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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.[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.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. This article is protected by copyright. All rights reserved.

BACKGROUND: 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. OBJECTIVE: 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). METHODS: 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. RESULTS: 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

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [

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 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.

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The report describes an updated, fully automated method for the production of [(11)C]butyrate, validated for use in clinical studies. A commercially available GE Tracerlab FX(M) synthesis module was reconfigured to allow for air-free introduction of n-propyl magnesium chloride and to incorporate Sep-Pak cartridges to simplify and shorten the purification process, as compared to purifying the product using traditional HPLC. The method takes 20 min from end-of-bombardment and reliably produces injectable doses of [(11)C]butyrate (8029 ± 1628 MBq (217 ± 44 mCi), 14 % radiochemical yield based on [(11)C]CO(2,) non-decay corrected) in high radiochemical purity (>97 %), n = 3. With radiotracer in hand, PET scans of rats confirmed uptake of the radiopharmaceutical in the brain. Rat biodistribution data was obtained and used in conjunction with OLINDA software to determine an estimated human total body effective dose of 3.20 × 10(−3) mSv/MBq (1.19 × 10(−2) rem/mCi), along with preliminary rodent PET imaging that confirmed brain uptake. Lastly, our first human [(11)C]butyrate PET studies using a dynamic bolus injection technique (n = 5), with a graphical Logan analysis using a white matter reference region, confirmed good radiotracer uptake in the brain and with relatively more prominent uptake in the cerebellar hemispheres, vermis, cingulum cortex and the thalami.

BACKGROUND AND PURPOSE: Mild Parkinsonian signs (MPS) are common in older adults. We hypothesized that MPS are associated with lower functional connectivity (FC) in dopamine-dependent cortico-striatal networks, and these associations vary with white matter hyperintensity (WMH), a risk factor for MPS. METHODS: We examined resting-state functional MRI in 266 participants (mean age 83; 57% female; 41% African American) with data on MPS (Unified Parkinson’s Disease Rating Scale), demographics, cognition, muscle-skeletal, and cardiometabolic health. FC between cortex and striatum was examined separately for sensorimotor, executive, and limbic functional subregions. Logistic regression tested the association of FC in each network with MPS, adjusted for covariates. Interactions of FC by WMH were tested; and analyses were repeated stratified by WMH above/below the median. RESULTS: Compared to those without MPS, those with MPS had lower cortico-striatal FC in the left executive network (adjusted odds ratio [95% confidence interval], p-value: 0.188 [0.043, 0.824], .027). The interaction with WMH was p = .064; left executive FC was inversely associated with MPS for high WMH (0.077 [0.010, 0.599], .014) but not low WMH participants (1.245 [0.128, 12.132], .850). CONCLUSIONS: MPS appear related to lower executive network FC, robust to adjustment for other risk factors, and stronger for those with higher burden of WMH. Future longitudinal studies should examine the interplay between cerebral small vessel disease and connectivity influencing MPS.

Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits. The 16 Parkinson's disease subjects (4 females/12 males; mean age: 64.4 ± 6.7 years; disease duration: 5.5 ± 4.2 years; Hoehn & Yahr stage: 2.3 ± 0.6 at entry) completed serial 11C-methyl-4-piperidinyl propionate acetylcholinesterase PET scans over a 4–8 year period (median 5 years). Three-dimensional stereotactic cortical surface projections and volume-of-interest analyses were performed. Cholinergic synapse integrity was assessed by the magnitude, k3, of acetylcholinesterase hydrolysis of 11C-methyl-4-piperidinyl propionate. Based on normative data, we generated Z-score maps for both the k3 and the k1 parameters, the latter as a proxy for regional cerebral blood flow. Compared with control subjects, baseline scans showed predominantly posterior cortical k3 deficits in Parkinson’s disease subjects. Interval change analyses showed evidence of posterior-to-anterior progression of cholinergic cortical deficits in the posterior cortices. In frontal cortices, an opposite gradient of anterior-to-posterior progression of cholinergic deficits was found. The topography of k3 changes exhibited regionally specific disconnection from k1 changes. Interval-change analysis based on k3/k1 ratio images (k3 adjustment for regional cerebral blood flow changes) showed interval reductions (up to 20%) in ventral frontal, anterior cingulate and Brodmann area 6 cortices. In contrast, interval k3 reductions in the posterior cortices, especially Brodmann areas 17–19, were largely proportional to k1 changes. Our results partially support the hypothesis of progressive posterior-to-cortical cholinergic denervation in Parkinson’s disease. This pattern appears characteristic of posterior cortices. In frontal cortices, an opposite pattern of anterior-to-posterior progression of cholinergic deficits was found. The progressive decline of posterior cortical acetylcholinesterase activity was largely proportional to declining regional cerebral blood flow, suggesting that posterior cortical cholinergic synapse deficits are part of a generalized loss of synapses. The disproportionate decline in regional frontal cortical acetylcholinesterase activity relative to regional cerebral blood flow suggests preferential loss or dysregulation of cholinergic synapses in these regions. Our observations suggest that cortical cholinergic synapse vulnerability in Parkinson's disease is mediated by both diffuse processes affecting cortical synapses and processes specific to subpopulations of cortical cholinergic afferents.

