Amidst an amygdala renaissance in Alzheimer's disease.

The amygdala was highlighted as an early site for neurofibrillary tau tangle pathology in Alzheimer's disease in the seminal 1991 article by Braak and Braak. This knowledge has, however, only received traction recently with advances in imaging and image analysis techniques. Here, we provide a cross-disciplinary overview of pathology and neuroimaging studies on the amygdala. These studies provide strong support for an early role of the amygdala in Alzheimer's disease and the utility of imaging biomarkers of the amygdala in detecting early changes and predicting decline in cognitive functions and neuropsychiatric symptoms in early stages. We summarize the animal literature on connectivity of the amygdala, demonstrating that amygdala nuclei that show the earliest and strongest accumulation of neurofibrillary tangle pathology are those that are connected to brain regions that also show early neurofibrillary tangle accumulation. Additionally, we propose an alternative pathway of neurofibrillary tangle spreading within the medial temporal lobe between the amygdala and the anterior hippocampus. The proposed existence of this pathway is strengthened by novel experimental data on human functional connectivity. Finally, we summarize the functional roles of the amygdala, highlighting the correspondence between neurofibrillary tangle accumulation and symptomatic profiles in Alzheimer's disease. In summary, these findings provide a new impetus for studying the amygdala in Alzheimer's disease and a unique perspective to guide further study on neurofibrillary tangle spreading and the occurrence of neuropsychiatric symptoms in Alzheimer's disease.

The relationship between playing musical instruments and cognitive trajectories: Analysis from a UK ageing cohort.

BACKGROUND: The accumulation of age-associated cognitive deficits can lead to Mild Cognitive Impairment (MCI) and dementia. This is a major public health issue for the modern ageing population, as it impairs health, independence and overall quality of life. Keeping the brain active during life has been associated with an increased cognitive reserve, therefore reducing the risk of cognitive impairment in older age. Previous research has identified a potential relationship between musicality and cognition. OBJECTIVES: Explore the relationship between musicality and cognitive function in a large cohort of older adults. METHODS: This was a nested study within the PROTECT-UK cohort, which collects longitudinal computerised assessments of cognitive function in adults over 40. Participants were invited to complete the validated Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ) to assess their musical experience and lifetime exposure to music. Linear regression analysis was performed using cognitive data from PROTECT-UK. RESULTS: Analysis identified an association between musicality and cognition in this cohort. Playing a musical instrument was associated with significantly better performance in working memory and executive function. Significant associations were also found between singing and executive function, and between overall musical ability and working memory. CONCLUSIONS: Our findings confirm previous literature, highlighting the potential value of education and engagement in musical activities throughout life as a means of harnessing cognitive reserve as part of a protective lifestyle for brain health.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

Self-reported sleep fragmentation and sleep duration and their association with cognitive function in PROTECT, a large digital community-based cohort of people over 50.

OBJECTIVE: Sleep is vital for normal cognitive function in daily life, but is commonly disrupted in older adults. Poor sleep can be detrimental to mental and physical health, including cognitive function. This study assessed the association between self-reported short (<6 h) and long (>9 h) sleep duration and sleep fragmentation (3≥ nightly awakenings) in cognitive function. METHODS: Cross-sectional data from 8508 individuals enroled in the PROTECT study aged 50 and above formed the basis of the univariate linear regression analysis conducted on four cognitive outcomes assessing visuospatial episodic memory (VSEM), spatial working memory, verbal working memory (VWM), and verbal reasoning (VR). RESULTS: Short (ß = -0.153, 95% CI [-0.258, -0.048], p = 0.004) and long sleep duration (ß = -0.459, 95% CI [-0.826, -0.091], p = 0.014) were significantly associated with poorer cognitive performance in VWM. Long sleep duration (ß = -2.986, 95% CI [-5.453, -0.518], p = 0.018) was associated with impaired VR. Short sleep (ß = -0.133, 95% CI [-0.196, -0.069], p = <0.001) and sleep fragmentation (ß = -0.043, 95% CI [-0.085, -0.001], p = 0.043) were associated with reduced VSEM. These associations remained significant when including other established risk factors for dementia and cognitive decline (e.g., depression, hypertension). CONCLUSIONS: Our findings suggest that short and long sleep durations and fragmented sleep, may be risk factors for a decline in cognitive processes such as working memory, VR and episodic memory thus might be potential targets for interventions to maintain cognitive health in ageing.

