Diffusion Tensor Imaging-Along the Perivascular-Space Index Is Associated with Disease Progression in Parkinson's Disease.

BACKGROUND: The glymphatic clearance pathway is a waste clearance system that allows for removal of soluble proteins such as amyloid ß (Aß) from the brain. Higher Aß levels are associated with cognitive dysfunction in Parkinson's disease (PD). Diffusion tensor imaging-along the perivascular space (DTI-ALPS) is an imaging measure proposed to indirectly measure glymphatic function. OBJECTIVES: Evaluate differences in DTI-ALPS-index between PD and healthy controls (HC) and characterize relationships between this proposed measure of glymphatic clearance, cognition, and disease severity in PD. METHODS: PD (n = 32) and HC (n = 23) participants underwent brain imaging to assess DTI-ALPS. PD participants were classified as PD-normal cognition (PD-NC; n = 20) or PD-mild cognitive impairment (PD-MCI; n = 12) based on a Level II comprehensive cognitive assessment. A subgroup of PD participants (n = 21) returned for annual assessments for up to 4 years after baseline. Longitudinal outcomes included changes in performance on the comprehensive cognitive assessment and changes in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: PD participants had lower DTI-ALPS-index compared to HC. PD participants classified as PD-MCI had significantly lower DTI-ALPS-index compared to PD-NC. Lower DTI-ALPS-index at baseline was associated with longitudinal cognitive decline and worse longitudinal disease severity. CONCLUSIONS: Glymphatic clearance, as measured with DTI-ALPS, has potential to serve as a marker of longitudinal disease progression. Interventions targeting glymphatic function should be explored for potential to slow cognitive decline in PD. © 2024 International Parkinson and Movement Disorder Society.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Development of Dynamic Measures to Assess Balance Confidence and State Anxiety While Walking at Increasing Speeds in Young and Older Adults.

The purpose of this study was to determine the test-retest reliability and construct validity of tools to assess how balance confidence (BC) and state anxiety (SA) change with progressively increasing walking speeds. Sixteen young adults and 15 older adults attended two sessions. Individuals began walking on a treadmill at 0.4 m/s Participants chose to continue increasing the treadmill speed (up to 2.0 m/s) or to discontinue the protocol while rating their BC and SA after completing each speed. BC at participants' fastest speed attempted demonstrated high and moderate test-retest reliability among young (intraclass correlation coefficient [ICC] = .908) and older adults (ICC = .704). SA for young adults and older adults was good (ICC = .833) and fair (ICC = .490), respectively. Our measures also correlated with measures of dynamic stability while walking for young (r = -.67, p = .008) and older adults (r = .54, p = .046). Our dynamic measures of BC and SA are valid and reliable in young and older adults.

Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof-of-Concept Trial.

BACKGROUND: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. OBJECTIVES: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). METHODS: Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. RESULTS: Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (-4.78) and solriamfetol (-4.82 to -5.72; P > 0.05). MWT improved dose-dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). CONCLUSIONS: Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Widespread Tau-Specific CD4 T Cell Reactivity in the General Population.

Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau-derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4+ T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease.

Intermittent Theta Burst Stimulation (iTBS) for Treatment of Chronic Post-Stroke Aphasia: Results of a Pilot Randomized, Double-Blind, Sham-Controlled Trial.

BACKGROUND Research indicates intermittent theta burst stimulation (iTBS) is a potential treatment of post-stroke aphasia. MATERIAL AND METHODS In this double-blind, sham-controlled trial (NCT01512264) participants were randomized to receive 3 weeks of sham (G0), 1 week of iTBS/2 weeks of sham (G1), 2 weeks of iTBS/1 week of sham (G2), or 3 weeks of iTBS (G3). FMRI localized residual language function in the left hemisphere; iTBS was applied to the maximum fMRI activation in the residual language cortex in the left frontal lobe. FMRI and aphasia testing were conducted pre-treatment, at ≤1 week after completing treatment, and at 3 months follow-up. RESULTS 27/36 participants completed the trial. We compared G0 to each of the individual treatment group and to all iTBS treatment groups combined (G1₋3). In individual groups, participants gained (of moderate or large effect sizes; some significant at P<0.05) on the Boston Naming Test (BNT), the Semantic Fluency Test (SFT), and the Aphasia Quotient of the Western Aphasia Battery-Revised (WAB-R AQ). In G1₋3, BNT, and SFT improved immediately after treatment, while the WAB-R AQ improved at 3 months. Compared to G0, the other groups showed greater fMRI activation in both hemispheres and non-significant increases in language lateralization to the left hemisphere. Changes in IFG connectivity were noted with iTBS, showing differences between time-points, with some of them correlating with the behavioral measures. CONCLUSIONS The results of this pilot trial support the hypothesis that iTBS applied to the ipsilesional hemisphere can improve aphasia and result in cortical plasticity.

