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Visual and visual processing deficits are implicated in freezing, falling, and cognitive impairments in Parkinson's disease (PD). In particular, contrast sensitivity deficits are common and may be related to cognitive impairment in PD. While dopaminergic deficits play a role in PD-related visual dysfunction, brain cholinergic systems also modulate many aspects of visual processing. The aim of this study was to explore regional cerebral cholinergic terminal density correlates of contrast sensitivity in PD. Ninety-one PD subjects underwent contrast sensitivity testing, motor testing, cognitive testing, and brain MRI and [ 18 F]-fluoroethoxybenzovesamicol [ 18 F]-FEOBV PET imaging. Whole brain false discovery error-corrected (p < 0.05) correlations revealed significant associations between VAChT deficits in pericentral, limbic, and visual processing regions and contrast sensitivity performance, independent of disease duration and dopaminergic medication doses. These results suggest that brain cholinergic deficits correlate with contrast sensitivity deficits in PD. Additionally, decreased Rabin contrast sensitivity scores were associated with lower total scores in the Parkinson's Disease Cognitive Rating Scale. These findings suggest that diminished cognitive performance correlated with contrast sensitivity partly reflects underlying vulnerabilities of brain cholinergic systems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prabesh Kanel reports financial support was provided by National Institutes of Health. Nicolaas Bohnen reports a relationship with National Institutes of Health that includes: funding grants. Roger Albin reports a relationship with Parkinson's Disease Foundation that includes: funding grants. No other relationships to declare If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Preliminary data suggest that gait abnormalities in Parkinson disease (PD) may be associated with sympathetic cardiac denervation. No kinematic gait studies were performed to confirm this observation. We aimed to correlate spatiotemporal kinematic gait parameters with cardiac sympathetic denervation as determined by cardiac [ 11 C]HED PET in PD., Methods: Retrospective database analysis of 27 PD patients with cardiac sympathetic denervation. All patients underwent spatiotemporal kinematic gait assessment (medication 'off' state), cardiac [ 11 C]HED and dopaminergic brain [ 11 C]DTBZ PET scans. We employed a hierarchical regression approach to examine associations between the extent of cardiac denervation, dopaminergic nigrostriatal neurodegeneration, and three gait parameters - velocity, step length and cadence., Results: More extensive cardiac denervation was associated with slower velocity (estimate: -1.034, 95% CI [-1.65, -0.42], p = 0.002), shorter step length (estimate: -0.818, 95% CI [-1.43, -0.21], p = 0.011) and lower cadence (estimate: -0.752, 95% CI [-1.28, -0.23], p = 0.007) explaining alone 30% (Adjusted-R²: 0.297), 20% (Adjusted-R²: 0.202) and 23% (Adjusted-R²: 0.227) of the variability, respecivetly. These associations remained independent of striatal dopaminergic impairment and confounding factors such as age, Hoehn and Yahr (HY) stages, peripheral neuropathy, cognition, and autonomic symptoms. In contrast, striatal dopaminergic denervation was significantly associated with step length (estimate: 0.883, 95% CI [0.29, 1.48], p = 0.005), explaining about 24% of the variability but was dependent of HY stage., Conclusions: More severe cardiac noradrenergic denervation was associated with lower gait velocity, independent of striatal dopaminergic denervation and HY stage, impacting both step length and cadence. These results suggest independent contributions of the peripheral autonomic system degeneration on gait dynsfunction in PD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Postural instability and gait disturbances (PIGD) represent a significant cause of disability in Parkinson's disease (PD). Cholinergic system dysfunction has been implicated in falls in PD. The occurrence of falls typically results in fear of falling (FoF) that in turn may lead to poorer balance self-efficacy. Balance self-efficacy refers to one's level of confidence in their ability to balance while completing activities of daily living like getting dressed, bathing, and walking. Lower self-efficacy, or greater FoF during these activities is a function of motor, cognitive, and emotional impairments and may impact quality of life in PD. Unlike known cholinergic reduction, especially in the right lateral geniculate and caudate nuclei, little is known about the role of cholinergic transporters in FoF or mobility self-efficacy in PD., Methods: [ 18 F]fluoroethoxybenzovesamicol ([ 18 F]FEOBV) positron emission tomography (PET) studies were conducted to assess vesicular acetylcholine transporter (VAChT) expression in 126 patients with PD (male (m) = 95, female (f) = 31). Participants had a mean age of 67.3 years (standard deviation (SD) = 7.1) and median Hoehn Yahr stage of 2.5. Patients also completed the Short Falls Efficacy Scale (sFES-I) as a survey measure of concerns about falling. [ 18 F]FEOBV data were processed in Statistical Parametric Mapping (SPM) using a voxel-wise regression model with sFES-I scores as the outcome measure., Results: Reduced [ 18 F]FEOBV binding in tectum, metathalamic (lateral more than medial geniculate nuclei), thalamus proper, bilateral mesiotemporal (hippocampal, parahippocampal, fusiform gyri and fimbriae), and right cerebellar lobule VI significantly associated with higher sFES-I scores ( p < 0.05, family-wise error (FWE) correction after Threshold-Free Cluster Enhancement (TFCE))., Conclusions: Unlike the more limited involvement of the brainstem-thalamic complex and caudate nuclei cholinergic topography associated with falls in PD, cholinergic reductions in the extended connectivity between the thalamic complex and the temporal limbic system via the fimbriae associates with FoF. Additional cholinergic changes were seen in the cerebellum. The temporal limbic system plays a role not only in episodic memory but also in spatial navigation, scene and contextual ( e.g. , emotional) processing. Findings may augur novel therapeutic approaches to treat poor mobility self-efficacy in PD., Clinical Trial Registration: No: NCT02458430. Registered 18 March, 2015, https://www., Clinicaltrials: gov/study/NCT02458430; No: NCT05459753. Registered 01 July, 2022, https://www., Clinicaltrials: gov/study/NCT05459753., (© 2024 The Author(s). Published by IMR Press.)

