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BACKGROUND AND OBJECTIVES: It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. METHODS: Participants from the Parkinsons Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

The Remote Assessment of Disease and Relapse – Alzheimer's Disease (RADAR-AD) consortium evaluated remote measurement technologies (RMTs) for assessing functional status in AD. The consortium engaged with the European Medicines Agency (EMA) to obtain feedback on identification of meaningful functional domains, selection of RMTs and clinical study design to assess the feasibility of using RMTs in AD clinical studies. We summarized the feedback and the lessons learned to guide future projects. [ABSTRACT FROM AUTHOR]

DailyColors™ is a supplement made up of several phytonutrients that aims to replicate elements from the Mediterranean diet. These include fruit, berry and vegetable extracts that are rich in key phytochemicals such as Quercetin, Catechins, Phloretin, Ellagic Acid, and Anthocyanins. Here, we determined the effects of DailyColors™ on the blood biomarkers associated with the diverse mechanisms implicated in ageing and age-related diseases, including mitochondrial function, inflammation, and oxidative stress, as well as on saliva's DNA methylation pattern. Thirty adult participants (mean (SD) age = 67.0 (7.5) years) with a body mass index over 25 were recruited into this randomised, double-blind, placebo-controlled, cross-over trial (two one-week treatment periods, separated by a one-week washout period). During the placebo period, we observed a significant increase in blood CD38 concentrations from the baseline to 24 h (p-value = 0.019). This was not observed in the active period. Increased CD38 is reportedly associated with subsequent mitochondrial dysfunction and inflammation. Next, there was a decreasing trend of plasma 4-HNE levels, an oxidative stress biomarker, after a one-week intake of DailyColors™. Furthermore, following a one-month open-label follow-up in 26 participants, we observed hypermethylation of the candidate CpG site cg13108341 (q-value = 0.021), which was against the observed trend for this site during ageing. Taken together, while minimal effects were observed in this study, DailyColors™ supplementation may be beneficial by altering and alleviating age-related changes. Longer and larger scale trials of DailyColors™ supplementation are warranted. [ABSTRACT FROM AUTHOR]

Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a variety of phenomena, such as illusions, presence and passage hallucinations occurring at early stages of LBD. The neural mechanisms of visual hallucinations are largely unknown. The hodotopic model posits that the hallucination state is due to abnormal activity in specialized visual areas, that occurs in the context of wider network connectivity alterations and that phenomenology of VH, including content and temporal characteristics, may help identify brain regions underpinning these phenomena. Here we investigated both the topological and hodological neural basis of visual hallucinations integrating grey and white matter imaging analyses. We studied LBD patients with VH and age matched healthy controls (HC). VH were assessed using a North-East-Visual-Hallucinations-Interview that captures phenomenological detail. Then we applied voxel-based morphometry and tract based spatial statistics approaches to identify grey and white matter changes. First, we compared LBD patients and HC. We found a reduced grey matter volume and a widespread damage of white tracts in LBD compared to HC. Then we tested the association between CVH and MVH and grey and white matter indices. We found that CVH duration was associated with decreased grey matter volume in the fusiform gyrus suggesting that LBD neurodegeneration-related abnormal activity in this area is responsible for CVH. An unexpected finding was that MVH severity was associated with a greater integrity of white matter tracts, specifically those connecting dorsal, ventral attention networks and visual areas. Our results suggest that networks underlying MVH need to be partly intact and functional for MVH experiences to occur, while CVH occur when cortical areas are damaged. The findings support the hodotopic view and the hypothesis that MVH and CVH relate to different neural mechanisms, with wider implications for the treatment of these symptoms in a clinical context. [ABSTRACT FROM AUTHOR]

Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies. The authors investigated associations of brain-derived-tau (BD-tau) with Aβ pathology, changes in cognition and MRI signatures. Staging Aβ-pathology according to neurodegeneration, using BD-tau, identifies individuals at risk of near-term cognitive decline and atrophy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHODS: Genome‐wide association meta‐analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations. [ABSTRACT FROM AUTHOR]

INTRODUCTION: iWHELD is a digital person‐centered care program for people with dementia in nursing homes adapted for remote delivery during the COVID‐19 pandemic. METHODS: A 16‐week two‐arm cluster‐randomized controlled trial in 149 UK nursing homes compared iWHELD with treatment as usual (TAU). Primary outcome was the overall quality of life with secondary outcomes of agitation and psychotropic use. RESULTS: iWHELD conferred benefit to quality of life on the primary (F = 4.3, p = 0.04) and secondary measures of quality of life (F = 6.45, p = 0.01) and reduced psychotropic medication use (χ2 = 4.08, p = 0.04) with no worsening of agitation. Benefit was seen in participants who contracted COVID‐19, those with agitation at baseline, and those taking psychotropic medications. DISCUSSION: iWHELD confers benefits to quality of life and key measures of well‐being, can be delivered during the challenging conditions of a pandemic, and should be considered for use alongside any emerging pharmacological treatment for neuropsychiatric symptoms. Highlights: iWHELD is the only remote, digital delivery nursing home training programme for dementia careiWHELD improved quality of life in people with dementia and reduced antipsychotic use without worsening of agitationResidents who contracted Covid‐19 during the study also experienced benefits from iWHELDiWHELD offers a valuable, pandemic‐safe tool for improving dementia care [ABSTRACT FROM AUTHOR]

