Background: This is a retrospective longitudinal study comparing 374 patients with Parkinson\'s disease (PD) who were treated in centers offering a specialized program of enhanced rehabilitation therapy in addition to expert outpatient care to 387 patients with PD, who only received expert outpatient care at movement disorders centers in Italy. Methods: The data are from subjects recruited in the Parkinson\'s Outcome Project (POP) at six Italian centers that are part of a multicenter collaboration for care quality improvement (the Fresco Network). The effects were measured with a baseline and a follow-up clinical evaluation of the Timed-Up-and-Go test (TUG), Parkinson\'s Disease Questionnaire (PDQ-39), and Multidimensional Caregiver Strain Index (MCSI), the number of falls and hospitalizations for any cause. We used a generalized linear mixed model with the dependent variables being the response variable, which included the covariates demographics, evaluation, and treatment variables. Results: We found that the subjects who underwent specialized enhanced rehabilitation had a better motor outcome over time than those who were managed by expert neurologists but had participated in community programs for exercise and other allied health interventions. The greatest effects were seen in patients in the early stages of the disease with a high amount of vigorous exercise per week in the last six months. Similar effects were seen for PDQ39, MCSI, the number of falls, and hospitalization. Conclusions: Long-term benefits to motor function and the quality of life in patients with PD and burden reduction in their caregivers can be achieved through a systematic program of specialized enhanced rehabilitation interventions.

Positron emission tomography imaging of misfolded proteins with high-affinity and selective radioligands has played a vital role in expanding our knowledge of neurodegenerative diseases such as Parkinson\'s and Alzheimer\'s disease. The pathogenesis of Huntington\'s disease, a CAG trinucleotide repeat disorder, is similarly linked to the presence of protein fibrils formed from mutant huntingtin (mHTT) protein. Development of mHTT fibril-specific radioligands has been limited by the lack of structural knowledge around mHTT and a dearth of available hit compounds for medicinal chemistry refinement. Over the past decade, the CHDI Foundation, a non-for-profit scientific management organisation has orchestrated a large-scale screen of small molecules to identify high affinity ligands of mHTT, with lead compounds now reaching clinical maturity. Here we describe the mHTT radioligands developed to date and opportunities for further improvement of this radiotracer class.

Aim: Currently, there exist no curative treatments for neurodegenerative disorders. Recently, there has been a resurgence of interest in the use of medicinal cannabis to improve neurological conditions. Methods: A 12-month, open label, dose-finding, safety and efficacy study was conducted including 48 subjects with a variety of neurodegenerative disorders. Results: In our participants, we observed a reduction in pain, improved sleep, enhanced well-being and less agitation. Conclusion: Our findings suggest that medicinal cannabis might be useful in patients with neurodegenerative disorders in controlling pain, enhancing sleep, reducing difficult behaviors, controlling unusual and complex symptoms when other treatments have failed - this offers medicinal cannabis a role in palliation.

OBJECTIVE: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer\'s disease [AD]), cerebrovascular disease (CVD), and Parkinson\'s disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses.
METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits.
RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively.
CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

UNASSIGNED: More than half of patients with Parkinson\'s disease will experience psychosis symptoms in the form of hallucinations or delusions at some point over the course of their disease. These symptoms can significantly impact patients\' health-related quality of life, cognitive abilities, and activities of daily living (ADLs) and function. Clinical assessment of how psychosis impacts these measures is crucial; however, few studies have assessed this sufficiently, in part due to a lack of appropriate scales for comprehensively assessing function.
UNASSIGNED: The objective was to assess how symptoms of Parkinson\'s disease psychosis (PDP) impact ADLs and function, cognitive function, and health-related quality of life.
UNASSIGNED: To address this unmet need, we utilized a modified version of the Functional Status Questionnaire (mFSQ) to measure the impact of psychosis on ADLs and function in patients with PDP treated with pimavanserin, a US Food and Drug Administration-approved medication to treat hallucinations and delusions associated with PDP.
UNASSIGNED: Eligible patients entered a 16-week, single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. The primary endpoint was change from baseline to Week 16 on the mFSQ. Secondary endpoints included the Movement Disorders Society-modified Unified Parkinson\'s Disease Rating Scale (MDS-UPDRS) I and II; Schwab and England ADL; Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I), and were also measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares mean (LSM).
UNASSIGNED: Our results in a proof-of-concept, 16-week, open-label clinical study in 29 patients demonstrated that an improvement in psychosis symptoms following treatment with pimavanserin was associated with improvements in multiple measures of ADLs and function. Notably, a significant improvement was found on the primary endpoint, change from baseline to Week 16 in mFSQ score [LSM [SE] 14.0 [2.50], n = 17; 95% CI (8.8, 19.3); p < 0.0001].
UNASSIGNED: These findings highlight the potential for improvement in function with improvement of psychosis symptoms in patients with PDP and suggest that the mFSQ may be a measurement tool to evaluate the level of improvement in function.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT04292223.

