Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson’s disease

Objective:Cognitive impairment and depression are among the most prevalent and most disabling non-motor symptoms in Parkinson’s disease (PD). The genetic factors that are associated with these symptoms remain uncertain. This systematic review aims to summarise the prevailing evidence from all genetic association studies investigating the genetic variants associated with cognitive impairment and depressive symptoms in people with PD.Method:A systematic review using five online databases: PubMed, PsycINFO, CINAHL, EMBASE and OpenGrey (PROSPERO protocol: CRD42017067431). We completed the quality assessment using the Q-Genie tool.Results:2353 articles were screened, and 43 articles were found to be eligible to be included. A meta-analysis of studies investigating LRRK2 rs34637584 confirmed that the minor allele carriers had significantly less cognitive impairment (p = 0.015). Further meta-analyses showed that GBA variants rs76763715 (p < 0.001) and rs421016 (p = 0.001) were significantly associated with more cognitive impairment in people with PD. Minor alleles of GBA variants rs76763715, rs421016, rs387906315 and rs80356773 were associated with more depressive symptoms in PD. Moreover, APOE ϵ4 allele has been associated with more cognitive impairment in PD. BDNF (rs6265) and CRY1 (rs2287161) variants have been associated with more depressive symptoms in people with PD.Conclusions:PD carriers of GBA variants are at high risk for cognitive decline and depression. Screening for these variants may facilitate early identification and effective management of these non-motor symptoms. The molecular mechanisms underlying favourable cognitive functioning in LRRK2 rs34637584 variant carriers warrant further investigation.Summations:1.Available evidence confirms that the LRRK2 variant rs34637584 is associated with less cognitive impairment in people with PD.2.GBA variants rs76763715 and rs421016 are associated with more severe cognitive impairment in people with PD.3.The GBA variants rs76763715, rs421016, rs387906315 and rs80356773 have been significantly associated with the onset of depressive symptoms in PD.Considerations:1.This systematic review has not included studies that were not published in English. It did not include gene expression and epigenetic studies.2.Most of the included genetic association studies were small, and they were prone to type II error.3.There was substantial heterogeneity among the included studies

Systematic review of gene expression studies in people with Lewy body dementia

Objectives:Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia, and it causes more morbidity and mortality than Alzheimer's disease. Several genetic associations of LBD have been reported, and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.Methods:We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEG) using Ingenuity Pathway Analyses.Results:We screened 3,809 articles and identified 31 eligible studies. 1,242 statistically significant (p[less than]0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of RNA-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.Conclusions:α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research

Can only intelligent children do mind reading: The relationship between intelligence and theory of mind in 8 to 11 years old

<p>Abstract</p> <p>Background</p> <p>The mind reading ability of children has evoked wide interest, but its relationship with general cognitive abilities remains obscure.</p> <p>Methods</p> <p>We studied the relationship between the mind reading ability and general intelligence. Children (N = 105) between 8 to 11 years from educational institutions were assessed for the mind reading ability using <it>Picture Sequencing Task </it>and <it>Unexpected Contents Theory of Mind task</it>. We used <it>Strengths and Difficulties Questionnaire </it>to rule out psychiatric morbidity. An independent investigator quantified intelligence and adaptive behavior with <it>Binet- Kamat Test of intelligence </it>and <it>Vineland Adaptive Behavior Scale </it>respectively. We employed bivariate and multivariate statistical tests.</p> <p>Results</p> <p>We demonstrated that mind reading ability was not significantly related to general intelligence or its domains except for the social intelligence after controlling the confounders methodologically and statistically.</p> <p>Conclusion</p> <p>These findings argue that mind reading skill exists as an independent cognitive domain and has clinical, research as well as educational implications.</p

Apathy and its response to antipsychotic review and non-pharmacological interventions in people with dementia living in nursing homes : WHELD, A factorial cluster randomised controlled trial