Recent evidence highlights the importance of trace metal micronutrients such as zinc (Zn) in coronary and vascular diseases. Zn2+ plays a signalling role in modulating endothelial nitric oxide synthase and protects the endothelium against oxidative stress by upregulation of glutathione synthesis. Excessive accumulation of Zn2+ in endothelial cells leads to apoptotic cell death resulting from dysregulation of glutathione and mitochondrial ATP synthesis, whereas zinc deficiency induces an inflammatory phenotype, associated with increased monocyte adhesion. Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor known to target hundreds of different genes. Activation of NRF2 affects redox metabolism, autophagy, cell proliferation, remodelling of the extracellular matrix and wound healing. As a redox-inert metal ion, Zn has emerged as a biomarker in diagnosis and as a therapeutic approach for oxidative-related diseases due to its close link to NRF2 signalling. In non-vascular cell types, Zn has been shown to modify conformations of the NRF2 negative regulators Kelch-like ECH-associated Protein 1 (KEAP1) and glycogen synthase kinase 3β (GSK3β) and to promote degradation of BACH1, a transcriptional suppressor of select NRF2 genes. Zn can affect phosphorylation signalling, including mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinases and protein kinase C, which facilitate NRF2 phosphorylation and nuclear translocation. Notably, several NRF2-targeted proteins have been suggested to modify cellular Zn concentration via Zn exporters (ZnTs) and importers (ZIPs) and the Zn buffering protein metallothionein. This review summarises the cross-talk between reactive oxygen species, Zn and NRF2 in antioxidant responses of vascular cells against oxidative stress and hypoxia/reoxygenation. [ABSTRACT FROM AUTHOR]

Estimates of the risk of dementia in Parkinson's disease (PDD) vary widely. We aimed to review the incidence of PDD and in a meta‐analysis estimate the pooled annual incidence and relative risk of PDD while also exploring factors that may contribute to heterogeneity between studies. Preferred Reporting Items for Systematic reviews and Meta‐Analyses guidelines were followed and MEDLINE and EMBASE were searched for articles reporting the number of cases of dementia in a population, followed longitudinally, with a minimum of 100 dementia‐free Parkinson's disease (PD) patients at baseline. Meta‐analyses and meta‐regressions were used to estimate the pooled incidence rate of PDD and the relative risk of PDD versus healthy controls (HC). A total of 32 studies were identified, 25 reporting the incidence of PDD and 10 reporting the relative risk of PDD versus HC. The pooled incidence rate of PDD was 4.45 (95% confidence interval [CI], 3.91–4.99) per 100 person‐years at risk, equating to a 4.5% annual risk of dementia in a PD prevalent population. The relative risk of PDD was estimated to be 3.25 (95% CI, 2.62–4.03) times greater than HC. Factors contributing to study heterogeneity and disparities in the estimated risk of PDD include the age of patients, year of recruitment, and study location. Significant gaps remain with no studies identified in several geographical regions. Future studies should stratify by age and standardize reporting to reduce overall heterogeneity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Anxiety and depression are common non‐motor symptoms in Parkinson's disease (PD) but remain under‐recognized and under‐treated.To evaluate functional outcomes associated with baseline anxiety or depression and effects related to the initiation of new psychiatric treatment.We analyzed 7 years of data from patients with de novo PD enrolled in the Parkinson's Progression Markers Initiative. Longitudinal regression models evaluated the association between baseline anxiety and depression with Schwab and England (SE) and MDS‐UPDRS total scores over time. Cox proportional hazard models assessed effects of baseline anxiety and depression on time to initiation of dopaminergic therapy. Piecewise linear regression models examined the association of treatment initiation for anxiety and depression with SE and MDS‐UPDRS.490 participants with baseline depression and anxiety data were included. Anxiety and depression were associated with lower SE (anxiety: β = −1.31, P = 0.038, depression: β = −1.96, P = 0.012, co‐morbid: β = −2.70, P = 0.003) and higher MDS‐UPDRS scores (anxiety: β = 5.37, P < 0.001, depression: β = 9.17, P < 0.001, co‐morbid: β = 10.50, P < 0.001) longitudinally. Anxiety was associated with faster time to dopamine replacement therapy initiation (HR 1.30, 95% CI 1.03–1.66, P = 0.03). 16 participants with anxiety initiated treatment for anxiety, which was associated with subsequent lower levodopa daily dose (slope change = −218.49, P = 0.018). 10 participants with depression initiated treatment of depression, which was associated with reduced MDS‐UPDRS total scores (slope change = −8.3, P < 0.001) and higher SE scores (slope change = 5.99, P = 0.004).Anxiety and depression at PD onset are associated with multiple negative longitudinal trajectories. However, preliminary findings suggest that anxiety and depression treatment may be linked with improved motor and non‐motor outcomes. [ABSTRACT FROM AUTHOR]

