Background: Individuals with dementia commonly experience sarcopenia (loss of muscle mass), dysphagia (swallowing difficulty) and malnutrition. Evidence indicates that dysphagia affects approximately 58.00% of older adults with dementia, while 32.50% are malnourished and 46.80% are at risk of malnutrition. Additionally, meta-analytic evidence links sarcopenia with mild cognitive impairment, Alzheimer’s disease and other dementias. Although these conditions may overlap, direct prevalence data for the full triad remain limited. This matters because dementia may impair attention, insight, communication and tolerance of lengthy assessments; therefore, bedside instruments need to be brief, low-burden, valid and clinically interpretable. This scoping review mapped bedside or ward-feasible screening and assessment tools across these three domains and summarised psychometric evidence in older adults with dementia. Methods: We conducted a Joanna Briggs Institute scoping review in line with PRISMA-ScR. MEDLINE, Web of Science Core Collection, Scopus, and PsycINFO were searched from 1990 to December 2025. Eligible peer-reviewed studies involved adults aged ≥60 years with dementia in inpatient, rehabilitation, or long-term/residential care and reported at least one sarcopenia, dysphagia/sarcopenic dysphagia, or malnutrition tool with at least one psychometric property in people with dementia . Two reviewers independently screened studies and charted data. Results: From 12,770 records, 3,636 duplicates were removed and 9,134 titles and abstracts were screened. Of 108 reports sought for retrieval, 99 full texts were assessed and 11 studies were included. Evidence was unevenly distributed: eight tool families, representing 11 named tool versions/methods, were identified, five for malnutrition or feeding difficulty, three for dysphagia and none for sarcopenia. All tool families were single-domain; no dyadic or tri-domain instrument or pathway had dementia-sample psychometric evidence. Among diagnostic studies, the Eating Assessment Tool-10 showed area under the curve values of 0.96 for unsafe swallowing and 0.81 for aspiration against videofluoroscopic swallowing study, while the Mini Nutritional Assessment showed 60.00% sensitivity and 94.70% specificity against established nutritional criteria. Conclusions: Available evidence in dementia care is strongest for malnutrition and feeding-related assessment, with fewer dysphagia studies and no eligible sarcopenia tool validation. These findings support dementia-specific sarcopenia validation and integrated multi-domain approaches feasible for routine bedside practice. Protocol and registration: The review was guided by a prospectively developed protocol registered in the Open Science Framework database (https://osf.io/f47x9)

Introduction Blood-based biomarkers that can aid diagnosis of Parkinson’s Disease (PD) dementia (PDD), and predict PDD onset in people with PD are urgently needed. Plasma small extracellular vesicles (SEV) reflect molecular changes in living human brain. Next-generation RNA-sequencing (RNA-Seq) of PDD plasma SEV can advance our understanding of PDD molecular pathology, and identify blood-based biomarkers. Hence, we conducted the first comprehensive transcriptomic analysis of PDD plasma SEV. Methods We investigated plasma SEV RNA of PDD, PD, and people without PD or dementia (Controls) using RNA-Seq (n=15/group; N=45). SEV were separated by ultracentrifugation, and characterized by cryo-transmission electron microscopy. We identified differentially expressed genes (DEGs) in PDD plasma SEV using an edgeR-based data analysis pipeline and verified them by high-throughput qPCR. We assessed functional implications of identified DEGs using Ingenuity Pathway and causal network analyses. Results We identified 51 transcriptome-wide significant (edgeR q<0.05) DEGs, compared to controls, and 26 transcriptome-wide significant DEGs, compared to PD, in PDD plasma SEV. The identified DEGs, which included WNT5A, MAPT, FOSB, MIR324, MIR574, MIR3161, and MIR6821 were significantly enriched among Tetrahydrofolate salvage, Reelin signalling, tRNA splicing, Wnt signalling, and ERBB signalling pathways. We identified eight potential multiplex plasma SEV RNA biomarker assays that can distinguish PDD from PD with at least 80% sensitivity and specificity using an artificial intelligence-based algorithm. Conclusion Future research on the identified dysfunctional molecular pathways may facilitate discovery of novel therapeutic targets for PDD. Diagnostic biomarker potential of the derived multiplex RNA biomarker assays should be investigated by larger clinical studies.