We review the epidemiologic literature on potential protective and risk factors in Parkinson's Disease (PD). Prior research identified numerous possible protective and risk factors. Potential protective factors include tobacco abuse, physical activity, urate levels, NSAID use, calcium channel blocker use, statin use, and use of some α1-adrenergic antagonists. Some potential protective factors could be products of reverse causation, including increased serum urate, tobacco abuse, and coffee-tea-caffeine consumption. Potential risk factors include traumatic brain injury, pesticide exposure, organic solvent exposure, lead exposure, air pollution, Type 2 Diabetes, some dairy products, cardiovascular disease, and some infections including Hepatitis C, H. pylori, and COVID-19. Potential non-environmental risk factors include bipolar disorder, essential tremor, bullous pemphigoid, and inflammatory bowel disease. There is an inverse relationship with PD and risk of most cancers. Though many potential protective and risk factors for PD were identified, research has not yet led to unique, rigorous prevention trials or successful disease-modifying interventions. While efforts to reduce exposure to some industrial toxicants are well justified, PD incidence might be most effectively reduced by mitigation of risks, such as Type 2 Diabetes, air pollution, traumatic brain injury, or physical inactivity, that are general public health intervention targets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roger Albin reports financial support was provided by National Institute of Neurological Disorders and Stroke. Roger Albin reports financial support was provided by Parkinson's Foundation. Roger Albin reports a relationship with Ionis Pharmaceuticals Inc that includes: consulting or advisory. Roger Albin reports a relationship with IQVIA that includes: consulting or advisory. Roger Albin reports a relationship with Biogen Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Anxiety in Parkinson disease (PD) negatively impacts quality of life. While research predominantly focuses on central nervous system changes, some evidence suggests a connection between peripheral autonomic dysfunctions and PD-related anxiety. The role of the peripheral autonomic nervous system in this context may be overlooked., Objectives: This study explores the link between anxiety symptoms and cardiac sympathetic denervation in PD using 11 C-meta-hydroxyephedrine ([ 11 C]HED) PET cardiac imaging., Methods: We studied 34 non-demented PD subjects, assessing anxiety levels through the Spielberg Anxiety State-Trait test trait section (STAI-T). Patients underwent comprehensive assessments along with [ 11 C]HED cardiac and [ 11 C]DTBZ brain PET. To identify subdimensions of STAI-T, we employed principal components analysis (PCA). We examined associations between the anxiety subdimensions and two measures of cardiac sympathetic denervation from [ 11 C]HED PET. We utilized correlation and linear regression models for these analyses., Results: PCA revealed two STAI-T results components: anxiety-depressive and pure anxiety subcomponents. Only pure anxiety significantly correlated with measures of cardiac sympathetic denervation (rhos -0.40, p = 0.018; 0.35, p = 0.043). Regression models confirmed a significant association, with cardiac sympathetic denervation explaining ∼20 % of pure anxiety variance, independent of sex, dopaminergic impairment, and anxiolytic treatments., Discussion: This study provides preliminary evidence of peripheral autonomic nervous system abnormalities contributing to PD-related anxiety, suggesting dysregulation in peripheral autonomic functions influencing anxiety perception., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

We review the descriptive epidemiology of Parkinson disease (PD). PD is a prevalent neurologic disorder in high Socio-Demographic Index (SDI) nations with rising prevalence in low and middle SDI nations. PD became a prevalent disorder in high SDI nations during the 20th century. Population growth, population aging, and increased disease duration are major drivers of rising PD prevalence. Exposure to industrial toxicants may also be a contributor to rising PD prevalence. PD is an age-related disorder with incidence likely peaking in the 8th decade of life and prevalence in the 9th decade of life. PD is notable for significant sex difference in PD risk with greater risk in men. There may be ancestral differences in PD prevalence and risk. PD is associated with moderately increased mortality though this may be underestimated. Despite significant research, there is considerable uncertainty about basic features of PD epidemiology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roger Albin reports financial support was provided by National Institute of Neurological Disorders and Stroke. Roger Albin reports financial support was provided by Parkinson's Foundation. Roger Albin reports a relationship with Ionis Pharmaceuticals Inc that includes: consulting or advisory. Roger Albin reports a relationship with IQVIA that includes: consulting or advisory. Roger Albin reports a relationship with Biogen Inc that includes: consulting or advisory. Mr. Grotewold has no potential competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease [Bayes factor against the null model (BF10) = 8.2] and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Decreased cholinergic binding within the recently identified centro-cingulate brain network robustly has been shown to robustly correlate with the severity of cognitive impairment in Parkinson disease (PD). This network with key hubs within the cingulum, operculum and peri-central cortical regions also correlates with elements of parkinsonian motor impairments, including postural instability and gait difficulties, such as falls or freezing. MRI neuroimaging studies have shown that the anterior midcingulate cortex is a key node for cognitive aspects of movement generation, i.e., intentional motor control. Recent evidence also suggests a novel aspect of organization of primary motor cortex, describing "effector" regions for fine movement control intercalated with interlinked "inter-effector" regions devoted to whole-body control. A distinguishing feature of inter-effector regions is tight linkage to the cingular and opercular regions. Such inter-effector regions have been proposed to be part of a greater somato-cognitive action network necessary for integration of goals and movement. Recent evidence also points to vulnerabilities of cholinergic nerve terminals in the centro-cingulate network in older non-PD adults. These features of normal aging underscore that cortical cholinergic terminal losses in age-associated neurodegenerative disorders are likely not exclusively the result of disease-specific etiologies but also related to otherwise normal aging. Practical implications of this overlap are that addressing disease-specific and general aging etiologies involved in neurodegeneration, may be of benefit in age-associated neurodegenerative disorders where significant cholinergic systems degeneration is present.

Postural instability and freezing of gait are the most debilitating dopamine-refractory motor impairments in advanced stages of Parkinson's disease because of increased risk of falls and poorer quality of life. Recent findings suggest an inability to efficaciously utilize vestibular information during static posturography among people with Parkinson's disease who exhibit freezing of gait, with associated changes in cholinergic system integrity as assessed by vesicular acetylcholine transporter PET. There is a lack of adequate understanding of how postural control varies as a function of available sensory information in patients with Parkinson's disease with freezing of gait. The goal of this cross-sectional study was to examine cerebral cholinergic system changes that associate with inter-sensory postural control processing features as assessed by dynamic computerized posturography and acetylcholinesterase PET. Seventy-five participants with Parkinson's disease, 16 of whom exhibited freezing of gait, underwent computerized posturography on the NeuroCom© Equitest sensory organization test platform, striatal dopamine, and acetylcholinesterase PET scanning. Findings demonstrated that patients with Parkinson's disease with freezing of gait have greater difficulty maintaining balance in the absence of reliable proprioceptive cues as compared to those without freezing of gait [β = 0.28 (0.021, 0.54), P = 0.034], an effect that was independent of disease severity [β = 0.16 (0.062, 0.26), P < 0.01] and age [β = 0.092 (-0.005, 0.19), P = 0.062]. Exploratory voxel-based analysis revealed an association between postural control and right hemispheric cholinergic network related to visual-vestibular integration and self-motion perception. High anti-cholinergic burden predicted postural control impairment in a manner dependent on right hemispheric cortical cholinergic integrity [β = 0.34 (0.065, 0.61), P < 0.01]. Our findings advance the perspective that