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Parkinson disease (PD) is a neurodegenerative disorder that causes motor and cognitive deficits, presenting complex challenges for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS) is a type of neuromodulation that can produce plastic changes in neural activity. rTMS has been trialed as a therapy to treat motor and non-motor symptoms in persons with Parkinson disease (PwP), particularly treatment-refractory postural instability and gait difficulties such as Freezing of Gait (FoG), but clinical outcomes have been variable. We suggest improving rTMS neuromodulation therapy for balance and gait abnormalities in PwP by targeting brain regions in cognitive-motor control networks. rTMS studies in PwP often targeted motor targets such as the primary motor cortex (M1) or supplementary motor area (SMA), overlooking network interactions involved in posture-gait control disorders. We propose a shift in focus toward alternative stimulation targets in basal ganglia-cortex-cerebellum networks involved in posture-gait control, emphasizing the dorsolateral prefrontal cortex (dlPFC), cerebellum (CB), and posterior parietal cortex (PPC) as potential targets. rTMS might also be more effective if administered during behavioral tasks designed to activate posture-gait control networks during stimulation. Optimizing stimulation parameters such as dosage and frequency as used clinically for the treatment of depression may also be useful. A network-level perspective suggests new directions for exploring optimal rTMS targets and parameters to maximize neural plasticity to treat postural instabilities and gait difficulties in PwP.

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: [18F]fluoroethoxybenzovesamicol ([18F]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. [18F]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 [18F]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.

Abstract We investigated the complex relations of socioeconomic status (SES) and healthy lifestyles with cognitive functions among older adults in 1313 participants, aged 60 years and older, from the National Health and Nutrition Examination Survey 2011–2014. Cognitive function was measured using an average of the standardized z-scores of the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning and delayed recall tests, the Animal Fluency Test, and the Digit Symbol Substitution Test. Latent class analysis of family income, education, occupation, health insurance, and food security was used to define composite SES (low, medium, high). A healthy lifestyle score was calculated based on smoking, alcohol consumption, physical activity, and the Healthy-Eating-Index-2015. In survey-weighted multivariable linear regressions, participants with 3 or 4 healthy behaviors had 0.07 (95% CI 0.005, 0.14) standard deviation higher composite cognitive z-score, relative to those with one or no healthy behavior. Participants with high SES had 0.37 (95% CI 0.29, 0.46) standard deviation higher composite cognitive z-score than those with low SES. No statistically significant interaction was observed between healthy lifestyle score and SES. Our findings suggested that higher healthy lifestyle scores and higher SES were associated with better cognitive function among older adults in the United States.

Deng et al. develop deep learning methods that identify Parkinson’s Disease (PD) patients using public accelerometer and position data with higher accuracy than when using gait/rest and voice-based models. Their study demonstrates the complementary predictive power of tapping, gait/rest and voice data and establishes integrative deep learning-based models for identifying PD.

BackgroundThere is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders–in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)–following a proof-of-concept study in Parkinson's disease published in 2005.MethodsTo provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials.Results10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class “B” evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class “U” evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class “C” evidence (possibly effective) for improvement of non-motor features and class “U” evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance.ConclusionsLimitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.

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

Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient’s clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.

Graphical Abstract

Acetylcholine plays a major role in brain cognitive and motor functions with regional cholinergic terminal loss common in several neurodegenerative disorders. We describe age-related declines of regional cholinergic neuron terminal density in vivo using the positron emission tomography (PET) ligand [18F](–)5-Fluoroethoxybenzovesamicol ([18F]FEOBV), a vesamicol analogue selectively binding to the vesicular acetylcholine transporter (VAChT). A total of 42 subjects without clinical evidence of neurologic disease (mean 50.55 [range 20–80] years, 24 Male/18 Female) underwent [18F]FEOBV brain PET imaging. We used SPM based voxel-wise statistical analysis to perform whole brain voxel-based parametric analysis (family-wise error corrected, FWE) and to also extract the most significant clusters of regions correlating with aging with gender as nuisance variable. Age-related VAChT binding reductions were found in primary sensorimotor cortex, visual cortex, caudate nucleus, anterior to mid-cingulum, bilateral insula, para-hippocampus, hippocampus, anterior temporal lobes/amygdala, dorsomedial thalamus, metathalamus, and cerebellum (gender and FWE-corrected, P

