Dietary fasting and time-restricted eating in Huntington's disease: therapeutic potential and underlying mechanisms.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT. HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep-wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.

Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Gait and balance in apolipoprotein Ɛ4 allele carriers in older adults and Parkinson's disease.

Background: Gait and balance impairments are among the most troublesome and heterogeneous in Parkinson's disease (PD). This heterogeneity may, in part, reflect genetic variation. The apolipoprotein E (APOE) gene has three major allelic variants (ε2, ε3 and ε4). Previous work has demonstrated that older adult (OA) APOE ε4 carriers demonstrate gait deficits. This study compared gait and balance measures between APOE ε4 carriers and non-carriers in both OA and PD. Methods: 334 people with PD (81 APOE ε4 carriers and 253 non-carriers) and 144 OA (41 carriers and 103 non-carriers) were recruited. Gait and balance were assessed using body-worn inertial sensors. Two-way analyses of covariance (ANCOVA) compared gait and balance characteristics between APOE ε4 carriers and non-carriers in people with PD and OA, controlling for age, gender, and testing site. Results: Gait and balance were worse in people with PD compared to OA. However, there were no differences between APOE ε4 carriers and non-carriers in either the OA or PD group. In addition, there were no significant group (OA/PD) by APOE ε4 status (carrier/non-carrier) interaction effects for any measures of gait or balance. Conclusions: Although we found expected impairments in gait and balance in PD compared to OA, gait and balance characteristics did not differ between APOE ε4 carriers and non-carriers in either group. While APOE status did not impact gait and balance in this cross-sectional study, future work is needed to determine whether progression of gait and balance deficits is faster in PD APOE Ɛ4 carriers.

Understanding health care needs among Veterans with Parkinson's disease: A survey study.

Among Veterans, it is estimated that 110,000 are living with Parkinson's disease (PD) in the United States. Whether or not Veterans living with PD are enrolled in the Veterans Health Administration (VHA), they may require special considerations when it comes to their care. We administered a survey to Parkinson's Foundation constituents with PD who had previously reported their Veteran status. Our goal was to identify areas where intervention can lead to improved health outcomes for Veterans living with Parkinson's disease. We specifically wanted to examine 1) the proportion of our Veteran constituents receiving services through the VHA, 2) the comprehensive care services that were utilized by Veterans living with PD, and 3) self-reported mental health and mobility status. We also wanted to compare those receiving care within and outside the VHA to see where there may be areas for improvement. With a response rate of 29.8% we received surveys from 409 United States Veterans with PD. As expected, mental health (MH) concerns in the previous 12 months were common with 36.0% of Veterans reporting concerns. Only 22.1% of respondents received care through VHA. Respondents with more falls and mental health concerns as well as those with higher levels of education and younger age were more likely to be seen at a VHA facility. In this sample, education level, household income, marital status, and VHA status were positively associated with increased health care utilization among Veterans. Those seen within the VHA were more likely to utilize MH and speech and language pathology consultation. This study highlights the importance of targeting educational outreach about care best practices for Veterans living with PD beyond VHA's current reach as well as the importance of access to good MH resources.

Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease.

The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and without GBA variants (mutation carriers and E326K polymorphism) and explore direct and indirect effects of GBA status on gait, balance, and cognition. 332 participants, 43 of whom had GBA variants, were recruited. Participants completed a comprehensive, objective assessment of gait and standing balance using body-worn inertial sensors. Group differences in gait and balance between PD with and without GBA variants were assessed with linear regression, adjusting for age, gender, clinical testing site, disease duration, and apolipoprotein E (APOE) ɛ4 status. Structural equation modeling (SEM) explored direct relationships between GBA status and gait and balance and indirect relationships between GBA status and gait and balance via cognition. The GBA variant group had more impaired gait (pace and variability) and balance (sway area/jerk and sway velocity), than the non-GBA variant group. SEM demonstrated cognition as a mediator of GBA status on gait and balance. The close relationships among GBA, gait/balance, and cognition suggest potential for novel therapeutics to target the GBA pathway and/or cognition to improve mobility in PD GBA variants.

Predictive Modeling of Alzheimer's and Parkinson's Disease Using Metabolomic and Lipidomic Profiles from Cerebrospinal Fluid.