cortical cholinergic system might play a role in supporting postural control after nigro-striatal dopaminergic losses in Parkinson's disease. Failure of cortex-dependent visual-vestibular integration may impair detection of postural instability in absence of reliable proprioceptive cues. Better understanding of how the cholinergic system plays a role in this process may augur novel treatments and therapeutic interventions to ameliorate debilitating symptoms in patients with advanced Parkinson's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Structural imaging of the cholinergic basal forebrain may provide a biomarker for cholinergic system integrity that can be used in motor and non-motor outcome studies in Parkinson's disease. However, no prior studies have validated these structural metrics with cholinergic nerve terminal in vivo imaging in Parkinson's disease. Here, we correlate cholinergic basal forebrain morphometry with the topography of vesicular acetylcholine transporter in a large Parkinson's sample., Methods: [ 18 F]-Fluoroethoxybenzovesamicol vesicular acetylcholine transporter positron emission tomography was carried out in 101 non-demented people with Parkinson's (76.24% male, mean age 67.6 ± 7.72 years, disease duration 5.7 ± 4.4 years). Subregional cholinergic basal forebrain volumes were measured using magnetic resonance imaging morphometry. Relationships were assessed via volume-of-interest based correlation analysis., Results: Subregional volumes of the cholinergic basal forebrain predicted cholinergic nerve terminal loss, with most robust correlations occurring between the posterior cholinergic basal forebrain and temporofrontal, insula, cingulum, and hippocampal regions, and with modest correlations in parieto-occipital regions. Hippocampal correlations were not limited to the cholinergic basal forebrain subregion Ch1-2. Correlations were also observed in the striatum, thalamus, and brainstem., Interpretation: Cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain. The relative lack of correlation between parieto-occipital binding and basal forebrain volumes may reflect the presence of more diffuse synaptopathy in the posterior cortex due to etiologies that extend well beyond the cholinergic system. ANN NEUROL 2023;93:991-998., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Protein misfolding and aggregation into oligomeric and fibrillar structures is a common feature of many neurogenerative disorders. Single-molecule techniques have enabled characterization of these lowly abundant, highly heterogeneous protein aggregates, previously inaccessible using ensemble averaging techniques. However, they usually rely on the use of recombinantly-expressed labeled protein, or on the addition of amyloid stains that are not protein-specific. To circumvent these challenges, we have made use of a high affinity antibody labeled with orthogonal fluorophores combined with fast-flow microfluidics and single-molecule confocal microscopy to specifically detect α-synuclein, the protein associated with Parkinson's disease. We used this approach to determine the number and size of α-synuclein aggregates down to picomolar concentrations in biologically relevant samples., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Postural instability and gait difficulties (PIGD) are a significant cause of disability and loss of quality of life (QoL) in Parkinson's Disease. Most research on clinical predictors of PIGD measures have focused on individual clinical often motor performance variables, However, PIGD motor features often result in fear of falling (FoF) lowering a patient's mobility self-efficacy. The purpose of this study was to assess composite measures of motor and self-efficacy determinants PIGD motor features in PD and compare these to analysis of individual clinical metrics., Methods: 75 PD participants underwent detailed motor and non-motor test batteries. Principal component analysis (PCA) was used to identify clusters of covarying correlates of slow walking, imbalance, falls, freezing of gait, FoG and compare these to traditional univariate analyses., Results: A single PCA-derived composite measure of motor performance and self-efficacy of mobility was the most robust determinant of all PIGD motor features except for falls. In contrast, analysis of the individual clinical variables showed more limited and diverging findings, including evidence of better cognitive performance but more severe motor parkinsonian ratings in the fall group., Conclusion: There are robust associations between composite measures of motor performance and self-efficacy of mobility and all PIGD motor features except for falls. Univariate analysis of individual clinical measures showed limited correlates of PIGD motor features. Patient's own perception of motor performance, FoF, and QoL deserve more attention as PIGD therapeutic targets in PD., Competing Interests: Declaration of competing interest The authors have no relevant financial or conflict of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [ 18 F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [ 18 F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ 2  = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The vestibular system has been implicated in the pathophysiology of episodic motor impairments in Parkinson's disease (PD), but specific evidence remains lacking., Objective: We investigated the relationship between the presence of freezing of gait and falls and postural failure during the performance on Romberg test condition 4 in patients with PD., Methods: Modified Romberg sensory conflict test, fall, and freezing-of-gait assessments were performed in 92 patients with PD (70 males/22 females; mean age, 67.6 ± 7.4 years; Hoehn and Yahr stage, 2.4 ± 0.6; mean Montreal Cognitive Assessment, 26.4 ± 2.8)., Results: Failure during Romberg condition 4 was present in 33 patients (35.9%). Patients who failed the Romberg condition 4 were older and had more severe motor and cognitive impairments than those without. About 84.6% of all patients with freezing of gait had failure during Romberg condition 4, whereas 13.4% of patients with freezing of gait had normal performance (χ 2  = 15.6; P < 0.0001). Multiple logistic regression analysis showed that the regressor effect of Romberg condition 4 test failure for the presence of freezing of gait (Wald χ 2  = 5.0; P = 0.026) remained significant after accounting for the degree of severity of parkinsonian motor ratings (Wald χ 2  = 6.2; P = 0.013), age (Wald χ 2  = 0.3; P = 0.59), and cognition (Wald χ 2  = 0.3; P = 0.75; total model: Wald χ 2  = 16.1; P < 0.0001). Patients with PD who failed the Romberg condition 4 (45.5%) did not have a statistically significant difference in frequency of patients with falls compared with patients with PD without abnormal performance (30.5%; χ 2  = 2.1; P = 0.15)., Conclusions: The presence of deficient vestibular processing may have specific pathophysiological relevance for freezing of gait, but not falls, in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Purpose: Abnormal balance is poorly responsive to dopaminergic therapy in Parkinson's disease (PD). Decreased vestibular efficacy may contribute to imbalance in PD. The purpose of this study was to investigate the relationship between vestibular measures of dynamic posturography and imbalance in PD while accounting for confounder variables., Methods: 106 patients with PD underwent dynamic posturography for the 6 conditions of the sensory integration test (SOT) using the Neurocom Equitest device. All SOT measures, nigrostriatal dopaminergic denervation ((+)-[ 11 C]DTBZ PET), brain acetylcholinesterase ([ 11 C]PMP PET), age, duration of disease, cognitive and parkinsonian motor scores, and ankle vibration sensitivity were used as regressors in a stepwise logistic regression model comparing PD patients with versus without imbalance defined as Hoehn and Yahr (HY) stage 2.5 or higher., Results: The presence of imbalance was significantly associated with vestibular ratio COP RMS (P = 0.002) independently from visual ratio COP velocity (P = 0.012), thalamic acetylcholinesterase activity (P = 0.0032), cognition (P = 0.006), motor severity (P = 0.0039), age (P = 0.001), ankle vibration sensitivity (P = 0.0008), and borderline findings for somatosensory ratio COP velocity (P = 0.074) and visual ratio COP RMS (P = 0.078). Nigrostriatal dopaminergic denervation did not achieve significance., Conclusions: The inability to efficaciously utilize vestibular information to retain upright stance is a determinant of imbalance in PD independent from visual and somatosensory processing changes and nigrostriatal dopaminergic losses. Thalamic, but not cortical, cholinergic denervation incrementally predicted balance abnormality. Further research is needed to investigate an intrinsic role of the cholinergic thalamus in multi-sensory, in particular vestibular, processing functions of postural control in PD., (Published by Elsevier B.V.)

Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity., (© 2022. The Author(s).)