OBJECTIVES:Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are collectively called as Lewy body dementia (LBD). Despite the urgent clinical need, there is no reliable protein biomarker for LBD. Hence, we conducted the first comprehensive systematic review of all Differentially Abundant Proteins (DAP) in all tissues from people with LBD for advancing our understanding of LBD molecular pathology that is essential for facilitating discovery of novel diagnostic biomarkers and therapeutic targets for LBD. METHODS:We identified eligible studies by comprehensively searching five databases and grey literature (PROSPERO protocol:CRD42020218889). We completed quality assessment and extracted relevant data. We completed narrative synthesis and appropriate meta-analyses. We analysed functional implications of all reported DAP using DAVID tools. RESULTS:We screened 11,006 articles and identified 193 eligible studies. 305 DAP were reported and 16 were replicated in DLB. 37 DAP were reported and three were replicated in PDD. Our meta-analyses confirmed six DAP (TAU, SYUA, NFL, CHI3L1, GFAP, CLAT) in DLB, and three DAP (TAU, SYUA, NFL) in PDD. There was no replicated blood-based DAP in DLB or PDD. The reported DAP may contribute to LBD pathology by impacting misfolded protein clearance, dopamine neurotransmission, apoptosis, neuroinflammation, synaptic plasticity and extracellular vesicles. CONCLUSION:Our meta-analyses confirmed significantly lower CSF TAU levels in DLB and CSF SYUA levels in PDD, when compared to Alzheimer's disease. Our findings indicate promising diagnostic biomarkers for LBD and may help prioritising molecular pathways for therapeutic target discovery. We highlight ten future research priorities based on our findings.

Lewy body dementias (LBD) are the second most common dementia. Several genes have been associated with LBD, but little is known about their contributions to LBD pathophysiology. Each gene may transcribe multiple RNA, and LBD brains have extensive RNA splicing dysregulation. Hence, we completed the first transcriptome-wide transcript-level differential expression analysis of post-mortem LBD brains for gaining more insights into LBD molecular pathology that are essential for facilitating discovery of novel therapeutic targets and biomarkers for LBD. We completed transcript-level quantification of next-generation RNA-sequencing data from post-mortem anterior cingulate (ACC) and dorsolateral prefrontal cortices (DLPFC) of people with pathology-verified LBD (LBD = 14; Controls = 7) using Salmon . We identified differentially expressed transcripts (DET) using edgeR and investigated their functional implications using DAVID . We performed transcriptome-wide alternative splicing analysis using DRIMseq . We identified 74 DET in ACC and 96 DET in DLPFC after Benjamini-Hochberg false discovery rate (FDR) correction (5%). There were 135 and 98 FDR-corrected alternatively spliced genes in ACC and DLPFC of LBD brains, respectively. Identified DET may contribute to LBD pathology by altering DNA repair, apoptosis, neuroplasticity, protein phosphorylation, and regulation of RNA transcription. We confirm widespread alternative splicing and absence of chronic neuroinflammation in LBD brains. Transcript-level differential expression analysis can reveal specific DET that cannot be detected by gene-level expression analyses. Therapeutic and diagnostic biomarker potential of identified DET, especially those from TMEM18, MICB, MPO, and GABRB3 , warrant further investigation. Future LBD blood-based biomarker studies should prioritise measuring the identified DET in small extracellular vesicles.