IMPORTANCE: Adapting one’s gait speed to external circumstances is critical for safe ambulation. Dopamine (DA), critical for adapting to increased task demands, predicts usual gait speed and may exert a greater role in complex tasks like rapid gait speed. OBJECTIVE: We hypothesized that a genotypic proxy indicator of greater prefrontal DA signaling would predict significantly faster rapid gait. DESIGN: Longitudinal cohort study over 8 years SETTING: Community-dwelling adults with no baseline mobility disability PARTICIPANTS: N = 2,353 participants from the Health ABC Study MEASUREMENTS: Repeated measures of walking speed (meters/sec) were obtained in response to: “walk as fast as possible… (rapid gait) or “walk at your usual pace (usual gait).” Catechol-O-methyltransferase (COMT) val158met polymorphism indicated DA signaling (val/val=higher metabolism, lower DA signaling; met/met=lower metabolism, higher DA signaling). RESULTS: Participants declined in rapid gait from 1.55 (SD=.33) to 1.35 m/s (SD=0.34). Across the full follow-up period, the met/met genotype was associated with significantly greater rapid gait slowing. In mixed effect models, between-group differences were independent of covariates, and remained similar after adjustment for sensorimotor function, cognition, depressive symptoms, and energy. Follow-up analyses indicated the met/met genotype had a significantly faster rapid gait speed compared to the val/val genotype for the first 3 years (p < .01) but not years 4–8 (p > .05). CONCLUSION: Greater prefrontal DA measured with COMT polymorphism may facilitate short-term adaptation to rapid walking demands that are lost over time. Studies should examine whether these effects are long-term and the underlying mechanistic pathways.

Background: In Parkinson’s disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice. Objective: To critically evaluate PD subtyping systems. Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their methodologic quality and clinical applicability using standardized checklists. Results: We included 38 studies. The majority were cross-sectional (n = 26, 68.4%), used a data-driven approach (n = 25, 65.8%), and non-clinical biomarkers were rarely used (n = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown. Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed.

Background Effects of fatigue on health in older age are well studied, yet little is known about the clinical relevance of energy perception. Aims To explore cross-sectional associations of self-reported energy with physical and mental health metrics in the Health, Aging, and Body Composition Study. Methods Participants rated their energy from 0 to 10; the outcome was energy dichotomized at the median (≥ 7 = higher energy). Four domains were assessed: depressive symptoms (Center for Epidemiologic Studies Depression Scale); physical performance (function: usual and rapid gait speed; fitness: 400-m walk time); physical activity (casual walking, walking for exercise, and intense exercise); and cognitive function (Modified Mini-Mental State Examination and Digit Symbol Substitution Test). Covariates bivariately associated with energy entered a multivariable logistic regression model, adjusted for demographics, chronic conditions, and strength. Results Depressive symptoms, physical performance and activity, but not cognition, were bivariately associated with energy (p p Discussion In this cohort with a range of chronic conditions and fatigue, perceiving higher energy levels may reflect better emotional and physical health. Conclusion Energy should be considered in multidimensional clinical assessments of older age.

The vestibular system has been implicated in the pathophysiology of episodic motor impairments in Parkinson's disease (PD), but specific evidence remains lacking.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.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).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 (χThe 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.

The[F-18]fluoroethoxybenzovesamicol ([F-18]-FEOBV) positron emission tomography (PET) ligand targets the vesicular acetylcholine transporter. Recent [F-18]FEOBV PET rodent studies suggest that regional brain [F-18]FEOBV binding may be modulated by dopamine D2-like receptor agents. We examined associations of regional brain [F-18]FEOBV PET binding in Parkinson's disease (PD) subjects without versus with dopamine D2-like receptor agonist drug treatment. PD subjects (n = 108; 84 males, 24 females; mean age 68.0 +/- 7.6 [SD] years), mean disease duration of 6.0 +/- 4.0 years, and mean Movement Disorder Society-revised Unified PD Rating Scale III 35.5 +/- 14.2 completed [F-18]FEOBV brain PET imaging. Thirty-eight subjects were taking dopamine D2-like agonists. Vesicular monoamine transporter type 2 [C-11]dihydrotetrabenazine (DTBZ) PET was available in a subset of 54 patients. Subjects on dopamine D2-like agonists were younger, had a longer duration of disease, and were taking a higher levodopa equivalent dose (LED) compared to subjects not taking dopamine agonists. A group comparison between subjects with versus without dopamine D2-like agonist use did not yield significant differences in cortical, striatal, thalamic, or cerebellar gray matter [F-18]FEOBV binding. Confounder analysis using age, duration of disease, LED, and striatal [C-11]DTBZ binding also failed to show significant regional [F-18]FEOBV binding differences between these two groups. Chronic D2-like dopamine agonist use in PD subjects is not associated with significant alterations of regional brain [F-18]FEOBV binding.

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease.

