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Background Parkinson's disease (PD) patients experience gut microbiota dysbiosis. Probiotic intervention could potentially serve as a safe and effective adjunctive therapeutic approach for PD, but its effects on rapid eye movement sleep behavior disorder (RBD) and motor symptoms in PD patients warrant further investigation. Objectives To examine the influence of probiotics on RBD, motor symptoms, gut microbiota, and serum metabolites in individuals with PD. Methods In this randomized controlled trial, PD patients were randomly allocated to either a probiotics or a control group while maintaining standard treatments. Clinical outcomes, including Unified Parkinson's Disease Rating Scale (UPDRS) and RBD Questionnaire‐Hong Kong (RBDQ‐HK) were assessed at baseline and post‐treatment. Furthermore, fecal and blood samples were collected from PD patients at both timepoints, with additional samples obtained from healthy controls for comparison. The 16S rRNA gene V3‐V4 region sequencing method was used to analyze gut microbiota composition, and untargeted metabolomic techniques were utilized to assess serum metabolite alterations, followed by correlation analysis. Results Fifty eligible PD patients were enrolled and randomly allocated into two groups. After 12 weeks of intervention, the probiotic group showed significant reductions in both UPDRS total scores (−4.8 ± 7.5 vs. 1.8 ± 13.1, p = 0.009) and RBDQ‐HK scores (−7.5 ± 6.5 vs. 0 ± 5.8, p = 0.015) compared to controls. Gut microbiota analysis revealed increased abundance of Actinobacteria, Negativicutes, and Bacillus, with reductions in Lactococcus, Comamonas, and Enterococcus after probiotic intervention. Furthermore, compared to normal controls, PD patients exhibited 9 significantly elevated and 11 significantly reduced metabolites; probiotic intervention altered the serum metabolome in PD patients. Conclusions This study demonstrated probiotics' potential to ameliorate RBD and motor symptoms while positively affecting the composition of the gut microbiota and serum metabolites in PD patients. Twelve‐week probiotics supplementation in Parkinson's disease (PD) patients demonstrated significant improvements in motor symptoms and REM sleep behavior disorder (RBD) symptoms. Additionally, the intervention exerted a modulatory effect on gut microbiota composition and plasma metabolite profiles, suggesting a potential role of probiotics in modulating the gut‐brain axis in PD.

Key Points Diagnosis of Parkinson disease (PD) requires motor symptoms, but it is now clear that the typical motor signs are preceded by preclinical and prodromal phases of the disease The utility of a marker of prodromal PD depends on the strength of evidence that it is a relevant marker, its specificity, its lead time, and the practicalities of assessment Identification of reliable markers requires prospective studies; studies in high-risk populations are susceptible to selection bias and limited generalizability The strongest marker of prodromal PD is rapid eye movement (REM) sleep behaviour disorder; other markers supported by strong evidence include subtle motor dysfunction, olfactory loss, autonomic dysfunction and affective disorders Markers of prodromal PD have been combined to predict the probability of prodromal PD, most notably in the International Parkinson Disease Movement Disorders Society task force diagnostic guidelines The earliest stages of Parkinson disease (PD) offer the best opportunity to intervene, but detecting early disease is difficult. In this Review, Postuma and Berg provide an overview of established and potential markers of prodromal PD, and consider how these markers can be combined to identify patients who have prodromal PD and could benefit from treatment. Efforts to develop neuroprotective therapy for Parkinson disease (PD) are focusing on the early stages of disease, which offer the best opportunity to intervene. Early PD can be divided into preclinical, prodromal and clinical stages; in this Review, we focus on the prodromal stage and markers that can be used to identify prodromal PD. We consider the necessary properties of a marker, before providing an overview of the proven and potential markers of prodromal PD, including clinical nonmotor markers, clinical motor markers, neuroimaging markers and tissue biomarkers. Markers for which the ability to predict conversion to PD is supported by the strongest evidence include olfactory loss, REM sleep behaviour disorder and constipation. Markers with the highest diagnostic strength include REM sleep behaviour disorder, dopaminergic imaging and subtle motor parkinsonism. The lead time — the period between the appearance of a marker and conversion to PD — is highly variable between markers, ranging from 5 years for impaired motor performance to >20 years for autonomic symptoms. The cost of screening for these markers also varies dramatically: some require just questionnaires, whereas others require sophisticated scanning techniques. Finally, we summarize how prodromal and risk markers can be combined to estimate the probability that an individual has prodromal PD, with a focus on the International Parkinson Disease and Movement Disorders Society (MDS) Prodromal Parkinson Criteria.