Latent subtypes of manic and/or irritable episode symptoms in two population-based cohorts.

BACKGROUND: Mood disorders are characterised by pronounced symptom heterogeneity, which presents a substantial challenge both to clinical practice and research. Identification of subgroups of individuals with homogeneous symptom profiles that cut across current diagnostic categories could provide insights in to the transdiagnostic relevance of individual symptoms, which current categorical diagnostic systems cannot impart. AIMS: To identify groups of people with homogeneous clinical characteristics, using symptoms of manic and/or irritable mood, and explore differences between groups in diagnoses, functional outcomes and genetic liability. METHOD: We used latent class analysis on eight binary self-reported symptoms of manic and irritable mood in the UK Biobank and PROTECT studies, to investigate how individuals formed latent subgroups. We tested associations between the latent classes and diagnoses of psychiatric disorders, sociodemographic characteristics and polygenic risk scores. RESULTS: Five latent classes were derived in UK Biobank (N = 42 183) and were replicated in the independent PROTECT cohort (N = 4445), including 'minimally affected', 'inactive restless', active restless', 'focused creative' and 'extensively affected' individuals. These classes differed in disorder risk, polygenic risk score and functional outcomes. One class that experienced disruptive episodes of mostly irritable mood largely comprised cases of depression/anxiety, and a class of individuals with increased confidence/creativity reported comparatively lower disruptiveness and functional impairment. CONCLUSIONS: Findings suggest that data-driven investigations of psychopathological symptoms that include sub-diagnostic threshold conditions can complement research of clinical diagnoses. Improved classification systems of psychopathology could investigate a weighted approach to symptoms, toward a more dimensional classification of mood disorders.

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Traumatic life experiences and post-traumatic stress symptoms in middle-aged and older adults with and without autistic traits.

OBJECTIVES: Research with younger adults has begun to explore associations between autism/autistic traits and vulnerability to Post Traumatic Stress Disorder (PTSD). Large scale studies and/or examination of age-effects have not been conducted. METHODS: Adults aged 50 years+ from the PROTECT study (n = 20,220) completed items about current and childhood socio-communicative difficulties characteristic of autism. Approximately 1% (n = 251) endorsed high autistic traits, henceforth the Autism Spectrum Traits (AST) group. Differences between the AST and an age-and sex-matched "Comparison Older Adults" (COA; n = 9179) group were explored for lifetime traumatic experiences and current symptoms of PTSD, depression, and anxiety. RESULTS: Almost 30% of the AST group, compared to less than 8% of the COA, reported severe trauma in childhood/adulthood, including emotional, physical or sexual abuse. Elevated current PTSD symptoms were reported by AST compared to COA. An interaction was observed between autistic traits and trauma severity; the effect of level of trauma on PTSD symptoms was significantly greater for AST versus COA participants. This interaction remained significant when controlling for current depression and anxiety symptoms. CONCLUSIONS: The findings suggest that high autistic traits may increase the likelihood of experiencing trauma across the lifespan, and the impact of severe trauma on PTSD symptoms. Older adults with high (vs. low) autistic traits may be at greater risk of experiencing PTSD symptoms in latter life. Future research should test whether the pattern of results is similar for diagnosed autistic adults.

Risky drinking and cognitive impairment in community residents aged 50 and over.

OBJECTIVES: Alcohol misuse is known to be a risk factor for dementia. This study aimed to explore the association between risky drinking and cognitive impairment in a cohort study of middle aged and older people at risk of dementia. METHOD: The sample comprised 15,582 people aged 50 and over drawn from the PROTECT study. Risky drinking was defined according to a score of 4 or above on the Alcohol Use Disorders Identification Test (AUDIT). Cognitive function was assessed on visual episodic memory, spatial working memory, verbal working memory and verbal reasoning. RESULTS: Risky drinkers at baseline were more likely to be younger, male, white British, married, of higher educational status, current or past tobacco smokers and to have moderate to severe depression than non-risky drinkers. Risky drinkers were also more likely to be impaired on self-reported instrumental activities of daily living and subjective cognitive decline. At baseline, risky drinkers were less likely than non-risky drinkers to show impairment on verbal reasoning and spatial working memory but not on visual episodic memory or verbal working memory. Risky drinking at baseline predicted decline in cognitive function on visual episodic memory, verbal reasoning and spatial working memory at 2 year follow-up, but only verbal working memory and spatial working memory remained significant outcomes after controlling for possible confounders. CONCLUSION: Although of small effect size, the association between risky drinking and impairment on measures of working memory and visuospatial function warrants further examination; particularly given the possibility of partial reversibility in alcohol related cognitive impairment.

