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BackgroundSleep disorders can occur in early Parkinson’s disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not been fully explored.ObjectiveTo describe the frequency, coexistence, and longitudinal change in excessive daytime sleepiness (EDS), insomnia, and probable REM sleep behavior disorder (pRBD) in early PD.MethodsData were obtained from the Parkinson’s Progression Markers Initiative (PPMI). EDS, insomnia, and pRBD were defined using the Epworth Sleepiness Scale, MDS-UPDRS Part I sub-item 1.7, and RBD screening questionnaire.Results218 PD subjects and 102 controls completed 5 years of follow-up. At baseline, 69 (31.7%) PD subjects reported one type of sleep disturbance, 25 (11.5%) reported two types of sleep disturbances, and three (1.4%) reported all three types of sleep disturbances. At 5 years, the number of PD subjects reporting one, two, and three types of sleep disturbances was 85 (39.0%), 51 (23.4%), and 16 (7.3%), respectively. Only 41(18.8%) patients were taking sleep medications. The largest increase in frequency was seen in insomnia (44.5%), followed by EDS (32.1%) and pRBD (31.2%). Insomnia was the most common sleep problem at any time over the 5-year follow-up. The frequency of sleep disturbances in HCs remained stable.ConclusionsThere is a progressive increase in the frequency of sleep disturbances in PD, with the number of subjects reporting multiple sleep disturbances increasing over time. Relatively a few patients reported multiple sleep disturbances, suggesting that they can have different pathogenesis. A large number of patients were not treated for their sleep disturbances.

: Gait disturbance is an early, cardinal feature of Parkinson's disease (PD) associated with falls and reduced physical activity. Progression of gait impairment in Parkinson's disease is not well characterized and a better understanding is imperative to mitigate impairment. Subtle gait impairments progress in early disease despite optimal dopaminergic medication. Evaluating gait disturbances over longer periods, accounting for typical aging and dopaminergic medication changes, will enable a better understanding of gait changes and inform targeted therapies for early disease. This study aimed to describe gait progression over the first 6 years of PD by delineating changes associated with aging, medication, and pathology. : One-hundred and nine newly diagnosed PD participants and 130 controls completed at least two gait assessments. Gait was assessed at 18-month intervals for up to 6 years using an instrumented walkway to measure sixteen spatiotemporal gait characteristics. Linear mixed-effects models assessed progression. : Ten gait characteristics significantly progressed in PD, with changes in four of these characteristics attributable to disease progression. Age-related changes also contributed to gait progression; changes in another two characteristics reflected both aging and disease progression. Gait impairment progressed irrespective of dopaminergic medication change for all characteristics except step width variability. : Discrete gait impairments continue to progress in PD over 6 years, reflecting a combination of, and potential interaction between, disease-specific progression and age-related change. Gait changes were mostly unrelated to dopaminergic medication adjustments, highlighting limitations of current dopaminergic therapy and the need to improve interventions targeting gait decline.

Low levels of physical activity (PA) and sleep disruption are commonly seen in older adult inpatients and are associated with poor health outcomes. Wearable sensors allow for objective continuous monitoring; however, there is no consensus as to how wearable sensors should be implemented. This review aimed to provide an overview of the use of wearable sensors in older adult inpatient populations, including models used, body placement and outcome measures. Five databases were searched; 89 articles met inclusion criteria. We found that studies used heterogenous methods, including a variety of sensor models, placement and outcome measures. Most studies reported the use of only one sensor, with either the wrist or thigh being the preferred location in PA studies and the wrist for sleep outcomes. The reported PA measures can be mostly characterised as the frequency and duration of PA (Volume) with fewer measures relating to intensity (rate of magnitude) and pattern of activity (distribution per day/week). Sleep and circadian rhythm measures were reported less frequently with a limited number of studies providing both physical activity and sleep/circadian rhythm outcomes concurrently. This review provides recommendations for future research in older adult inpatient populations. With protocols of best practice, wearable sensors could facilitate the monitoring of inpatient recovery and provide measures to inform participant stratification and establish common objective endpoints across clinical trials.

BackgroundMild cognitive impairment (MCI) is common in early Parkinson's disease (PD). We evaluated the stability of PD-MCI over time to determine its clinical utility as a marker of disease.Methods212 newly diagnosed participants with PD were recruited into a longitudinal study and reassessed after 18 and 36 months. Participants completed a range of clinical and neuropsychological assessments. PD-MCI was classified using Movement Disorders Society Task Force level I (Montreal Cognitive Assessment <26) and level II (using cut-offs of 1, 1.5 and 2SD) criteria.ResultsAfter 36 months, 75% of participants returned; 8% of patients had developed a dementia all of which were previously PD-MCI. Applying level I criteria, 70% were cognitively stable, 19% cognitively declined and 11% improved over 36 months. Applying level II criteria (1, 1.5 and 2SD), 25% were cognitively stable, 41% cognitively declined, 15% improved and 19% fluctuated over 36 months. 18% of participants reverted to normal cognition from PD-MCI.DiscussionCognitive impairment in PD is complex, with some individuals' function fluctuating over time and some reverting to normal cognition. PD-MCI level I criteria may have greater clinical convenience, but more comprehensive level II criteria with 2SD cut-offs may offer greater diagnostic certainty.

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N -formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis. The association between certain mitochondrial DNA variants and increased risk of late-onset diseases in humans could be explained by a direct role of mitochondrial DNA in the regulation of cellular proteostasis.