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [ 18 F]fluoroethoxybenzovesamicol ([ 18 F]-FEOBV) PET binding in Parkinson' disease (PD) patients with and without vestibular sensory conflict deficits (VSCD). To examine associations between VSCD-associated cholinergic brain deficits and postural instability and gait difficulties (PIGD). PD persons (M70/F22; mean age 67.6 ± 7.4 years) completed clinical assessments for imbalance, falls, freezing of gait (FoG), modified Romberg sensory conflict testing, and underwent VAChT PET. Volumes of interest (VOI)-based analyses included detailed thalamic and cerebellar parcellations. VSCD-associated VAChT VOI selection used stepwise logistic regression analysis. Vesicular monoamine transporter type 2 (VMAT2) [ 11 C]dihydrotetrabenazine (DTBZ) PET imaging was available in 54 patients. Analyses of covariance were performed to compare VSCD-associated cholinergic deficits between patients with and without PIGD motor features while accounting for confounders. PET sampling passed acceptance criteria in 73 patients. This data-driven analysis identified cholinergic deficits in five brain VOIs associating with the presence of VSCD: medial geniculate nucleus (MGN) (P < 0.0001), para-hippocampal gyrus (P = 0.0043), inferior nucleus of the pulvinar (P = 0.047), fusiform gyrus (P = 0.035) and the amygdala (P = 0.019). Composite VSCD-associated [ 18 F]FEOBV-binding deficits in these 5 regions were significantly lower in patients with imbalance (- 8.3%, F = 6.5, P = 0.015; total model: F = 5.1, P = 0.0008), falls (- 6.9%, F = 4.9, P = 0.03; total model F = 4.7, P = 0.0015), and FoG (- 14.2%, F = 9.0, P = 0.0043; total model F = 5.8, P = 0.0003), independent of age, duration of disease, gender and nigrostriatal dopaminergic losses. Post hoc analysis using MGN VAChT binding as the single cholinergic VOI demonstrated similar significant associations with imbalance, falls and FoG. VSCD-associated cholinergic network changes localize to distinct structures involved in multi-sensory, in particular vestibular, and multimodal cognitive and motor integration brain regions. Relative clinical effects of VSCD-associated cholinergic network deficits were largest for FoG followed by postural imbalance and falls. The MGN was the most significant region identified., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention., Objective: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment., Methods: Fifty-seven newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [ 18 F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD-NC) or mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed., Results: Results show bidirectional cholinergic innervation changes in PD. Both PD-NC and PD-MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher-than-normal binding was most prominent in PD-NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala., Conclusion: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early-stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Previous studies of animal models of Parkinson disease (PD) suggest an imbalance between striatal acetylcholine and dopamine, although other studies have questioned this. To our knowledge, there are no previous in vivo neuroimaging studies examining striatal acetylcholine-dopamine imbalance in PD patients. Using cholinergic and dopaminergic PET ( 18 F-fluoroethoxybenzovesamicol [ 18 F-FEOBV] and 11 C-dihydrotetrabenazine [ 11 C-DTBZ], respectively) and correlational tractography, our aim was to investigate the acetylcholine-dopamine interaction at 2 levels of dopaminergic loss in PD subjects: integrity loss of the nigrostriatal dopaminergic white matter tract and loss at the presynaptic-terminal level. Methods: The study involved 45 subjects with mild to moderate PD (36 men, 9 women; mean age, 66.3 ± 6.3 y, disease duration, 5.8 ± 3.6 y; Hoehn and Yahr stage, 2.2 ± 0.6) and 15 control subjects (9 men, 6 women; mean age, 69.1 ± 8.6 y). PET imaging was performed using standard protocols. We first estimated the integrity of the dopaminergic nigrostriatal white matter tracts in PD subjects by incorporating molecular information from striatal 11 C-DTBZ PET into the fiber tracking process using correlational tractography (based on quantitative anisotropy [QA], a measure of tract integrity). Subsequently, we used voxel-based correlation to test the association of the mean QA of the nigrostriatal tract of each cerebral hemisphere with the striatal 18 F-FEOBV distribution volume ratio (DVR) in PD subjects. The same analysis was performed for 11 C-DTBZ DVR in 12 striatal subregions (presynaptic-terminal level). Results: Unlike 11 C-DTBZ DVR in striatal subregions, the mean QA of the nigrostriatal tract of the most affected hemisphere showed a negative correlation with a striatal cluster of 18 F-FEOBV DVR in PD subjects (corrected P = 0.039). We also found that the mean 18 F-FEOBV DVR within this cluster was higher in the PD group than in the control group ( P = 0.01). Cross-validation analyses confirmed these findings. We also found an increase in bradykinesia ratings associated with increased acetylcholine-dopamine imbalance in the most affected hemisphere ( r = 0.41, P = 0.006). Conclusion: Our results provide evidence for the existence of striatal acetylcholine-dopamine imbalance in early PD and may provide an avenue for testing in vivo effects of therapeutic strategies aimed at restoring striatal acetylcholine-dopamine balance in PD., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus., Methods: The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants' history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation., Results: Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ 2  = 7.1, p = 0.008, df = 1) and depression (χ 2  = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5-6.4, χ 2  = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3-5.0, χ 2  = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra., Conclusion: These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4β2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4β2* nAChR partial agonist varenicline., Methods: Nondemented PD participants with cholinergic deficits were identified with [ 18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4β2* nAChR occupancy after subacute oral varenicline treatment was measured with [ 18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability., Results: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements., Interpretation: Varenicline occupied α4β2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4β2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142., (© 2021 American Neurological Association.)