Introduction In Parkinson’s disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) might either precede the appearance of motor symptoms, or develop during the disease course. PD patients with RBD are characterized by a higher burden of cognitive impairment and hallucinations. However, few studies have analyzed the clinical characteristics of PD patients according to the timeline of RBD onset. Methods PD patients have been retrospectively enrolled. Presence and onset of probable RBD (pRBD) has been evaluated using RBD Screening Questionnaire (score ≥ 6). Presence of Mild Cognitive Impairment (MCI) at baseline has been evaluated using the MDS criteria level II. Presence of motor complications and hallucinations has been evaluated at a 5-year follow-up. Results A total of 115 PD patients (65 men, 56.5%; mean age 62.5 ± 9.7 years; mean disease duration 3.7 ± 3.9 years) have been enrolled. Out of these, 63 fulfilled the diagnosis of pRBD (54.8%) with 21 (33.3%) reporting the RBD onset before the onset of the motor symptoms (PD-RBDpre), and 42 (66.7%) after the motor symptoms (PD-RBDpost). At enrolment presence of MCI was associated with PD-RBDpre patients (OR 5.04; 95% CI 1.33–19.05; p value 0.02). At follow-up, a higher risk of developing hallucinations was also associated with PD-RBDpre (OR 4.68; 95% CI 1.24–17.63; p  = 0.022). Conclusions PD patients with RBD occurring before the onset of motor symptoms represent a subgroup of patients with a more severe cognitive phenotype and with a higher risk of developing hallucinations along the disease course, with significant implications in terms of prognostic stratification and therapeutic approach.

Approximately 50% of older adults complain of difficulty sleeping. Poor sleep results in increased risk of significant morbidity and mortality. The decrements seen in the sleep of the older adult are often due to a decrease in the ability to get needed sleep. However, the decreased ability is less a function of age and more a function of other factors that accompany aging, such as medical and psychiatric illness, increased medication use, advances in the endogenous circadian clock and a higher prevalence of specific sleep disorders. Given the large number of older adults with sleep complaints and sleep disorders, there is a need for health care professionals to have an increased awareness of these sleep disturbances to better enable them to assess and treat these patients. A thorough sleep history (preferably in the presence of their bed partner) is required for a proper diagnosis, and when appropriate, an overnight sleep recording should be done. Treatment of primary sleep problems can improve the quality of life and daytime functioning of older adults. This paper reviews the diagnoses and characteristics of sleep disorders generally found in the older adult. While aimed at the practicing geriatrician, this paper is also of importance for any gerontologist interested in sleep.

Background and Purpose Obstructive sleep apnea (OSA) frequently occurs in Parkinson Disease (PD), probably caused by upper airway dysfunctions or shared pathogenetic mechanisms. OSA may precede PD diagnosis or worsen throughout its course, but its relationship with clinical features and dopaminergic medication remains unclear. This meta‐analysis aimed to provide a reliable estimate of OSA prevalence in the PD population (PD‐OSA) and to clarify its clinical associated factors to help clinicians in understanding the underlying pathophysiological mechanisms. Methods A systematic literature search was performed up to April 2023 using the PubMed, Scopus, and PsycINFO databases. Articles were included if they provided data on PD patients with and without OSA. Pooled prevalence for PD‐OSA was calculated using the proportions of PD participants diagnosed with OSA. Demographic and clinical features associated with PD‐OSA were explored by comparing PD patients with and without OSA. Results Seventeen studies were included in the meta‐analysis. Pooled OSA prevalence was 45% of a total sample of 1448 PD patients and was associated with older age, male sex, higher body mass index (BMI), more severe motor disturbances and periodic limb movements, reduced risk of rapid eye movement sleep behavior disorder, intake of dopamine agonists, and worse excessive daytime sleepiness. No relationship emerged with cognitive functioning and neuropsychiatric manifestations. Conclusions OSA affects nearly half of PD patients as a secondary outcome of predisposing factors such as older age and higher BMI in addition to PD‐related motor impairment. Future studies should focus on determining the impact of both clinical features and dopaminergic medication on the development of PD‐OSA.