Summary: Large-scale population screening and in-home monitoring for patients with Parkinson's disease (PD) has so far been mainly carried out by traditional healthcare methods and systems. Development of mobile health may provide an independent, future method to detect PD. Current PD detection algorithms will benefit from better generalizability with data collected in real-world situations. In this paper, we report the top-performing smartphone-based method in the recent DREAM Parkinson's Disease Digital Biomarker Challenge for digital diagnosis of PD. Utilizing real-world accelerometer records, this approach differentiated PD from control subjects with an area under the receiver-operating characteristic curve of 0.87 by 3D augmentation of accelerometer records, a significant improvement over other state-of-the-art methods. This study paves the way for future at-home screening of PD and other neurodegenerative conditions affecting movement. The Bigger Picture: In-home digital surveillance has been proposed as the future for chronic, neurodegenerative disease such as Parkinson's disease (PD), which can be monitored by wearable devices from its motor-related symptoms. However, the disparities between uncontrolled in-home environments have introduced obstacles to the population-level application of digital screening of PD. In this study, we developed the first-place solution in the recent DREAM Parkinson's Disease Digital Biomarker Challenge, which calls for optimal algorithms to extract digital biomarkers of PD from crowd-sourced movement records. To combat the spatial and temporal bias in different movement records, we applied a variety of data-augmentation methods, which significantly improves the performance of the deep-learning model. Besides PD, our method provides a path for large-scale population screening and in-home monitoring using wearable devices in other related neurodegenerative disorders.

Tourette syndrome is a common neurodevelopmental disorder defined by the presence of tics, stereotyped involuntary movements and phonations. Considerable evidence points to developmental abnormalities of the basal ganglia as tic substrates. Basal ganglia dysfunction does not account for important features of Tourette syndrome, including its natural history, male predominance, and the characteristic quality and distribution of tics. The latter mainly involve eye, face, and head movements, in addition to a variety of simple to complex phonations. A major normal function of these movements, and of phonations as well, is social signaling. Many important species- and sex-specific stereotyped social behaviors are mediated by a phylogenetically conserved network of subcortical nuclei, the social behavior network (SBN). Some SBN nuclei are sexually dimorphic, and SBN function is modulated strongly by gonadal steroids. Recent studies indicate that the SBN meshes with the basal ganglia to form a larger network, the Social Decision Making Network (SDM; O’Connell and Hofmann [2011]). The SDM concept overlaps significantly with Holstege’s (1993) model of an emotional motor system mediating socially relevant facial movements and phonations. Dopaminergic signaling within the basal ganglia component of the SDM may regulate social act motivation with the SBN component responsible for act expression. Developmental SDM abnormalities can explain all major Tourette syndrome features, including natural history, male predominance, the characteristic distribution of tics, and their stereotyped quality. Some data directly support this hypothesis. Tourette syndrome may be a disorder of social communication manifesting primarily as abnormal involuntary movements.

Retardation of aging processes is a plausible approach to delaying the onset or slowing the progression of common neurodegenerative disorders. We review the results of experiments using murine genetic models of Alzheimer disease and Huntington disease to evaluate the effects of retarding aging. While positive results are reported in several of these experiments, there are several discrepancies in behavioral and pathologic outcomes both within and between different experiments. Similarly, different experiments yield varying assessments of potential proximate mechanisms of action of retarding aging. The anti-aging interventions used for some experiments include some that show only modest effects on lifespan, and others that have proven hard to reproduce. Several experiments used aggressive transgenic neurodegenerative disease models that may be less relevant in the context of age-related diseases. The experience with these models and interventions may be useful in designing future experiments assessing anti-aging interventions for disease-modifying treatment of neurodegenerative diseases.

Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearance-related proteins into inclusions occur in many protein folding diseases, including polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3. Consistent with this result, in a cell-based system mutant HTT interacts with UBQLN2 through the UBA domain while the SCA3 disease protein ATXN3, a deubiquitinating enzyme, does not interact with UBQLN2. Differential recruitment of UBQLN2 to aggregates in HD and SCA3 underscores the heterogeneity of inclusions in polyglutamine diseases and suggests that components of neuronal protein quality control may be differentially perturbed in distinct polyQ diseases.

Chorea-Acanthocytosis (ChAc) is a rare hereditary neurological disorder characterized by abnormal movements, red blood cell pathology, and progressive neurodegeneration. Little is understood of the pathogenesis of ChAc and related disorders (collectively Neuroacanthocytosis). The Eighth International Chorea-Acanthocytosis Symposium was held in May 2016 in Ann Arbor, MI, USA, and focused on molecular mechanisms driving ChAc pathophysiology. Accompanying the meeting, members of the neuroacanthocytosis research community and other invited scientists met in a workshop to discuss the current understanding and next steps needed to better understand ChAc pathogenesis. These discussions identified several broad and critical needs for advancing ChAc research and patient care, and led to the definition of 18 specific action points related to functional and molecular studies, animal models, and clinical research. These action points, described below, represent tractable research goals to pursue for the next several years.

Huntington disease (HD) is a dominantly inherited human neurodegenerative disorder characterized by motor deficits, cognitive impairment, and psychiatric symptoms leading to inexorable decline and death. Since the identification of the huntingtin gene and the characteristic expanded CAG repeat/polyglutamine mutation, multiple murine genetic models and one rat genetic model have been generated. These models fall into two general categories: transgenic models with ectopic expression of the characteristic expanded CAG codon mutation, and knock-in models with expression of mutant huntingtin under control of endogenous regulatory elements. Rodent genetic models are valuable tools for studying mechanisms of pathogenesis in HD and for preclinical evaluation of possible therapies. In this mini-review, we provide a concise comparative summary of rodent genetic models of HD.