© 2020, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Purpose of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders. Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET, offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels. Summary: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration.

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. 11C-dihydrotetrabenazine (11C-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 11C-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 11C-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). 11C-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 11C-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 11C-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. ispartof: JOURNAL OF NUCLEAR MEDICINE vol:62 issue:4 pages:545-552 ispartof: location:United States status: published

Balance impairment and falls are among the most prevalent and morbid conditions affecting older adults. A critical contributor to balance and gait function is the vestibular system; however, there remain substantial knowledge gaps regarding age-related vestibular loss and its contribution to balance impairment and falls in older adults. Given these knowledge gaps, the National Institute on Aging and the National Institute on Deafness and Other Communication Disorders convened a multidisciplinary workshop in April 2019 that brought together experts from a wide array of disciplines, such as vestibular physiology, neuroscience, movement science, rehabilitation, and geriatrics. The goal of the workshop was to identify key knowledge gaps on vestibular function and balance control in older adults and develop a research agenda to make substantial advancements in the field. This article provides a report of the proceedings of this workshop. Three key questions emerged from the workshop, specifically: (i) How does aging impact vestibular function?; (ii) How do we know what is the contribution of age-related vestibular impairment to an older adult’s balance problem?; and more broadly, (iii) Can we develop a nosology of balance impairments in older adults that can guide clinical practice? For each of these key questions, the current knowledge is reviewed, and the critical knowledge gaps and research strategies to address them are discussed. This document outlines an ambitious 5- to 10-year research agenda for increasing knowledge related to vestibular impairment and balance control in older adults, with the ultimate goal of linking this knowledge to more effective treatment.

Objectives: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [F-18]- fluoroethoxybenzovesamicol ([F-18]- FEOBV) radioligand.Methods: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [F-18]-FEOBV PET.Results: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated non-diffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices.Conclusions: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

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 (18F-fluoroethoxybenzovesamicol [18F-FEOBV] and 11C-dihydrotetrabenazine [11C-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 11C-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 18F-FEOBV distribution volume ratio (DVR) in PD subjects. The same analysis was performed for 11C-DTBZ DVR in 12 striatal subregions (presynaptic-terminal level). Results: Unlike 11C-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 18F-FEOBV DVR in PD subjects (corrected P = 0.039). We also found that the mean 18F-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. ispartof: JOURNAL OF NUCLEAR MEDICINE vol:63 issue:3 pages:438-445 ispartof: location:United States status: published

Mitochondrial complex I (MC-I) is an essential component of brain bioenergetics and can be quantified and studied using positron emission tomography (PET). A specific high affinity

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.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.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.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.

PURPOSE OF REVIEW: Brain cholinergic denervation is a major feature of Alzheimer’s disease (AD) and Dementia with Lewy bodies (DLB). We reviewed the topography of assessed by cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented. RECENT FINDINGS: VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. SUMMARY: Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections are likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.

Background Anticholinergic medications are associated with fall risk. Higher dopaminergic signaling may provide resilience to these effects. We tested interactions between anticholinergic medication use and dopaminergic genotype on risk for recurrent falls over 10 years. Methods Participants in the Health, Aging, and Body Composition (Health ABC) study (n = 2 372, mean age = 73.6; 47.8% men; 60.0% White) without disability or anticholinergic use at baseline were followed for up to 10 years for falls. Medication use was documented in 7 of 10 years. Highly anticholinergic medications were defined by Beers criteria, 2019. Recurrent falls were defined as ≥2 in the 12 months following medication assessment. Generalized estimating equations tested the association of anticholinergic use with recurrent falls in the following 12 months, adjusted for demographics, health characteristics, and anticholinergic use indicators. Effect modification by dopaminergic genotype (catechol-O-methyltransferase [COMT]; Met/Met, higher dopamine signaling, n = 454 vs Val carriers, lower dopamine signaling, n = 1 918) was tested and analyses repeated stratified by genotype. Results During follow-up, 841 people reported recurrent falls. Anticholinergic use doubled the odds of recurrent falls (adjusted odds ratio [OR] [95% CI] = 2.09 [1.45, 3.03]), with suggested effect modification by COMT (p = .1). The association was present in Val carriers (adjusted OR [95% CI] = 2.16 [1.44, 3.23]), but not in Met/Met genotype (adjusted OR [95% CI] = 1.70 [0.66, 4.41]). Effect sizes were stronger when excluding baseline recurrent fallers. Conclusion Higher dopaminergic signaling may provide protection against increased 12-month fall risk from anticholinergic use. Assessing vulnerability to the adverse effects of anticholinergic medications could help in determination of risk/benefit ratio for prescribing and deprescribing anticholinergics in older adults.

BACKGROUND: The Parkinson’s Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson’s disease, healthy controls, and carriers of the most common Parkinson’s disease-related genetic mutations, which aims to define biomarkers of Parkinson’s disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson’s disease that correlate with reduced DAT binding. METHODS: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual’s age. We used t tests, χ(2) tests, and Fisher’s exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number . FINDINGS: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

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.

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/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.