Previous histopathologic and animal studies have shown axonal impairment and loss of connectivity of the nigrostriatal pathway in Parkinson disease (PD). However, there are conflicting reports from in vivo human studies. 11 C-dihydrotetrabenazine ( 11 C-DTBZ) is a vesicular monoamine type 2 transporter PET ligand that allows assessment of nigrostriatal presynaptic dopaminergic terminal integrity. Correlational tractography based on diffusion MRI can incorporate ligand-specific information provided by 11 C-DTBZ PET into the fiber-tracking process. The purpose of this study was to assess the in vivo association between the integrity of the nigrostriatal tract (defined by correlational tractography) and the degree of striatal dopaminergic denervation based on 11 C-DTBZ PET. Methods: The study involved 30 subjects with mild to moderate PD (23 men and 7 women; mean age, 66 ± 6.2 y; disease duration, 6.4 ± 4.0 y; Hoehn and Yahr stage, 2.1 ± 0.6; Movement Disorder Society [MDS]-revised Unified Parkinson Disease Rating Scale [UPDRS] [I-III] total score, 43.4 ± 17.8) and 30 control subjects (18 men and 12 women; mean age, 62 ± 10.3 y). 11 C-DTBZ PET was performed using standard synthesis and acquisition protocols. Correlational tractography was performed to assess quantitative anisotropy (QA; a measure of tract integrity) of white matter fibers correlating with information derived from striatal 11 C-DTBZ data using the DSI Studio toolbox. Scans were realigned according to least and most clinically affected cerebral hemispheres. Results: Nigrostriatal tracts were identified in both hemispheres of PD patients. Higher mean QA values along the identified tracts were significantly associated with higher striatal 11 C-DTBZ distribution volume ratios (least affected: r = 0.57, P = 0.001; most affected: r = 0.44, P = 0.02). Lower mean QA values of the identified tract in the LA hemisphere associated with increased severity of bradykinesia sub-score derived from MDS-UPDRS part III ( r = -0.42; P = 0.02). Cross-validation revealed the generalizability of these results. Conclusion: These findings suggest that impaired integrity of dopaminergic nigrostriatal nerve terminals is associated with nigrostriatal axonal dysfunction in mild to moderate PD. Assessment of nigrostriatal tract integrity may be suitable as a biomarker of early- or even prodromal-stage PD., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: The cholinergic system plays a key role in cognitive impairment in Parkinson's disease (PD). Previous acetylcholinesterase positron emission tomography imaging studies found memory, attention, and executive function correlates of global cortical cholinergic losses. Vesicular acetylcholine transporter positron emission tomography allows for more accurate topographic assessment of not only cortical but also subcortical cholinergic changes., Objective: The objectiveof this study was to investigate the topographic relationship between cognitive functioning and regional cholinergic innervation in patients with PD., Methods: A total of 86 nondemented patients with PD (mean ± SD age 67.8 ± 7.6 years, motor disease duration 5.8 ± 4.6 years), and 12 healthy control participants (age 67.8 ± 7.8 years) underwent cholinergic [ 18 F]Fluoroethoxybenzovesamicol positron emission tomography imaging. Patients with PD underwent neuropsychological assessment. The z scores for each cognitive domain were determined using an age-matched, gender-matched, and educational level-matched control group. Correlations between domain-specific cognitive functioning and cholinergic innervation were examined, controlling for motor impairments and levodopa equivalent dose. Additional correlational analyses were performed using a mask limited to PD versus normal aging binding differences to assess for disease-specific versus normal aging effects., Results: Voxel-based whole-brain analysis demonstrated partial overlapping topography across cognitive domains, with most robust correlations in the domains of memory, attention, and executive functioning (P < 0.01, corrected for multiple comparisons). The shared pattern included the cingulate cortex, insula/operculum, and (visual) thalamus., Conclusion: Our results confirm and expand on previous observations of cholinergic system involvement in cognitive functioning in PD. The topographic overlap across domains may reflect a partially shared cholinergic functionality underlying cognitive functioning, representing a combination of disease-specific and aging effects. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Objective: To determine whether β-amyloidopathy correlates with apathy rating scores independently of mood changes and other neurodegenerative processes in Parkinson disease (PD)., Methods: In this cross-sectional study, patients with PD (n = 64, 48 male and 16 female, mean age 69.2 ± 6.7 years, Hoehn & Yahr stage 2.7 ± 0.5, Montreal Cognitive Assessment score 25.3 ± 3.0) underwent [ 11 C]Pittsburgh compound B β-amyloid, [ 11 C]dihydrotetrabenazine vesicular monoamine transporter type 2 (VMAT2), and [ 11 C]methyl 4 piperidinyl propionate acetylcholinesterase brain PET imaging and clinical assessments, including the Marin Apathy Evaluation Scale, Clinician Version. Patients were recruited on the basis of having at least 1 risk factor for PD dementia, but they were excluded if they had dementia., Results: Mean apathy rating score was 25.4 ± 6.4, reflecting predominantly subclinical apathy. Apathy rating scale scores correlated with amyloid binding, cognitive, depressive, and anxiety scores but not significantly with age, duration of disease, striatal VMAT2, or cholinergic binding. Multiple regression analysis model ( p < 0.0001) showed significant regressor effects for global β-amyloid burden ( p = 0.0038) with significant covariate effects for global cognitive z scores ( p = 0.028) and for anxiety ( p = 0.038) but not with depressive scores. Voxel-based analysis showed robust correlation between apathy rating scale scores and β-amyloid binding in bilateral nuclei accumbens, inferior frontal, and cingulate cortices (family-wise error rate-corrected p < 0.005)., Conclusion: Apathy is independently associated with β-amyloidopathy in patients with PD at risk of dementia. Regional brain findings are most robust for β-amyloidopathy in the nuclei accumbens, inferior frontal, and cingulate regions. Findings may provide an explanation for the often treatment-refractory nature of apathy in advancing PD despite optimized dopaminergic and antidepressant pharmacotherapy., Clinicaltrialsgov Identifier: NCT01565473., (© 2019 American Academy of Neurology.)

Diverse but complementary methodologies are required to uncover the complex determinants and pathophysiology of freezing of gait. To develop future therapeutic avenues, we need a deeper understanding of the disseminated functional-anatomic network and its temporally associated dynamic processes. In this targeted review, we will summarize the latest advances across multiple methodological domains including clinical phenomenology, neurogenetics, multimodal neuroimaging, neurophysiology, and neuromodulation. We found that (i) locomotor network vulnerability is established by structural damage, e.g. from neurodegeneration possibly as result from genetic variability, or to variable degree from brain lesions. This leads to an enhanced network susceptibility, where (ii) modulators can both increase or decrease the threshold to express freezing of gait. Consequent to a threshold decrease, (iii) neuronal integration failure of a multilevel brain network will occur and affect one or numerous nodes and projections of the multilevel network. Finally, (iv) an ultimate pathway might encounter failure of effective motor output and give rise to freezing of gait as clinical endpoint. In conclusion, we derive key questions from this review that challenge this pathophysiological view. We suggest that future research on these questions should lead to improved pathophysiological insight and enhanced therapeutic strategies., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction : Gait and balance disorders in Parkinson's disease (PD) represent a major therapeutic challenge as frequent falls and freezing of gait impair quality of life and predict mortality. Limited dopaminergic therapy responses implicate non-dopaminergic mechanisms calling for alternative therapies. Areas covered : The authors provide a review that encompasses pathophysiological changes involved in axial motor impairments in PD, pharmacological approaches, exercise, and physical therapy, improving physical activity levels, invasive and non-invasive neurostimulation, cueing interventions and wearable technology, and cognitive interventions. Expert opinion : There are many promising therapies available that, to a variable degree, affect gait and balance disorders in PD. However, not one therapy is the 'silver bullet' that provides full relief and ultimately meaningfully improves the patient's quality of life. Sedentariness, apathy, and emergence of frailty in advancing PD, especially in the setting of medical comorbidities, are perhaps the biggest threats to experience sustained benefits with any of the available therapeutic options and therefore need to be aggressively treated as early as possible. Multimodal or combination therapies may provide complementary benefits to manage axial motor features in PD, but selection of treatment modalities should be tailored to the individual patient's needs.