Objectives: Apathy is common, impactful, and difficult to manage in people with dementia. We evaluated the efficacy of non-pharmacological interventions, exercise and social interaction, in combination with antipsychotic review, to reduce apathy in people with dementia living in nursing homes in a cluster randomised controlled trial (RCT). Methods: Well-being and health for people with dementia (WHELD) programme included a 2X2X2 factorial cluster RCT involving people with dementia living in 16 nursing homes in UK. All homes received training in person-centred care, and were randomised to receive antipsychotic review, social interaction, and exercise, either alone or in combinations. Apathy was one of the secondary outcomes of the WHELD trial, and it was measured by the Neuropsychiatric Inventory-nursing home version at baseline and nine months (N=273). We employed multilevel mixed effects linear regression models to assess the impact of the interventions on apathy. Results: Prevalence of apathy was 44.0% (n=120; 95% CI 38.1-49.9%) at baseline. Severity of apathy had significant positive correlations with dementia severity, neuropsychiatric symptoms, depressive symptoms, agitation, and the needs of the people with dementia (p&lt;0.001). Antipsychotic review reduced antipsychotic use, but it significantly increased apathy (β=5.37; SE=0.91; p&lt;0.001). However, antipsychotic review in combination with either social interaction (β=-5.84; SE=1.15; p&lt;0.001) or exercise (β=-7.54; SE=0.93; p&lt;0.001) significantly reduced apathy. Conclusions: Antipsychotic review can play a significant role in improving apathy in people with dementia living in nursing homes, when combined with psychosocial interventions such as social interaction and exercise. Guidance must be adapted to reflect this subtlety in care

Extracellular vesicle microRNA mediated transcriptional regulation may contribute to Dementia with Lewy Bodies molecular pathology

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. We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB ( , , , , , and ) using and databases. We analysed functional implications of these targets using gene set enrichment analysis, and analysed their protein interactions using pathway analysis. These SEV miRNA may regulate 4,278 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. Our findings provide 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 led to novel therapeutic avenues for DLB

Differential expression of m5C RNA methyltransferase genes NSUN6 and NSUN7 in Alzheimer’s disease and traumatic brain injury

Epigenetic processes have become increasingly relevant in understanding disease-modifying mechanisms. 5-Methylcytosine methylations of DNA (5mC) and RNA (m5C) 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 m5C 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

Systematic review of pharmacological interventions for people with Lewy body dementia

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

Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science

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

Post-mortem cortical transcriptomics of Lewy body dementia reveal mitochondrial dysfunction and lack of neuroinflammation

Objectives: Prevalence of Lewy body dementias (LBD) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. LBD cause earlier mortality, more intense neuropsychiatric symptoms, more caregivers' burden, and higher costs than AD. The molecular mechanisms underlying LBD are largely unknown. As advancing molecular level mechanistic understanding is essential for identifying reliable peripheral biomarkers and novel therapeutic targets for LBD, we aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in post-mortem LBD brains. Methods: We investigated the transcriptomics of post-mortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. We verified the identified DEG using high-throughput quantitative polymerase chain reactions. Functional implications of identified DEG, and the consequent metabolic reprogramming were evaluated by Ingenuity pathway analyses, genome-scale metabolic modelling, reporter metabolite analyses, and in-silico gene silencing.Results: We identified and verified 12 novel DEGs (MPO, SELE, CTSG, ALPI, ABCA13, GALNT6, SST, RBM3, CSF3, SLC4A1, OXTR, and RAB44) in LBD brains with genome-wide statistical significance. We documented statistically significant downregulation of severalcytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence towards neurodegeneration in LBD.Conclusion: Our findings support that chronic microglial activation and neuroinflammation, well-documented in AD, are notably absent in LBD. The lack of neuroinflammation in LBD brains were corroborated by statistically significant downregulation of several inflammatory markers. Identified DEGs, especially downregulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation

Hospitalization in people with dementia with Lewy bodies: Frequency, duration, and cost implications

Introduction: Increased hospitalization is a major component of dementia impact on individuals and cost, but has rarely been studied in dementia with Lewy bodies (DLB). Our aim was to describe the risk and duration of hospital admissions in patients with DLB, and compare these to those in Alzheimer’s disease (AD) and the general population. Methods: A large database of mental health and dementia care in South London was used to assemble a cohort of patients diagnosed with DLB. These were 1:4 matched with patients diagnosed with AD on age, gender, and cognitive status. Results: Rates of hospital admissions in the year after dementia diagnosis were significantly higher in 194 patients with DLB than in 776 patients with AD (crude incidence rate ratio 1.50; 95% confidence interval: 1.28–1.75) or the catchment population (indirectly standardized hospitalization rate 1.22; 95% confidence interval: 1.06–1.39). Patients with DLB had on average almost four additional hospital days per person-year than patients with AD. Multivariate Poisson regression models indicated poorer physical health early in the disease course as the main driver of this increased rate of hospitalization, whereby neuropsychiatric symptoms additionally explained the higher number of hospital days. Discussion: Patients with DLB are more frequently admitted to general hospitals and utilize inpatient care to a substantially higher degree than patients with AD or the general elderly population. These data highlight an opportunity to reduce hospital days by identifying DLB earlier and providing more targeted care focused on the specific triggers for hospitalization and associations of prolonged stay