Characterized by dream-enactment motor manifestations arising from rapid eye movement (REM) sleep, REM sleep behavior disorder (RBD) is frequently encountered in Parkinson’s disease (PD). Yet the specific neurostructural changes associated with RBD in PD patients remain to be revealed by neuroimaging. Here we identified such neurostructural alterations by comparing large samples of magnetic resonance imaging (MRI) scans in 69 PD patients with probable RBD, 240 patients without RBD and 138 healthy controls, using deformation-based morphometry (p < 0.05 corrected for multiple comparisons). All data were extracted from the Parkinson’s Progression Markers Initiative. PD patients with probable RBD showed smaller volumes than patients without RBD and than healthy controls in the pontomesencephalic tegmentum, medullary reticular formation, hypothalamus, thalamus, putamen, amygdala and anterior cingulate cortex. These results demonstrate that RBD is associated with a prominent loss of volume in the pontomesencephalic tegmentum, where cholinergic, GABAergic and glutamatergic neurons are located and implicated in the promotion of REM sleep and muscle atonia. It is additionally associated with more widespread atrophy in other subcortical and cortical regions whose loss also likely contributes to the altered regulation of sleep-wake states and motor activity underlying RBD in PD patients.

Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P  = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P  = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P  = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P  = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P  = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P  = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.

There is sufficient evidence that the pathological process that causes Parkinson’s disease begins years before the clinical diagnosis is made. Over the last 15 years, there has been much interest in the existence of a prodrome in some patients, with a particular focus on non-motor symptoms such as reduced sense of smell, REM-sleep disorder, depression, and constipation. Given that the diagnostic criteria for Parkinson’s disease depends on the presence of bradykinesia, it is somewhat surprising that there has been much less research into the possibility of subtle motor dysfunction as a pre-diagnostic pointer. This review will focus on early motor features and provide some advice on how to detect and measure them.

This retrospective single-center polysomnography-based study was designed to assess the frequency of REM sleep behavior disorder (RBD) in consecutive patients with Parkinsonism, including Parkinson disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. We observed RBD in 77% of 540 Parkinson patients, with rising frequency at higher age and regardless of sex, in >89% of 89 patients with dementia with Lewy bodies or multiple system atrophy, and in <15% of 42 patients with progressive supranuclear palsy or corticobasal degeneration. Thus, the prevalence of RBD in sporadic Parkinson disease might be higher than previously assumed, particularly in elderly patients.

REM sleep behavior disorder (RBD) has a tighter link with synucleinopathies than other neurodegenerative disorders. Parkinson’s Disease (PD) patients with RBD have a more severe motor and cognitive impairment; biomarkers for RBD are currently unavailable. Synaptic accumulation of α-Syn oligomers and their interaction with SNARE proteins is responsible for synaptic dysfunction in PD. We verified whether oligomeric α-Syn and SNARE components in neural-derived extracellular vesicles (NDEVs) in serum could be biomarkers for RBD. Forty-seven PD patients were enrolled, and the RBD Screening Questionnaire (RBDSQ) was compiled. A cut-off score > 6 to define probable RBD (p-RBD) and probable non-RBD (p non-RBD) was used. NDEVs were isolated from serum by immunocapture, and oligomeric α-Syn and SNARE complex components VAMP-2 and STX-1 were measured by ELISA. NDEVs’ STX-1A resulted in being decreased in p-RBD compared to p non-RBD PD patients. A positive correlation between NDEVs’ oligomeric α-Syn and RBDSQ total score was found (p = 0.032). Regression analysis confirmed a significant association between NDEVs’ oligomeric α-Syn concentration and RBD symptoms (p = 0.033) independent from age, disease duration, and motor impairment severity. Our findings suggest that synuclein-mediated neurodegeneration in PD-RBD is more diffuse. NDEVs’ oligomeric α-Syn and SNARE complex components’ serum concentrations could be regarded as reliable biomarkers for the RBD-specific PD endophenotype.