Background: Aggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression., Objectives: To analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative., Methods: Over up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed., Results: The inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan., Conclusions: CSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Persons with Parkinson's disease (PwP) have many known risk factors for suicide and suicidal ideation (SI). Despite this, there is limited understanding of suicidality in this population. We conducted a systematic review to synthesise the available literature on suicidality in PwP and highlight areas for potential intervention and further research. We identified 116 articles discussing SI, suicidal behaviours, suicide attempts and/or fatal suicide in PwP. These articles describe prevalence, suicide methods, risk factors for suicide and SI and treatment of suicidality. In this review, we summarise the current literature and provide suggestions for how clinicians can identify and treat PwP who are at risk for suicide, for example, through aggressive treatment of depression and improved screening for access to lethal means., Competing Interests: Competing interests: KAM receives support from Abbott for research support for his role as site PI for DBS trial, outside the submitted work. There are no other competing interests to report., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: When using free-water diffusion imaging or positron emission tomography (PET), it is established that substania nigra microstructure and presynaptic dopamine activity are impaired in early PD. It is not well understood if these two forms of degeneration are redundant, or if they each provide a unique contribution to the clinical motor and cognitive symptoms., Methods: A total of 129 PD and 75 control individuals underwent motor and cognitive evaluations, and in vivo [11C]dihydrotetrabenazine (DTBZ) monoaminergic brain PET imaging and diffusion imaging. Correlations between free-water in the substantia nigra and striatal PET measures were analyzed. Unbiased multiple regression using a backward elimination method was performed between clinical severity and all imaging measures., Results: Inverse correlations were found between free-water in posterior substantia nigra and DTBZ binding in putamen and caudate. Multiple regression revealed that increased free-water in the posterior substantia nigra, decreased DTBZ binding in putamen, and age were predictors of higher Hoehn and Yahr stage, MDS-UPDRS III scores, and posture and gait sub-scores. Increased posterior substantia nigra free-water alone was associated tremor scores. Free-water in caudate and putamen did not predict measures of motor performance. Decreased DTBZ binding in caudate, increased free-water in caudate and posterior substantia nigra were associated with higher dementia ratings., Conclusions: These findings suggest that free-water in the posterior substantia nigra and presynaptic dopamine imaging in striatum are uniquely associated with the clinical symptoms of PD, indicating that each imaging modality may be measuring a unique mechanism relevant to nigrostriatal degeneration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Past animal and human studies robustly report that the cholinergic system plays an essential role in both top-down and bottom-up attentional control, as well as other aspects of cognition (see Ballinger et al., 2016 for a recent review). However, current understanding of how two major cholinergic pathways in the human brain (the basal forebrain-cortical pathway, and the brainstem pedunculopontine-thalamic pathway) contribute to specific cognitive functions remains somewhat limited. To address this issue, we examine how individual variation in the integrity of striatal-dopaminergic, thalamic-cholinergic, and cortical-cholinergic pathways (measured using Positron Emission Tomography in patients with Parkinson's disease) was associated with individual variation in the initial goal-directed focus of attention, the ability to sustain attentional performance over time, and the ability to avoid distraction from a highly-salient, but irrelevant, environmental stimulus. Compared to healthy controls, PD patients performed similarly in the precision of attention-dependent judgments of duration, and in sustaining attention over time. However, PD patients' performance was strikingly more impaired by the distractor. More critically, regression analyses indicated that only cortical-cholinergic integrity, not thalamic-cholinergic or striatal-dopaminergic integrity, made a specific contribution to the ability to resist distraction after controlling for the other variables. These results demonstrate that the basal forebrain cortical cholinergic system serves a specific role in executing top-down control to resist external distraction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Executive functions are complex both in the cognitive operations involved and in the neural structures and functions that support those operations. This complexity makes executive function highly vulnerable to the detrimental effects of aging, brain injury, and disease, but may also open paths to compensation. Neural compensation is often used to explain findings of additional or altered patterns of brain activations by older adults or patient populations compared to young adults or healthy controls, especially when associated with relatively preserved performance. Here we test the hypothesis of an alternative form of compensation, between different neuromodulator systems. 135 patients with Parkinson's Disease (PD) completed vesicular monoamine transporter type2 (VMAT2) and acetylcholinesterase PET scanning to assess the integrity of nigrostriatal dopaminergic, thalamic cholinergic, and cortical cholinergic pathways, and a behavioral test (Stroop + task-switching) that puts high demands on conflict processing, an important aspect of executive control. Supporting the compensatory hypothesis, regression models controlling for age and other covariates revealed an interaction between caudate dopamine and cortical cholinergic integrity: Cortical cholinergic integrity was a stronger predictor of conflict processing in patients with relatively low caudate dopaminergic function. These results suggest that although frontostriatal dopaminergic function plays a central role in executive control, cholinergic systems may also make an important contribution. The present results suggest potential pathways for remediation, and that the appropriate interventions for each patient may depend on their particular profile of decline. Furthermore, they help to elucidate the brain systems that underlie executive control, which may be important for understanding other disorders as well as executive function in healthy adults., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls., Methods: Ninety-four PD subjects underwent clinical assessment and VAChT ([ 18 F]FEOBV) PET., Results: Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions., Interpretation: Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538-549., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Background/objective: Fatigue is a common debilitating symptom in Parkinson's disease (PD) of unclear etiology. Hypotension and blood pressure variability are common in PD though their relationship to other non-motor symptoms is less well understood., Methods: We conducted a cross-sectional study to explore differences in 24-hour ambulatory blood pressure measurements in PD subjects (n = 35) with and without fatigue. Subjects underwent hourly systolic (SBP) and diastolic (DBP) blood pressure testing in their home environment. The presence of fatigue was assessed using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 1. We compared blood pressure measurements in fatigued vs. non-fatigued PD subjects, assessed over 4 epochs: overnight, morning, midday, and evening., Results: PD subjects with symptoms of fatigue demonstrated lower mean DBP, compared to those without fatigue (67.8±4.8 mmHg vs. 75.6±9.4 t = 2.57, p = 0.014). These intergroup differences were most notable in the morning. The two groups did not differ in scoring on the Survey of Autonomic Symptoms or on an office-based blood assessment of SBP or DBP performed on the day of 24-hour monitor initiation., Conclusions: Fatigue in PD may be a clinical manifestation of low-grade systemic hypotension.

Sleep disturbances are common and a major source of disability in Parkinson's disease (PD). Primary and secondary insomnia, rapid eye movement sleep behavior disorder (RDB), central sleep apnea, restless legs, and nocturnal akinesia are common sleep disturbances in PD. Prodromal presence of RBD is associated with a more severe motor and non-motor PD subtype implying a significant disease-modifying effect of this parasomnia. Other disease-modifying mechanisms of sleep disturbances in PD include impaired glymphatic clearance, endoplasmic reticulum stress, nocturnal brain deoxygenation and inflammatory processes among others. Impairments of neural circuit switching and imbalance between inhibitory and excitatory neuronal populations are likely responsible for episodic sleep disturbances, in particular RBD. As neural circuits may predict patterns of α-synuclein propagation in the nervous system, impairments of such circuits are of high relevance for PD pathophysiology. Future research is needed to determine whether appropriate treatment for disturbed sleep might slow progression of PD.