In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing patients with Alzheimer's disease (AD), Parkinson's disease (PD), and healthy age-matched controls. We emphasize several statistical challenges associated with metabolomic studies where the number of measured metabolites far exceeds sample size. We found strong separation in the metabolome between PD and controls, as well as between PD and AD, with weaker separation between AD and controls. Consistent with existing literature, we found alanine, kynurenine, tryptophan, and serine to be associated with PD classification against controls, while alanine, creatine, and long chain ceramides were associated with AD classification against controls. We conducted a univariate pathway analysis of untargeted and targeted metabolite profiles and find that vitamin E and urea cycle metabolism pathways are associated with PD, while the aspartate/asparagine and c21-steroid hormone biosynthesis pathways are associated with AD. We also found that the amount of metabolite missingness varied by phenotype, highlighting the importance of examining missing data in future metabolomic studies.

Oligoclonal Bands in Multiple System Atrophy: Case Report and Proposed Mechanisms of Immunogenicity.

Multiple System Atrophy (MSA) is a neurodegenerative disease with heterogeneous manifestations and is therefore difficult to diagnose definitively. Because of this, oftentimes an extensive workup for mimickers is undertaken. We herein report a case where the history and cerebrospinal fluid (CSF) findings of oligoclonal bands suggested an inflammatory disorder. Immunomodulatory therapy failed to ameliorate symptoms or alter the trajectory of continued physical decline, prompting re-visitation of the diagnosis. Oligoclonal bands, while generally viewed as specific to multiple sclerosis or other inflammatory conditions, may be seen in other disease processes. Therefore, this finding should not exclude consideration of neurodegenerative disease.

A Metabolomic Aging Clock Using Human Cerebrospinal Fluid.

Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that, in regression models using "-omic" platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these "omic clocks" provide measures of biological age. This paper presents predictive models for age using metabolomic profiles of cerebrospinal fluid (CSF) from healthy human subjects and finds that metabolite and lipid data are generally able to predict chronological age within 10 years. We use these models to predict the age of a cohort of subjects with Alzheimer's and Parkinson's disease and find an increase in prediction error, potentially indicating that the relationship between the metabolome and chronological age differs with these diseases. However, evidence is not found to support the hypothesis that our models will consistently overpredict the age of these subjects. In our analysis of control subjects, we find the carnitine shuttle, sucrose, biopterin, vitamin E metabolism, tryptophan, and tyrosine to be the most associated with age. We showcase the potential usefulness of age prediction models in a small data set (n = 85) and discuss techniques for drift correction, missing data imputation, and regularized regression, which can be used to help mitigate the statistical challenges that commonly arise in this setting. To our knowledge, this work presents the first multivariate predictive metabolomic and lipidomic models for age using mass spectrometry analysis of CSF.

Role of Directional Configuration in Deep Brain Stimulation for Essential Tremor: A Single Center Experience.

Background: Traditionally, the standard of care for medication refractory essential tremor has been to utilize omnidirectional deep brain stimulation of the ventral intermediate nucleus. The advent of directional stimulation allows for spatial restriction of the stimulation on selected targets without involving the neighboring structures, thereby limiting off-target side effects and improving clinical utility. Methods: We performed a retrospective review of patients between February 2017 and September 2019 who had received ventral intermediate nucleus deep brain stimulation that allowed for directional programming (specifically Abbott/St. Jude). Initial and final major programming sessions post-operatively (approximately 30- and 90-days post-surgery) were examined to determine frequency and reason for use of directional programming. Results: A total of 33 total patients were identified. A little over half were males (58%, N = 19), with an average age of 68 years old (SD 9.3) at the time of surgery, and a disease duration of almost 30 years (27.2, SD 19) with a wide range from 2-62 years. After initial programming, over 50% (17 of 33) of patients were using directional configurations. This increased to 85% (28 of 33) at the 90-day programming. Reasons for conversion to directional configuration included avoidance of side effects (specifically, muscle contractions (9/33), paresthesia (5/33), dysarthria (1/33) and gait ataxia (1/33)) or improved tremor control (12/33). Discussion: Our single-center experience suggests that in the large majority of cases, directional leads were utilized and offered advantages in tremor control or side effect avoidance.

Semantic fluency and processing speed are reduced in non-cognitively impaired participants with Parkinson's disease.

Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10 years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B = -3.77, 95% CIs [-5.76 to -1.77], p < .001, and B = -2.02, 95% CIs [-3.12, -0.92], p < .001, respectively), even after excluding those with moderate to severe motor symptoms (B = -2.73, 95% CIs [-4.94 to -0.53], p = .015 and B = -2.11, 95% CIs [-3.32 to -0.91], p < .001, respectively) or longer disease duration (B = -3.89, 95% CIs [-6.14 to -1.63], p < .001 and B = -1.58, 95% CIs [-2.78 to -0.37], p = .010, respectively). Semantic verbal fluency remained significantly negatively associated with PD diagnosis after controlling for processing speed (B = -1.66, 95% CIs [-2.79 to -0.53], p = .004).Conclusions: Subtle decline in specific cognitive domains may be present among people diagnosed with PD but without evidence to support a formal cognitive diagnosis. These results suggest the importance of early awareness of the potential for diminishing aspects of cognition in PD even among those without mild cognitive impairment or dementia.

Approach to Posture and Gait in Huntington's Disease.

Disturbances of gait occur in all stages of Huntington's disease (HD) including the premanifest and prodromal stages. Individuals with HD demonstrate the slower speed of gait, shorter stride length, and increased variability of gait parameters as compared to controls; cognitive disturbances in HD often compound these differences. Abnormalities of gait and recurrent falls lead to decreased quality of life for individuals with HD throughout the disease. This scoping review aims to outline the cross-disciplinary approach to gait evaluation in HD and will highlight the utility of objective measures in defining gait abnormalities in this patient population.

A Report of Tamoxifen and Parkinson's Disease in a US Population and a Review of the Literature.

BACKGROUND: Tamoxifen, a selective estrogen receptor modulator, has been shown to variably affect Parkinson's disease (PD) risk. OBJECTIVE: The aim of this study was to review epidemiological literature and evaluate the rate of PD in women with breast cancer with tamoxifen exposure in a US population. METHODS: A literature search was conducted to identify relevant studies. We performed a retrospective cohort analysis using the Nurses' Health Study Version One to report descriptive statistics. RESULTS: Most studies suggest there may be a time-dependent effect of tamoxifen on PD risk, with the risk increasing with time from exposure. However, rates of PD in persons exposed to tamoxifen overall appear to be low. In our cohort, PD was evident in 6.2 per 1,000 of those with tamoxifen use and 3.6 per 1,000 of those without tamoxifen use. Time from breast cancer to PD diagnosis was 9.7 years among women with tamoxifen exposure and 11.7 among women without. CONCLUSIONS: Tamoxifen may be associated with an increased risk for PD. Further research is needed to elucidate the role of estrogen and selective estrogen antagonism in PD. © 2021 International Parkinson and Movement Disorder Society.

Relationships Between Sensorimotor Inhibition and Mobility in Older Adults With and Without Parkinson's Disease.

BACKGROUND: Reduced cortical sensorimotor inhibition is associated with mobility and cognitive impairments in people with Parkinson's disease (PD) and older adults (OAs). However, there is a lack of clarity regarding the relationships among sensorimotor, cognitive, and mobility impairments. The purpose of this study was to determine how cortical sensorimotor inhibition relates to impairments in mobility and cognition in people with PD and OAs. METHOD: Cortical sensorimotor inhibition was characterized with short-latency afferent inhibition (SAI) in 81 people with PD and 69 OAs. Six inertial sensors recorded single- and dual-task gait and postural sway characteristics during a 2-minute walk and a 1-minute quiet stance. Cognition was assessed across the memory, visuospatial, executive function, attention, and language domains. RESULTS: SAI was significantly impaired in the PD compared to the OA group. The PD group preformed significantly worse across all gait and postural sway tasks. In PD, SAI significantly correlated with single-task foot strike angle and stride length variability, sway area, and jerkiness of sway in the coronal and sagittal planes. In OAs, SAI significantly related to single-task gait speed and stride length, dual-task stride length, and immediate recall (memory domain). No relationship among mobility, cognition, and SAI was observed. CONCLUSIONS: Impaired SAI related to slower gait in OA and to increased gait variability and postural sway in people with PD, all of which have been shown to be related to increased fall risk.

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Sensorimotor Inhibition and Mobility in Genetic Subgroups of Parkinson's Disease.

Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) ε4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 ε4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 ε4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p < 0.01) in PD compared to OA. Postural sway area/jerkiness (p < 0.01) and velocity (p < 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD ε4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: ε4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD ε4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status.

Multivariate prediction of dementia in Parkinson's disease.

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n = 827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.