BACKGROUND:People with dementia (PwD) and their carers often consider maintaining good quality of life (QoL) more important than improvements in cognition or other symptoms of dementia. There is a clinical need for identifying interventions that can improve QoL of PwD. There are currently no evidence-based guidelines to help clinicians, patients and policy makers to make informed decisions regarding QoL in dementia. AIMS:To conduct the first comprehensive systematic review of all studies that investigated efficacy of any pharmacological or non-pharmacological intervention for improving QoL of PwD. METHOD:Our review team identified eligible studies by comprehensively searching nine databases. We completed quality assessment, extracted relevant data and performed GRADE assessment of eligible studies. We conducted meta-analyses when three or more studies investigated an intervention for improving QoL of PwD. RESULTS:We screened 14 389 abstracts and included 324 eligible studies. Our meta-analysis confirmed level 1 evidence supporting the use of group cognitive stimulation therapy for improving QoL (standardised mean difference 0.25; P = 0.003) of PwD. Our narrative data synthesis revealed level 2 evidence supporting 42 non-pharmacological interventions, including those based on cognitive rehabilitation, reminiscence, occupational therapy, robots, exercise or music therapy. Current evidence supporting the use of any pharmacological intervention for improving QoL in dementia is limited. CONCLUSIONS:Current evidence highlights the importance of non-pharmacological interventions and multidisciplinary care for supporting QoL of PwD. QoL should be prioritised when agreeing care plans. Further research focusing on QoL outcomes and investigating combined pharmacological and non-pharmacological interventions is urgently needed.

BACKGROUND:Older people with serious mental ill health have high levels of physical comorbidity. Despite this, mental health services receive limited physical health support from primary or secondary care. This study investigated the facilitators and barriers to delivering physical healthcare for older people in mental health settings. METHODS:In total, 54 semi-structured interviews (REC:22/IEC08/0022) were conducted with different stakeholders [staff (n = 28), patients (n = 7), carers (n = 19)] across two mental health hospitals. Interviews explored the facilitators and barriers to delivering physical healthcare for older people (>65 years) receiving secondary mental healthcare (dementia and psychiatric disorders). Data were analysed thematically, underpinned by a framework of integrated care for individuals living with multimorbidity. RESULTS:A 'multidisciplinary approach' was valued, particularly to identify patients for targeted physical health support. There was felt to be a loss of physical health 'training and skills' over time, particularly amongst nursing and medical staff. Admissions to the acute hospital were potentially avoidable through improved 'support and availability of physical health expertise', to provide more proactive than reactive care. Alongside improved training and support, managing advanced care planning, end of life care and polypharmacy were perceived to facilitate improved physical healthcare in mental health settings. CONCLUSIONS:Lack of senior physical health leadership (e.g. geriatrician or general practitioner) and loss of skills and confidence in managing physical health in mental health settings have led to a low threshold for admissions to the acute hospital. In particular, services should support advanced care planning and end of life care from physical causes in mental health settings.

BACKGROUND:Many older people are now living with co-occurring physical and mental health disorders, but these often managed separately. The aim of this systematic review was to explore integrated physical-mental health care services available internationally for older people living with mental health diagnoses, and whether these result in improved health outcomes. METHODS:Medline, Embase, CINAHL, PsycINFO and Scopus were searched with a predefined search strategy (PROSPERO: CRD42022383824), generating 6210 articles. Studies were included where an integrated physical-mental health care service model was utilised in a population of older people (aged >60 years) with a mental health diagnosis (including dementia or cognitive impairment) and at least one concomitant physical health condition requiring physical health care input. All studies were assessed for risk of bias (ROB 2.0, ROBINS-I) and results were synthesised narratively. RESULTS:Nine studies were included across inpatient (n = 6, 1262 patients) and community (n = 3, 466 patients) settings. Studies were rated as low-moderate risk of bias. These covered joint physical-mental health wards, liaison services, embedded physicians in mental health wards, and joint multidisciplinary teams. Services with greater integration (e.g., joint wards) had more benefits for patients and carers. There were few benefits to traditional outcomes (e.g., hospital admissions, mortality), but greater care quality, carer satisfaction, and improved mood and engagement were demonstrated. CONCLUSIONS:Multidisciplinary integrated care resulted in improvement of a range of health outcomes for older people with combined physical and mental health needs. Larger and more robust studies are needed to explore the development of these service models further, with cost-effectiveness analyses.