Background: Constipation is a prodromal feature of Parkinson's disease (PD) and the gastrointestinal (GI) tract is implicated in the pathogenesis of PD. However, no studies have demonstrated ante-mortem relationships between nigrostriatal dysfunction and GI dysautonomia in PD., Methods: The Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT) assesses dysautonomia in the multi-center Parkinson's Progression Marker Initiative (PPMI). We used linear mixed-effects models and reliable change indices (RCIs) to examine longitudinal associations between dysautonomia and dopamine transporter (DAT) striatal binding ratios (SBRs) measured by single-photon emission computerized tomography in PPMI participants over four years (n = 397 at baseline)., Results: Adjusted mixed-models of longitudinal data showed that constipation-but not orthostatic hypotension or urinary dysfunction-was associated with reduced SBR in both caudate (P < 0.001) and putamen (P = 0.040). In both regions, SBR reductions between baseline and 4-year follow-up were significant and measurable (P < 0.0001), with larger decline and variance in the caudate nucleus. Four-year change in caudate-but not putaminal-SBR was significantly associated with RCI-indicated progression of GI dysautonomia (P = 0.031), but not other types of dysautonomia. These associations remained after adjusting for the use of medications or supplements to control constipation. Consistent with prior PPMI reports, motor impairment progression was not associated with SBR reduction., Conclusions: GI dysautonomia correlates with reductions in DAT availability; constipation is most closely associated with caudate-DAT reduction. Worsening GI-dysautonomia and reduced bowel movements may accompany advancing nigral degeneration or changes in nigrostriatal dopamine function., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Peripheral neuropathy is a common condition in the elderly that can affect balance and gait. Postural imbalance and gait difficulties in Parkinson's disease (PD), therefore, may stem not only from the primary neurodegenerative process but also from age-related medical comorbidities. Elucidation of the effects of peripheral neuropathy on these difficulties in PD is important to provide more targeted and effective therapy. The purpose of this study was to investigate the association between lower-limb peripheral neuropathy and falls and gait performance in PD while accounting for disease-specific factors., Methods: From a total of 140 individuals with PD, 14 male participants met the criteria for peripheral neuropathy and were matched 1:1 for Hoehn & Yahr stage and duration of disease with 14 male participants without peripheral neuropathy. All participants underwent fall (retrospectively) and gait assessment, a clinical evaluation, and [ 11 C]dihydrotetrabenazine and [ 11 C]methylpiperidin-4-yl propionate PET imaging to assess dopaminergic and cholinergic denervation, respectively., Results: The presence of peripheral neuropathy was significantly associated with more falls (50% vs. 14%, p = 0.043), as well as a shorter stride length (p = 0.011) and greater stride length variability (p = 0.004), which resulted in slower gait speed (p = 0.016) during level walking. There was no significant difference in nigrostriatal dopaminergic denervation, cortical and thalamic cholinergic denervation, and MDS-UPDRS motor examination scores between groups., Conclusion: Lower-limb peripheral neuropathy is significantly associated with more falls and gait difficulties in PD. Thus, treating such neuropathy may reduce falls and/or improve gait performance in PD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuations and severe dysphoria. The impact of these affective symptoms may be overlooked in the treatment of motor fluctuations. Our goal was to examine the relationship between motor fluctuations, their treatment status, and suicidality in PD participants., Methods: We analyzed data from the Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study of 223 individuals with PD. Suicidality was measured using items from four depression scales: Hamilton Depression Rating Scale (HAM-D-17); Montgomery-Åsberg Depression Rating Scale (MADRS); Inventory for Depressive Symptomatology (IDS-C); and the self-rated Beck Depression Inventory (BDI). Multivariable Poisson regression analyses tested whether self-reported motor fluctuations and their treatment status were associated with suicidality while controlling for recognized risk factors., Results: Thirty-seven participants (16.6%) self-reported suicidality and 89 (39.5%) self-reported motor fluctuations, of whom 21 (23.6%) perceived their fluctuations as untreated. Participants reporting untreated motor fluctuations more frequently had a current depressive disorder (p < 0.001) and endorsed suicidality (p = 0.006) than participants with treated or no fluctuations. They also had significantly higher total scores on the HAM-D-17, MADRS, IDS-C, and BDI depression scales (p < 0.001 for each). Regression analyses showed significant associations between untreated motor fluctuations and higher scores on suicide questions extracted from the HAM-D-17, MADRS, and IDS-C (p < 0.01 for each)., Conclusions: PD patients with untreated motor fluctuations are at increased risk for suicidal thoughts and should be monitored for mood changes as treatment is adapted., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

In this study, we apply a multidisciplinary approach to investigate falls in PD patients using clinical, demographic and neuroimaging data from two independent initiatives (University of Michigan and Tel Aviv Sourasky Medical Center). Using machine learning techniques, we construct predictive models to discriminate fallers and non-fallers. Through controlled feature selection, we identified the most salient predictors of patient falls including gait speed, Hoehn and Yahr stage, postural instability and gait difficulty-related measurements. The model-based and model-free analytical methods we employed included logistic regression, random forests, support vector machines, and XGboost. The reliability of the forecasts was assessed by internal statistical (5-fold) cross validation as well as by external out-of-bag validation. Four specific challenges were addressed in the study: Challenge 1, develop a protocol for harmonizing and aggregating complex, multisource, and multi-site Parkinson's disease data; Challenge 2, identify salient predictive features associated with specific clinical traits, e.g., patient falls; Challenge 3, forecast patient falls and evaluate the classification performance; and Challenge 4, predict tremor dominance (TD) vs. posture instability and gait difficulty (PIGD). Our findings suggest that, compared to other approaches, model-free machine learning based techniques provide a more reliable clinical outcome forecasting of falls in Parkinson's patients, for example, with a classification accuracy of about 70-80%.

Objective: Serotoninergic neurotransmission may modulate β-amyloid peptide (Aβ) metabolism through upregulation of α-secretase. Early Parkinson disease (PD) shows variable serotoninergic denervation, which may impact Aβ deposition., Methods: We conducted 3 analyses to explore associations between serotoninergic neurotransmission and cerebral Aβ burden in PD. The first was a cross-sectional imaging study of PD subjects (n = 23) using the serotoninergic transporter positron emission tomography (PET) ligand [ 11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) and amyloid PET Pittsburgh compound B ([ 11 C]PiB). The second was a baseline study of Parkinson's Progression Markers Initiative (PPMI) subjects exploring the influence of serotoninergic medications on cerebrospinal fluid (CSF) Aβ-42 levels (n = 389), controlling for age, sex, Geriatric Depression Scale, disease duration, and education. Third, we fit an interval censored proportional hazard model with longitudinal PPMI data (n = 367) to test whether serotoninergic medication use associates with reduced risk of PD cognitive decline, defined as time to reach a Montreal Cognitive Assessment score ≤ 20, adjusting for baseline caudate dopamine transporter [ 123 I]ioflupane single photon emission computed tomography and CSF Aβ-42 levels., Results: Serotoninergic DASB distribution volume ratio (DVR) inversely associated with PiB DVR in the cerebral cortex (Pearson r = -0.478, p = 0.021) but not the striatum (r = -0.264, p = 0.224). In the baseline PPMI analysis, serotoninergic medication use for ≥6 months associated with a lower level of CSF Aβ-42 (t = -2.20, p = 0.029). In the longitudinal PPMI model, baseline serotoninergic medication use associated with a reduced risk of cognitive decline (t = -2.03, p = 0.043) after controlling for covariates., Interpretation: Cortical Aβ burden in PD associates inversely with serotoninergic innervation. Serotoninergic medications may alter Aβ metabolism and reduce the risk of PD cognitive decline. Ann Neurol 2018;83:994-1002., (© 2018 American Neurological Association.)