Participating in habitual physical activity (HPA) may slow onset of dependency and disability for people with Parkinson’s disease (PwP). While cognitive and physical determinants of HPA are well understood, psychosocial influences are not. This pilot study aimed to identify psychosocial factors associated with HPA to guide future intervention development. Sixty-four PwP participated in this study; forty had carer informants. PwP participants wore a tri-axial accelerometer on the lower back continuously for seven days at two timepoints (18 months apart), measuring volume, pattern and variability of HPA. Linear mixed effects analysis identified relationships between demographic, clinical and psychosocial data and HPA from baseline to 18 months. Key results in PwP with carers indicated that carer anxiety and depression were associated with increased HPA volume (p < 0.01), while poorer carer self-care was associated with reduced volume of HPA over 18 months (p < 0.01). Greater carer strain was associated with taking longer walking bouts after 18 months (p < 0.01). Greater carer depression was associated with lower variability of HPA cross-sectionally (p = 0.009). This pilot study provides preliminary novel evidence that psychosocial outcomes from PwP’s carers may impact HPA in Parkinson’s disease. Interventions to improve HPA could target both PwP and carers and consider approaches that also support psychosocial wellbeing.

Neurodegeneration in Parkinson’s disease (PD) precedes diagnosis by years. Early neurodegeneration may be reflected in RNA levels and measurable as a biomarker. Here, we present the largest quantification of whole blood linear and circular RNAs (circRNA) in early-stage idiopathic PD, using RNA sequencing data from two cohorts (PPMI = 259 PD, 161 Controls; ICICLE-PD = 48 PD, 48 Controls). We identified a replicable increase in TMEM252 and LMNB1 gene expression in PD. We identified novel differences in the expression of circRNAs from ESYT2 , BMS1P1 and CCDC9 , and replicated trends of previously reported circRNAs. Overall, using circRNA as a diagnostic biomarker in PD did not show any clear improvement over linear RNA, minimising its potential clinical utility. More interestingly, we observed a general reduction in circRNA expression in both PD cohorts, accompanied by an increase in RNASEL expression. This imbalance implicates the activation of an innate antiviral immune response and suggests a previously unknown aspect of circRNA regulation in PD.

Introduction A subset of people with Parkinson's disease (PD) develop dementia faster than others. We aimed to profile PD cognitive subtypes at risk of dementia based on their rate of cognitive decline. Method Latent class mixed models stratified subtypes in Parkinson's Progression Markers Initiative (PPMI) (N = 770) and ICICLE‐PD (N = 212) datasets based on their decline in the Montreal Cognitive Assessment over at least 4 years. Baseline demographic and cognitive data at diagnosis were compared between subtypes to determine their clinical profile. Results Four subtypes were identified: two with stable cognition, one with steady decline, and one with rapid decline. Performance on Judgement of Line Orientation, but not category fluency, was associated with a steady decline in the PPMI dataset, and deficits in category fluency, but not visuospatial function, were associated with a steady decline in the ICICLE‐PD dataset. Discussion People with PD susceptible to cognitive decline demonstrate unique clinical profiles at diagnosis, although this differed between cohorts. Highlights Four cognitive subtypes were revealed in two Parkinson's disease samples. Unique profiles of cognitive impairment were related to cognitive decline. Judgement of Line Orientation/category fluency predictive of steady decline. Global deficits related to rapid cognitive decline and increased dementia risk.

Beta-adrenoceptor-blockers and agonists have been associated with an increased and decreased risk of Parkinson’s disease (PD), respectively. We aimed to investigate whether these medications are linked to clinical heterogeneity and progression in PD. Longitudinal data from the Parkinson’s Incident Cohorts Collaboration ( n  = 1107) were analysed. Baseline clinical status and progression to Hoehn & Yahr stage 3 (H&Y3) or dementia were compared in beta-blocker or beta-agonist users versus non-users of each drug. Baseline motor and cognitive variables were similar in beta-blocker users ( n  = 195) versus non-users and beta-agonist users ( n  = 68) versus non-users, following adjustment for relevant confounders. Beta-blocker users ( n  = 156) progressed faster to H&Y3 ( p  = 0.002), accounting for relevant confounders (Hazard Ratio (HR) = 1.538; p  = 0.011), while beta-agonist users ( n  = 54) progressed similarly to non-users. Neither drug was associated with progression to dementia. These findings support the possibility that beta-adrenoceptor drugs may have potential in modifying aspects of PD progression. Further investigation is essential to identify any causative component in the relationship.

Cognitive impairment is common in Parkinson’s disease (PD). However, the psychosocial impact of living and coping with PD and cognitive impairment in people with PD and their carers have not been explored. This paper draws on a qualitative study that explores the subjective impact of cognitive impairment on people with PD and their carers. Thirty-six one-to-one interviews were completed; people with PD were from three groups: normal cognition, mild cognitive impairment, and dementia. Data collection and analysis were iterative, and verbatim transcripts were analysed using thematic analysis. Themes were interpreted in consultation with coping and adaptation theory. The analysis revealed four main themes: threats to identity and role, predeath grief and feelings of loss in carers, success and challenges to coping in people with PD, and problem-focused coping and finding meaning in caring. Our data highlight how cognitive impairment can threaten an individual’s self-perception; the ostensible effects of cognitive impairment depended on the impact individual’s perceived cognitive impairment had on their daily lives. For carers, cognitive impairment had a greater emotional impact than the physical symptoms of PD. The discussion that developed around protective factors provides possible opportunities for future interventions, such as psychological therapies to improve successful adjustment.