The implementation of cognitive health apps in patients with mild cognitive impairment (MCI) is challenging because of their cognitive, age, and other clinical characteristics. In this project, we aimed to evaluate the usability and feasibility of the Rehastart app tested in MCI patients. Eighteen subjects affected by MCI due to neurodegenerative disorders (including Parkinson\'s disease, multiple sclerosis, and amnestic/multidomain MCI) and eighteen healthcare professionals were recruited to this study. Patients were registered on the app by clinicians and they were assigned a protocol of specific cognitive exercises. The recruitment was conducted in the period between March and June 2023. The trial testing of the app consisted of three sessions per week for three weeks, with each session lasting about 30 min. After three weeks, the participants as well as medical personnel were invited to rate the usability and feasibility of the Rehastart mobile application. The instruments employed to evaluate the usability and feasibility of the app were the System Usability Scale (SUS), The Intrinsic Motivation Inventory (IMI) and the Client Satisfaction Questionnaire (CSQ). We did not find statistically significant differences on the SUS (p = 0.07) between healthcare professionals and patients. In addition, we found promising results on subscales of the Intrinsic Motivation Inventory, suggesting high levels of interest and enjoyment when using the Rehastart app. Our study demonstrated that smartphone-based telerehabilitation could be a suitable tool for people with MCI due to neurodegenerative disorders, since the Rehastart app was easy to use and motivating for both patients and healthy people.

Previous observational studies suggested an association between sepsis and neurodegenerative diseases, but causality remains unclear.
Determining the causal association between sepsis and four neurodegenerative diseases (Alzheimer\'s disease, Parkinson\'s disease, amyotrophic lateral sclerosis, and Lewy body dementia) through bidirectional two-sample Mendelian randomization (MR) analysis.
Genome-wide association study summary statistics for all traits were obtained from publicly available databases. Inverse variance weighted (IVW) was the primary method for evaluating causal associations. In addition, three additional MR methods (MR-Egger, weighted median, and maximum likelihood method) were employed to supplement IVW. Furthermore, various sensitivity tests were conducted to assess the reliability: 1) Cochrane\'s Q test for assessing heterogeneity; 2) MR-Egger intercept test and MR-PRESSO global test for evaluating horizontal pleiotropy; 3) leave-one-out sensitivity test for determining the stability.
The results of IVW indicated that sepsis significantly increased the risk of Alzheimer\'s disease (OR = 1.11, 95% CI: 1.01-1.21, p = 0.025). In addition, three additional MR methods suggested parallel results. However, no causal effect of sepsis on the three other neurodegenerative diseases was identified. Subsequently, reverse MR analysis indicated that the four neurodegenerative diseases do not causally affect sepsis. Furthermore, sensitivity tests demonstrated the reliability of the MR analyses, suggesting no heterogeneity or horizontal pleiotropy.
The present study contributes to a deeper comprehension of the intricate interplay between sepsis and neurodegenerative disorders, thereby offering potential avenues for the development of therapeutic agents that can effectively mitigate the multifarious complications associated with sepsis.

The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM2.5, PM10, NO2, and NOX exposure and the occurrence of Parkinson\'s disease (PD) and Alzheimer\'s disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10-8) with PM2.5, PM10, NO2, and NOX. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO2 exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95% CI: 1.13 to 19.62, P = 0.034) and genetically PM10 exposure exhibited a significant association with a heightened risk of AD (OR = 1.93, 95% CI: 1.03-3.59, P = 0.040). Further MVMR analysis demonstrated that the causal effect between NO2 and PD disappeared (OR = 3.489, 95% CI: 0.01 to 2.1e + 03, P = 0.703), and only PM10 was associated with an increased risk of AD (OR = 6.500, 95% CI: 1.10 to 38.51, P = 0.039). Sensitivity analysis showed no detectable heterogeneity and pleiotropy (P > 0.05). Our findings demonstrate that NO2 and PM10 exposure may contribute to a risk of PD and AD, respectively. Future research is necessary to elucidate potential physiopathological mechanisms.

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Chronic stress and depression are potential risk factors for mild cognitive impairment and dementia, including Alzheimer disease. The aim was to investigate whether any such risk is additive.
Cohort study including 1 362 548 people (665 997 women, 696 551 men) with records in the Region Stockholm administrative healthcare database (VAL). Exposure was a recorded ICD-10 diagnosis of chronic stress, depression, or both, recorded in 2012 or 2013. Outcome was a diagnosis of Alzheimer disease, other dementia, or mild cognitive impairment recorded from 2014 through 2022. Odds ratios with 99% confidence intervals (CI) adjusted for age, sex, neighborhood socioeconomic status, diabetes, and cardiovascular disorders were calculated.
During the exposure period, 4 346 patients were diagnosed with chronic stress, 40 101 with depression, and 1 898 with both. The average age at baseline was around 40 years in all groups. In the fully adjusted model, the odds ratio of Alzheimer disease was 2.45 (99% CI 1.22-4.91) in patients with chronic stress, 2.32 (99% CI 1.85-2.90) in patients with depression, and 4.00 (99% CI 1.67-9.58) in patients with chronic stress and depression. The odds ratio of mild cognitive impairment was 1.87 (99% CI 1.20-2.91) in patients with chronic stress, 2.85 (99% CI 2.53-3.22) in patients with depression, and 3.87 (99% CI 2.39-6.27) in patients with both. When other dementia was analyzed, the odds ratio was significant only in patients with depression, 2.39 (99% CI 1.92-2.96).
Documented chronic stress increased the risk of mild cognitive impairment and Alzheimer disease. The same was seen with depression. The novel finding is the potential additive effect of chronic stress to depression, on risk of MCI and AD.