Dementia with Lewy bodies (DLB) is a significant public health issue. It is the second most common neurodegenerative dementia and presents with severe neuropsychiatric symptoms. Genomic and transcriptomic analyses have provided some insight into disease pathology. Variants within SNCA, GBA, APOE, SNCB, and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB. Yet, the understanding of DLB molecular pathology is incomplete. This precipitates the current clinical position whereby there are no available disease-modifying treatments or blood-based diagnostic biomarkers. Data science methods have the potential to improve disease understanding, optimising therapeutic intervention and drug development, to reduce disease burden. Genomic prediction will facilitate the early identification of cases and the timely application of future disease-modifying treatments. Transcript-level analyses across the entire transcriptome and machine learning analysis of multi-omic data will uncover novel signatures that may provide clues to DLB pathology and improve drug development. This review will discuss the current genomic and transcriptomic understanding of DLB, highlight gaps in the literature, and describe data science methods that may advance the field.

OBJECTIVE:Dementia with Lewy bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells. Post-mortem DLB brains and serum SEV from those with DLB share common miRNA signatures, and their functional implications are uncertain. Hence, we aimed to investigate potential targets of DLB-associated SEV miRNA and to analyse their functional implications.METHODS:We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB (MIR26A1, MIR320C2, MIR320D2, MIR548BA, MIR556, and MIR4722) using miRBase and miRDB databases. We analysed functional implications of these targets using EnrichR gene set enrichment analysis and analysed their protein interactions using Reactome pathway analysis.RESULTS:These SEV miRNA may regulate 4278 genes that were significantly enriched among the genes involved in neuronal development, cell-to-cell communication, vesicle-mediated transport, apoptosis, regulation of cell cycle, post-translational protein modifications, and autophagy lysosomal pathway, after Benjamini-Hochberg false discovery rate correction at 5%. The miRNA target genes and their protein interactions were significantly associated with several neuropsychiatric disorders and with multiple signal transduction, transcriptional regulation, and cytokine signalling pathways.CONCLUSION:Our findings provide in-silico evidence that potential targets of DLB-associated SEV miRNAs may contribute to Lewy pathology by transcriptional regulation. Experimental validation of these dysfunctional pathways is warranted and could lead to novel therapeutic avenues for DLB.

With the increase in large multimodal cohorts and high-throughput technologies, the potential for discovering novel biomarkers is no longer limited by data set size. Artificial intelligence (AI) and machine learning approaches have been developed to detect novel biomarkers and interactions in complex data sets. We discuss exemplar uses and evaluate current applications and limitations of AI to discover novel biomarkers. Remaining challenges include a lack of diversity in the data sets available, the sheer complexity of investigating interactions, the invasiveness and cost of some biomarkers, and poor reporting in some studies. Overcoming these challenges will involve collecting data from underrepresented populations, developing more powerful AI approaches, validating the use of noninvasive biomarkers, and adhering to reporting guidelines. By harnessing rich multimodal data through AI approaches and international collaborative innovation, we are well positioned to identify clinically useful biomarkers that are accurate, generalizable, unbiased, and acceptable in clinical practice. HIGHLIGHTS: Artificial intelligence and machine learning approaches may accelerate dementia biomarker discovery. Remaining challenges include data set suitability due to size and bias in cohort selection. Multimodal data, diverse data sets, improved machine learning approaches, real-world validation, and interdisciplinary collaboration are required.