Summary: Background: Development of valid, non-invasive biomarkers for parkinsonian syndromes is crucially needed. We aimed to assess whether non-invasive diffusion-weighted MRI can distinguish between parkinsonian syndromes using an automated imaging approach. Methods: We did an international study at 17 MRI centres in Austria, Germany, and the USA. We used diffusion-weighted MRI from 1002 patients and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) to develop and validate disease-specific machine learning comparisons using 60 template regions and tracts of interest in Montreal Neurological Institute space between Parkinson's disease and atypical parkinsonism (multiple system atrophy and progressive supranuclear palsy) and between multiple system atrophy and progressive supranuclear palsy. For each comparison, models were developed on a training and validation cohort and evaluated in an independent test cohort by quantifying the area under the curve (AUC) of receiving operating characteristic curves. The primary outcomes were free water and free-water-corrected fractional anisotropy across 60 different template regions. Findings: In the test cohort for disease-specific comparisons, the diffusion-weighted MRI plus MDS-UPDRS III model (Parkinson's disease vs atypical parkinsonism had an AUC 0·962; multiple system atrophy vs progressive supranuclear palsy AUC 0·897) and diffusion-weighted MRI only model had high AUCs (Parkinson's disease vs atypical parkinsonism AUC 0·955; multiple system atrophy vs progressive supranuclear palsy AUC 0·926), whereas the MDS-UPDRS III only models had significantly lower AUCs (Parkinson's disease vs atypical parkinsonism 0·775; multiple system atrophy vs progressive supranuclear palsy 0·582). These results indicate that a non-invasive imaging approach is capable of differentiating forms of parkinsonism comparable to current gold standard methods. Interpretations: This study provides an objective, validated, and generalisable imaging approach to distinguish different forms of parkinsonian syndromes using multisite diffusion-weighted MRI cohorts. The diffusion-weighted MRI method does not involve radioactive tracers, is completely automated, and can be collected in less than 12 min across 3T scanners worldwide. The use of this test could positively affect the clinical care of patients with Parkinson's disease and parkinsonism and reduce the number of misdiagnosed cases in clinical trials. Funding: National Institutes of Health and Parkinson's Foundation.

OBJECTIVES:In this study, we developed a model of presymptomatic treatment of Alzheimer disease (AD) after a screening diagnostic evaluation and explored the circumstances required for an AD prevention treatment to produce aggregate net population benefit. METHODS:Monte Carlo simulation methods were used to estimate outcomes in a simulated population derived from data on AD incidence and mortality. A wide variety of treatment parameters were explored. Net population benefit was estimated in aggregated QALYs. Sensitivity analyses were performed by individually varying the primary parameters. FINDINGS:In the base-case scenario, treatment effects were uniformly positive, and net benefits increased with increasing age at screening. A highly efficacious treatment (i.e. relative risk 0.6) modeled in the base-case is estimated to save 20 QALYs per 1000 patients screened and 221 QALYs per 1000 patients treated. CONCLUSIONS:Highly efficacious presymptomatic screen and treat strategies for AD are likely to produce substantial aggregate population benefits that are likely greater than the benefits of aspirin in primary prevention of moderate risk cardiovascular disease (28 QALYS per 1000 patients treated), even in the context of an imperfect treatment delivery environment.

Sleep dysfunction and excessive daytime sleepiness are common in Parkinson disease (PD). Several studies suggest that PD patients exhibit high prevalence of sleep-disordered breathing (SDB). PD has a complex profile of neurochemical deficits in which abnormalities of different neurotransmitter systems may play significant and differing roles in the development of non-motor features. In the present study, we investigated whether SDB in PD is related to serotoninergic neuron degeneration. We used a cross-sectional design to assess the correlation between SDB and measures of caudal brainstem serotonin neuron integrity. Fifty one PD participants with mean disease duration of 6.0 (SD 3.7) years and mean age of 63.9 (SD 6.2) years were studied. We measured caudal brainstem serotoninergic innervation with [(11)C]DASB positron emission tomography (PET) imaging and striatal dopaminergic innervation with [(11)C]DTBZ PET imaging. SDB was assessed with polysomnography (PSG) and sleepiness with multiple sleep latency tests. Greater than half of participants exhibited PSG evidence of significant SDB; 12 participants had normal PSGs, 6 had mild SDB, 20 had moderate SDB, and 13 had severe SDB. We found no association between severity of SDB and caudal brainstem serotoninergic innervation in PD participants. Striatal dopaminergic denervation did not correlate with severity of SDB. We did find significant correlations between measures of motor function impairment and sleep quantity and quality in PD. Neither serotoninergic nor dopaminergic neuron degeneration is likely to play a major role in SDB observed in PD patients.