Background: Gait dysfunction is a common symptom of Parkinson's disease that can cause significant disability and put patients at risk for falls. These symptoms show variable responsiveness to dopaminergic therapy., Objective: To determine whether dopaminergic (rs1076560 DRD2 G > T and rs4680 catechole-o-methyltranspherase (COMT) Val158Met) or brain derived neurotrophic factor (rs6265 BDNF Val66Met) genetic polymorphisms are associated with gait function and medication responsiveness in Parkinson's disease., Method: Gait function was evaluated on two days for patients (ON and OFF medication in a counterbalanced fashion) and a single session for controls. Investigators were blinded to genotype during data collection. Associations between genotype and medication responsiveness were analyzed using mixed model ANOVAs. A priori hypotheses were tested using GAITRite ® electronic mat spatiotemporal gait parameters including step length, step width, velocity, portion of double and single support per gait cycle, and variability of these measures ON and OFF medication., Results: We found that the DRD2 polymorphism, but neither COMT nor BDNF, was consistently associated with gait function and medication responsiveness in the patients. Specifically, Parkinson's disease patients with reduced striatal D2 expression (DRD2 T allele carriers) had worse gait dysfunction and showed greater dopamine responsiveness of gait function compared to patients who were homozygous for the G allele. There was no effect of any of the genetic polymorphisms on gait for controls., Conclusions and Relevance: The findings suggest that genetic subgrouping, in particular for DRD2, may be used to identify Parkinson's disease patient subgroups that are more dopamine responsive for gait function., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Dopaminergic therapy in Parkinson's disease (PD) can be associated with both motoric (e.g., dyskinesias) and neuropsychiatric adverse effects. Examples of the latter include Dopamine Dysregulation Syndrome (DDS) and impulse control disorder (ICD), which are separate but related behavioral/psychiatric complications of treatment in PD. Dysregulation of volition characterizes both dyskinesias and DDS/ICD; thus, we analyzed potential disease-related correlates in a large PD cohort., Methods: We analyzed cross-sectional data from 654 participants collected through the NINDS Parkinson's Disease Biomarkers Program. DDS/ICD symptoms and dyskinesias were assessed using the Movement Disorders Society (revised) Unified Parkinson's Disease Rating Scale. Potential associated variables were selected from PD-validated or PD-specific scales of neuropsychiatric or motoric status. Multivariable models with DDS/ICD or dyskinesia presence outcomes were produced with backward stepwise regression to identify factors independently associated with DDS/ICD and/or dyskinesias., Results: Fifty-three (8.1%) participants endorsed DDS and/or ICD symptoms and 150 (22.9%) were dyskinetic. In multivariable analysis, psychosis was independently associated with both dyskinesias (p = 0.006) and DDS/ICD (p < 0.001). Unpredictable motor fluctuations (p = 0.026) and depression (p = 0.023) were also associated with DDS/ICD; female sex (p = 0.025), low tremor score (p = 0.001) and high akinesia-rigidity score (p < 0.001) were associated with dyskinesias., Conclusions: Our findings suggest that psychosis may be an important marker of impaired volition across motor and cognitive domains. Unpredictable motor fluctuations, psychosis, and depression may together comprise a phenotypic profile of patients at increased risk for DDS/ICD. Similarly, dyskinetic PD patients should be closely monitored for psychotic symptoms and treated appropriately., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non-demented PD participants is associated with domain-specific cognitive impairment on the Mini-Mental State Exam (MMSE)., Methods: The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two-year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM-IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time-varying relationship between MMSE subscale scores and psychosis, adjusting for potential confounding variables identified through univariable analysis., Results: Thirty-one unique psychosis cases were recorded among non-demented participants. Fifty total evaluations with psychosis present were analyzed. In multivariable regressions, psychosis was associated with lower scores on the orientation (relative odds ratio, rOR: 0.73; 95% CI: 0.58-0.93; p = 0.011), language (rOR: 0.64; 95% CI: 0.48-0.86; p = 0.003), and intersecting pentagon (rOR: 0.43; 95% CI: 0.20-0.92 p = 0.030) subscales of the MMSE., Conclusions: In PD, executive dysfunction, disorientation, and impaired language comprehension may be associated with psychosis. Our findings suggest that the corresponding MMSE subscales may be useful in identifying participants with a higher likelihood of developing psychosis. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Currently all aspects of Parkinson's disease (PD) treatment are less than ideal and would benefit from new interventions. We focus on problems associated with brain neurotransmitters amenable to more specific subreceptor and temporal manipulation. In addition, we consider potentially treatable CNS non-PD co-pathologies or co-morbidities that may exacerbate progression of various aspects of PD.

Background: Medical comorbidities, including cardiovascular risk factors such as hypertension and diabetes, influence disease progression in Parkinson disease (PD) and may be variably present in different clinical populations., Objective/methods: We conducted a retrospective nested case-control study of 29 Veterans with PD and 29 non-Veteran PD controls. The groups were matched for age, gender, and disease duration. Both groups underwent clinical and imaging testing as part of their participation in a larger cross-sectional PD observational study at our research center. Veterans were recruited primarily from movement disorders neurology clinics at the Ann Arbor Veterans Affairs (VA) Health System. Non-Veterans were recruited primarily from analogous clinics at the University of Michigan Health System. We explored differences in cardiovascular risks factor burden between the groups., Results: Veterans with PD showed higher scores on the simplified Framingham 10-year general cardiovascular disease risk calculator (FR score; 27.3% (11.5) vs. 20.7% (6.8); t = -2.66, p = 0.011) and fewer years of self-reported education (14.5 (2.5) vs. 16.7 (2.6); t = 3.33, p = 0.002). After adjusting for age, disease duration, education, and the use of antihypertensive medications, Veterans showed higher FR scores (t = 2.95, p = 0.005) and a higher intra-subject ratio of FR score to age-and-gender normalized FR score (t = 2.49, p = 0.016), representing an elevated component of modifiable cardiovascular risk factor burden., Conclusion: Cardiovascular comorbidities are common in Veterans with PD and may be more severe than in non-Veteran PD populations. These findings merit replication in other representative cohorts. Veterans may be a preferred population for clinical trials evaluating cardiovascular risk factor management on PD progression.