OBJECTIVE:COVID-19 may lead to a range of clinical outcomes among older people with psychiatric and medical conditions. Evidence guiding management of future outbreaks among this vulnerable population in psychiatric hospital settings are sparse. In this study, we examined the correlates of poor clinical outcomes related to COVID-19 and explored the perspectives of COVID-19 survivors hospitalized in psychiatry settings.METHOD:The correlates of poor clinical outcomes related to COVID-19 were examined using a retrospective chart review of 81 older people hospitalized in psychiatry settings. Correlates of clinical outcomes related to COVID-19 were assessed by multiple logistic regression models. In addition, the perspectives of 10 COVID-19 survivors were explored by qualitative interviews. The qualitative data was subject to thematic analysis.RESULTS:Although 25.9% (n = 21) participants were asymptomatic, there was high COVID-19 related mortality (14.8%; n = 12). Vitamin-D deficiency, anticholinergic burden, and isolation policies within psychiatric wards were significantly (p < 0.05) related to COVID-19 related deaths. In qualitative interviews, participants emphasized the importance of strengthening local support networks and making vaccination centers more accessible.CONCLUSIONS:Reducing anticholinergic prescriptions and improving isolation policies may help to mitigate poor clinical outcomes. Future research investigating the impact of vitamin-D supplementation on COVID-19 related outcomes is warranted.

Epigenetic processes have become increasingly relevant in understanding disease-modifying mechanisms. 5-Methylcytosine methylations of DNA (5mC) and RNA (m 5 C) have functional transcriptional and RNA translational consequences and are tightly regulated by writer, reader and eraser effector proteins. To investigate the involvement of 5mC/5hmC and m 5 C effector proteins contributing to the development of dementia neuropathology, RNA sequencing data of 31 effector proteins across four brain regions was examined in 56 aged non-affected and 51 Alzheimer’s disease (AD) individuals obtained from the Aging, Dementia and Traumatic Brain Injury Study. Gene expression profiles were compared between AD and controls, between neuropathological Braak and CERAD scores and in individuals with a history of traumatic brain injury (TBI). We found an increase in the DNA methylation writers DNMT1 , DNMT3A and DNMT3B messenger RNA (mRNA) and a decrease in the reader UHRF1 mRNA in AD samples across three brain regions whilst the DNA erasers GADD45B and AICDA showed changes in mRNA abundance within neuropathological load groupings. RNA methylation writers NSUN6 and NSUN7 showed significant expression differences with AD and, along with the reader ALYREF , differences in expression for neuropathologic ranking. A history of TBI was associated with a significant increase in the DNA readers ZBTB4 and MeCP2 ( p < 0.05) and a decrease in NSUN6 ( p < 0.001) mRNA. These findings implicate regulation of protein pathways disrupted in AD and TBI via multiple pre- and post-transcriptional mechanisms including potentially acting upon transfer RNAs, enhancer RNAs as well as nuclear-cytoplasmic shuttling and cytoplasmic translational control. The targeting of such processes provides new therapeutic avenues for neurodegenerative brain conditions. Graphical abstract

Objective Lewy body dementia (LBD) is the second most common neurodegenerative dementia, and it causes earlier mortality and more morbidity than Alzheimer's disease. Reviewing current evidence on its pharmacological management is essential for developing evidence-based clinical guidelines, and for improving the quality of its clinical care. Hence, we systematically reviewed all studies that investigated the efficacy of any medication for managing various symptoms of LBD. Method We identified eligible studies by searching 15 databases comprehensively. We completed quality assessment, extracted relevant data, and performed GRADE assessment of available evidence. We conducted meta-analyses when appropriate (PROSPERO:CRD42020182166). Results We screened 18,884 papers and included 135 studies. Our meta-analyses confirmed level-1 evidence for Donepezil's efficacy of managing cognitive symptoms of dementia with Lewy bodies (DLB) (SMD = 0.63; p < 0.001) and Parkinson's Disease Dementia (PDD) (SMD = 0.43; p < 0.01), and managing hallucinations in DLB (SMD=-0.52; p = 0.02). Rivastigmine and Memantine have level-2 evidence for managing cognitive and neuropsychiatric symptoms of DLB. Olanzapine and Yokukansan have similar evidence for managing DLB neuropsychiatric symptoms. Level-2 evidence support the efficacy of Rivastigmine and Galantamine for managing cognitive and neuropsychiatric symptoms of PDD. Conclusion We list evidence-based recommendations for the pharmacological management of DLB and PDD, and propose specific clinical guidelines for improving their clinical management. Supplemental data for this article can be accessed online at https://doi.org/10.1080/13607863.2022.2032601 .