Background: Very late-onset psychosis (VLOP) is associated with higher rates of dementia but the proportion who develop dementia with Lewy bodies (DLB) is unknown. We aimed to identify individuals with VLOP who develop dementia and DLB and characterize the risk factors for progression., Methods: Anonymized data were retrieved from electronic records for individuals with VLOP. Patients developing dementia after psychosis were identified, in addition to those with > 2 core features of DLB at the time of dementia or DLB identified by a natural language processing application (NLP-DLB). Demographic factors, Health of the National Outcome Scale (HoNOS) and symptoms at index psychosis were explored as predictors of progression to dementia., Results: In 1425 patients with VLOP over 4.29 years (mean) follow up, 197 (13.8%) received a subsequent diagnosis of dementia. Of these, 24.4% ( n = 48) had > 2 core features of DLB and 6% ( n = 12) had NLP-DLB. In cox proportional hazard models, older age and cognitive impairment at the time of psychosis were associated with increased risk of incident dementia. Visual hallucinations and 2+ core features of DLB at index psychosis were associated with increased risk of dementia with 2+ symptoms of DLB but not all-cause dementia. Two or more core features of DLB at index psychosis were associated with 81% specificity and 67% sensitivity for incident NLP-DLB., Conclusions: In patients with VLOP who develop dementia, core features of DLB are common. Visual hallucinations or two core features of DLB in VLOP should prompt clinicians to consider DLB and support further investigation.

Background: The cognitive effects of sports-related concussion (SRC) have been the subject of vigorous debate but there has been little research into long-term outcomes in non-athlete populations., Methods: This cohort study of UK community-dwelling adults (aged 50-90 years) was conducted between November 2015 and November 2020, with up to 4 years annual follow-up (n=15 214). Lifetime history of concussions was collected at baseline using the Brain Injury Screening Questionnaire. The first analysis grouped participants by type of concussion (no concussion, only SRC, only non-SRC (nSRC), mixed concussions (both SRC and nSRC)) and the second grouped the participants by number (0, 1, 2 or 3+ SRC or nSRC). Mixed models were used to assess the effect of concussion on outcomes including four cognitive domains and one behavioural measure (Mild Behavioural Impairment-C)., Results: Analysis of the included participants (24% male, mean age=64) at baseline found that the SRC group had significantly better working memory (B=0.113, 95% CI 0.038, 0.188) and verbal reasoning (B=0.199, 95% CI 0.092, 0.306) compared with those without concussion. Those who had suffered one SRC had significantly better verbal reasoning (B=0.111, 95% CI 0.031, 0.19) and attention (B=0.115, 95% CI 0.028, 0.203) compared with those with no SRC at baseline. Those with 3+ nSRCs had significantly worse processing speed (B=-0.082, 95% CI -0.144 to -0.019) and attention (B=-0.156, 95% CI -0.248 to -0.063). Those with 3+ nSRCs had a significantly worse trajectory of verbal reasoning with increasing age (B=-0.088, 95% CI -0.149 to -0.026)., Conclusions: Compared with those reporting no previous concussions, those with SRC had no cognitive or behavioural deficits and seemed to perform better in some tasks. As indicated by previous studies, sports participation may confer long-term cognitive benefits., Competing Interests: Competing interests: CB collected consulting fees from the following companies: Acadia, AARP, Addex, Biohaven, Eli Lily and Company, Enterin Inc, Exciva, H.Lundbeck A.S, Janssen Pharmaceuticals, Novo Nordisk, Orion Corp., Otsuka America Pharm Inc, Sunovion Pharm Inc, Suven, Roche, Axosome and Biogen. CB is on Advisory Boards for the following companies: Acadia, Roche, Novo-Nordisk, AARP, Biogen and Synexus. CB received an Honorarium from Harvard University for speaking. AH is the owner and director of Future Cognition Ltd, a software development company the consulted on the development of the cognitive assessment software., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)