Effects of exercise on sleep in neurodegenerative disease.

As the population ages, the incidence and prevalence of neurodegenerative disorders will continue to increase. Persons with neurodegenerative disease frequently experience sleep disorders, which not only affect quality of life, but potentially accelerate progression of the disease. Unfortunately, pharmacological interventions are often futile or have adverse effects. Therefore, investigation of non-pharmacological interventions has the potential to expand the treatment landscape for these disorders. The last decade has observed increasing recognition of the beneficial role of exercise in brain diseases, and neurodegenerative disorders in particular. In this review, we will focus on the therapeutic role of exercise for sleep dysfunction in four neurodegenerative diseases, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Available data suggest that exercise may have the potential to improve sleep disorders and attenuate neurodegeneration, particularly in Alzheimer's disease and Parkinson's disease. However, additional research is required in order to understand the most effective exercise therapy for these indications; the best way to monitor the response to interventions; the influence of exercise on sleep dysfunction in Huntington's disease and amyotrophic lateral sclerosis; and the mechanisms underlying exercise-induced sleep modifications.

Randomized, Controlled Trial of Exercise on Objective and Subjective Sleep in Parkinson's Disease.

BACKGROUND: Sleep dysfunction is common and disabling in persons with Parkinson's Disease (PD). Exercise improves motor symptoms and subjective sleep quality in PD, but there are no published studies evaluating the impact of exercise on objective sleep outcomes. The goal of this study was to to determine if high-intensity exercise rehabilitation combining resistance training and body-weight interval training, compared with a sleep hygiene control improved objective sleep outcomes in PD. METHODS: Persons with PD (Hoehn & Yahr stages 2-3; aged ≥45 years, not in a regular exercise program) were randomized to exercise (supervised 3 times a week for 16 weeks; n = 27) or a sleep hygiene, no-exercise control (in-person discussion and monthly phone calls; n = 28). Participants underwent polysomnography at baseline and post-intervention. Change in sleep efficiency was the primary outcome, measured from baseline to post-intervention. Intervention effects were evaluated with general linear models with measurement of group × time interaction. As secondary outcomes, we evaluated changes in other aspects of sleep architecture and compared the effects of acute and chronic training on objective sleep outcomes. RESULTS: The exercise group showed significant improvement in sleep efficiency compared with the sleep hygiene group (group × time interaction: F = 16.0, P < 0.001, d = 1.08). Other parameters of sleep architecture also improved in exercise compared with sleep hygiene, including total sleep time, wake after sleep onset, and slow-wave sleep. Chronic but not acute exercise improved sleep efficiency compared with baseline. CONCLUSIONS: High-intensity exercise rehabilitation improves objective sleep outcomes in PD. Exercise is an effective nonpharmacological intervention to improve this disabling nonmotor symptom in PD. © 2020 International Parkinson and Movement Disorder Society.

Does restless legs syndrome impact cognitive function via sleep quality in adults with Parkinson's disease?

Purpose: Restless legs syndrome (RLS) is a sleep disorder that results in sleep dysfunction. Sleep disruption can have profound negative consequences in adults with Parkinson's disease (PD), potentially including cognitive dysfunction. This study examined the relationships among RLS, cognition, and sleep quality in persons with PD.Materials and methods: Participants (N = 79) with idiopathic PD completed six questionnaires evaluating RLS, sleep quality, daytime sleepiness, global cognitive function, sleep apnea risk, and depression. Participants were further examined for body mass index composition and motor symptom severity (MDS-UPDRS Part III).Results: Persons with RLS (n = 25) had significantly worse cognitive function (p = 0.035, d = -0.56) and sleep quality (p < 0.0001, d = -1.19), and more daytime sleepiness (p = 0.009, d = 0.67) than those without RLS (n = 54). Cognitive function was not significantly correlated with sleep quality (rs = 0.113) or daytime sleepiness (rs = -0.001). The association between RLS and cognition was not attenuated by controlling for sleep quality or daytime sleepiness.Conclusions: This study is unique as it is the first to consider the possibility that RLS in PD may be associated with cognitive deficits through a pathway involving sleep quality. Persons with RLS and PD have greater deficits in both sleep quality and cognitive function than individuals without RLS; however, cognitive dysfunction among those with PD and RLS in this sample is not accounted for by sleep quality.

Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.