Prevalence of Dementia with Lewy bodies (DLB) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. Accurate distinction between these two most common subtypes of dementia is essential because they differ in their prognosis, neuropsychiatric symptoms, pharmacological management,1 and sensitivity to medication adverse effects. Misdiagnosing DLB as AD, and prescribing an antipsychotic medication for treating persistent visual hallucinations and associated challenging behaviours may lead to life-threatening adverse events.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Aims and MethodThis study evaluated a pilot psychiatry summer school for GCSE students in terms of participant experience, effects on attitudes to mental illness and perception of psychiatry as a career option. This was done using the Community Attitudes towards the Mentally Ill scale, career choice questionnaires and a discussion group following the week-long programme attended by 26 students.ResultsStudents were significantly more likely to choose psychiatry after the summer school (P = 0.01). There were statistically significant changes in scores for social restrictiveness (P = 0.04) and community mental health ideology (P = 0.02). Qualitative analysis generated four themes: variation in expectations, limited prior knowledge, perception of the summer school itself and uniformly positive attitudes to psychiatry after the summer school.Clinical implicationsTargeting students at this early stage appears to be an underexplored positive intervention for improving both attitudes towards mental illness and recruitment to psychiatry.

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood. In this study, we assess affective behaviors and associated neurobiology in Brd1+/- mice along with their responses to Fluoxetine and Imipramine. This involves behavioral, neurostructural, and neurochemical characterizations along with regional cerebral gene expression profiling combined with integrative functional genomic analyses. We report behavioral changes in female Brd1+/- mice with translational value to depressive symptomatology that can be alleviated by the administration of antidepressant medications. Behavioral changes are accompanied by altered brain morphometry and imbalances in monoaminergic systems. In accordance, gene expression changes across brain tissues reveal altered neurotransmitter signaling and cluster in functional pathways associated with depression including 'Adrenergic-, GPCR-, cAMP-, and CREB/CREM-signaling'. Integrative gene expression analysis specifically links changes in amygdaloid intracellular signaling activity to the behavioral treatment response in Brd1+/- mice. Collectively, our study highlights the importance of BRD1 as a modulator of affective pathology and adds to our understanding of the molecular mechanisms underlying affective disorders and their treatment response.

OBJECTIVE:There is an urgent clinical need for identifying blood-based diagnostic biomarkers for Dementia with Lewy Bodies (DLB). Transcriptomic studies have reported unique RNA changes in postmortem DLB brains. Small extracellular vesicles (SEV) that transport RNA between brain and peripheral circulation enable identifying molecular changes in living human brain. Hence, we aimed to identify differentially expressed RNA in serum SEVs from people with DLB. METHODS:We investigated serum SEV total RNA profiles in people with DLB (n = 10) and age and gender matched comparisons (n = 10) using next-generation RNA-sequencing. SEVs were separated by ultracentrifugation with density gradient and were characterized by nanoparticle analysis and western blotting. We verified the differential expression levels of identified differentially expressed genes (DEG) using high-throughput qPCR. Functional implications of identified DEG were evaluated using Ingenuity pathway analyses. RESULTS:We identified 846 nominally significant DEG including 30 miRNAs in DLB serum SEVs. We identified significant downregulation of proinflammatory genes, IL1B, CXCL8, and IKBKB. Previously reported postmortem DLB brain DEGs were significantly enriched (χ2=4.99; df=1; p = 0.03) among the identified DEGs, and the differential expression of 40 postmortem DLB brain DEGs could be detected in serum SEVs of people living with DLB. Functional pathway and network analyses highlighted the importance of immunosenescence, ubiquitin proteasome system (UPS) dysfunction, DNA repair, and RNA post-transcriptional modification deficits in DLB pathology. CONCLUSION:Identified DEGs, especially reduced expression levels of inflammation, and UPS-associated RNA, may aid diagnosing DLB, and their biomarker potential warrants further investigation in larger clinical cohorts. Our findings corroborate the absence of chronic neuroinflammation in DLB.

Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.