as primary outcome measures in 125 studies (16.3%), cognitive measures in 48 (6.3%), mood features in 37 (4.8%), and dyskinesias in 30 (3.9%). Trials using balance problems and falls as a primary outcome increased in frequency per year between 2007 and 2016 (Z = ‐2.128, p = 0.033) unlike the proportion of trials evaluating cognitive dysfunction including dementia (Z = ‐0.380, p = 0.704), mood symptoms including stress and anxiety (Z = 0.345, p = 0.730), or dyskinesias (Z = 0.340, p = 0.734), which did not show temporal changes. 231 (59.1%) completed trials had results published in manuscript form as of 5/1/2017, leaving 40.9% of trials unpublished.ConclusionsPD trials focusing on balance problems and falls are becoming more common. About 40% of completed PD trials are unpublished, reflecting suboptimal utilization of participant efforts.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146271/1/mdc312665_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146271/2/mdc312665.pd

Case Report Motor Speech Apraxia in a 70-Year-Old Man with Left Dorsolateral Frontal Arachnoid Cyst: A [ 18 F]FDG PET-CT Study

Motor speech apraxia is a speech disorder of impaired syllable sequencing which, when seen with advancing age, is suggestive of a neurodegenerative process affecting cortical structures in the left frontal lobe. Arachnoid cysts can be associated with neurologic symptoms due to compression of underlying brain structures though indications for surgical intervention are unclear. We present the case of a 70-year-old man who presented with a two-year history of speech changes along with decreased initiation and talkativeness, shorter utterances, and dysnomia. [ 18 F]Fluorodeoxyglucose (FDG) Positron Emission and Computed Tomography (PET-CT) and magnetic resonance imaging (MRI) showed very focal left frontal cortical hypometabolism immediately adjacent to an arachnoid cyst but no specific evidence of a neurodegenerative process

Color discrimination errors associate with axial motor impairments in Parkinson’s Disease

BackgroundVisual function deficits are more common in imbalance‐predominant compared to tremor‐predominant PD, suggesting a pathophysiological role of impaired visual functions in axial motor impairments.ObjectiveTo investigate the relationship between changes in color discrimination and motor impairments in PD while accounting for cognitive or other confounder factors.MethodsPD subjects (n = 49, age 66.7 ± 8.3 years; Hoehn & Yahr stage 2.6 ± 0.6) completed color discrimination assessment using the Farnsworth‐Munsell 100 Hue Color Vision Test, neuropsychological, motor assessments, and [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 PET imaging. MDS‐UPDRS sub‐scores for cardinal motor features were computed. Timed Up & Go mobility and walking tests were assessed in 48 subjects.ResultsBivariate correlation coefficients between color discrimination and motor variables were significant only for the Timed Up & Go test (RS = 0.44, P = 0.0018) and the MDS‐UPDRS axial motor scores (RS = 0.38, P = 0.0068). Multiple regression confounder analysis using the Timed Up & Go as outcome parameter showed a significant total model (F(5,43) = 7.3, P < 0.0001) with significant regressor effects for color discrimination (standardized β = 0.32, t = 2.6, P = 0.012), global cognitive Z‐score (β = −0.33, t = −2.5, P = 0.018), duration of disease (β = 0.26, t = 1.8, P = 0.038), but not for age or striatal dopaminergic binding. The color discrimination test was also a significant independent regressor in the MDS‐UPDRS axial motor model (standardized β = 0.29, t = 2.4, P = 0.022; total model t(5,43) = 6.4, P = 0.0002).ConclusionsColor discrimination errors associate with axial motor features in PD independent of cognitive deficits, nigrostriatal dopaminergic denervation, and other confounder variables. These findings may reflect shared pathophysiology between color discrimination visual impairments and axial motor burden in PD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141397/1/mdc312527.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141397/2/mdc312527_am.pd

Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB)

Extra‐nigral pathological conditions are common in Parkinson's disease with freezing of gait: An in vivo positron emission tomography study

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 SocietyPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108363/1/mds25929.pd

Motor Speech Apraxia in a 70-Year-Old Man with Left Dorsolateral Frontal Arachnoid Cyst: A [18F]FDG PET-CT Study

Motor speech apraxia is a speech disorder of impaired syllable sequencing which, when seen with advancing age, is suggestive of a neurodegenerative process affecting cortical structures in the left frontal lobe. Arachnoid cysts can be associated with neurologic symptoms due to compression of underlying brain structures though indications for surgical intervention are unclear. We present the case of a 70-year-old man who presented with a two-year history of speech changes along with decreased initiation and talkativeness, shorter utterances, and dysnomia. [18F]Fluorodeoxyglucose (FDG) Positron Emission and Computed Tomography (PET-CT) and magnetic resonance imaging (MRI) showed very focal left frontal cortical hypometabolism immediately adjacent to an arachnoid cyst but no specific evidence of a neurodegenerative process

Regional serotonin terminal density in aging human brain: A [11C]DASB PET study

There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan. In this cross-sectional study, we used [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile positron emission tomography to quantify brain regional serotonin transporter density in 46 normal subjects, ranging from 25 to 84 years of age. Both voxel-based analyses, using sex as a covariate, and volume-of-interest-based analyses were performed. Both analyses revealed age-related declines in [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile binding in numerous brain regions, including several neocortical regions, striatum, amygdala, thalamus, dorsal raphe, and other subcortical regions. Similar to some other neurotransmitter systems of subcortical origin, we found evidence of age-related declines in regional serotonin terminal density in both cortical and subcortical regions

Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson’s Disease

BackgroundBoth Parkinson’s disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized.ObjectivesTo use serotonin transporter [11C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD.MethodsWe performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest.ResultsPatients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA–parkinsonian subtype (n = 8) and patients with MSA–cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson’s Disease Rating Scale motor score in patients with MSA but not patients with PD.ConclusionsBrainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175232/1/mds29220.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175232/2/mds29220_am.pd

[18F]FDOPA PET and clinical features in parkinsonism due to manganism

Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinson\u27s disease (PD). We describe the clinical features and results of positron emission tomography with 6-[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1-weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese-associated parkinsonism may overlap with that of PD