Loneliness, physical activity, and mental health during COVID-19: a longitudinal analysis of depression and anxiety in adults over the age of 50 between 2015 and 2020.

OBJECTIVE: Loneliness and physical activity are important targets for research into the impact of COVID-19 because they have established links with mental health, could be exacerbated by social distancing policies, and are potentially modifiable. In this study, we aimed to identify whether loneliness and physical activity were associated with worse mental health during a period of mandatory social distancing in the UK. DESIGN: Population-based observational cohort study. SETTING: Mental health data collected online during COVID-19 from an existing sample of adults aged 50 and over taking part in a longitudinal study of aging. All had comparable annual data collected between 2015 and 2019. PARTICIPANTS: Three-thousand two-hundred and eighty-one participants aged 50 and over. MEASUREMENTS: Trajectories of depression (measured by PHQ-9) and anxiety (measured by GAD-7) between 2015 and 2020 were analyzed with respect to loneliness, physical activity levels, and a number of socioeconomic and demographic characteristics using zero-inflated negative binomial regression. RESULTS: In 2020, PHQ-9 score for loneliness, adjusted for covariates, was 3.23 (95% CI: 3.01-3.44), an increase of around 1 point on all previous years in this group and 2 points higher than people not rated lonely, whose score did not change in 2020 (1.22, 95% CI: 1.12-1.32). PHQ-9 was 2.60 (95% CI: 2.43-2.78) in people with decreased physical activity, an increase of .5 on previous years. In contrast, PHQ-9 in 2020 for people whose physical activity had not decreased was 1.66, 95% CI: 1.56-1.75, similar to previous years. A similar relationship was observed for GAD-7 though the absolute burden of symptoms lower. CONCLUSION: After accounting for pre-COVID-19 trends, we show that experiencing loneliness and decreased physical activity are risk factors for worsening mental health during the pandemic. Our findings highlight the need to examine policies which target these potentially modifiable risk factors.

Effectiveness of Dementia Care Mapping™ to reduce agitation in care home residents with dementia: an open-cohort cluster randomised controlled trial.

OBJECTIVES: Agitation is common and problematic in care home residents with dementia. This study investigated the (cost)effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation in this population. METHOD: Pragmatic, cluster randomised controlled trial with cost-effectiveness analysis in 50 care homes, follow-up at 6 and 16 months and stratified randomisation to intervention (n = 31) and control (n = 19). Residents with dementia were recruited at baseline (n = 726) and 16 months (n = 261). Clusters were not blinded to allocation. Three DCM cycles were scheduled, delivered by two trained staff per home. Cycle one was supported by an external DCM expert. Agitation (Cohen-Mansfield Agitation Inventory (CMAI)) at 16 months was the primary outcome. RESULTS: DCM was not superior to control on any outcomes (cross-sectional sample n = 675: 287 control, 388 intervention). The adjusted mean CMAI score difference was -2.11 points (95% CI -4.66 to 0.44, p = 0.104, adjusted ICC control = 0, intervention 0.001). Sensitivity analyses supported the primary analysis. Incremental cost per unit improvement in CMAI and QALYs (intervention vs control) on closed-cohort baseline recruited sample (n = 726, 418 intervention, 308 control) was £289 and £60,627 respectively. Loss to follow-up at 16 months in the original cohort was 312/726 (43·0%) mainly (87·2%) due to deaths. Intervention dose was low with only a quarter of homes completing more than one DCM cycle. CONCLUSION: No benefits of DCM were evidenced. Low intervention dose indicates standard care homes may be insufficiently resourced to implement DCM. Alternative models of implementation, or other approaches to reducing agitation should be considered.

Psychosis in Alzheimer's Disease.

PURPOSE OF REVIEW: To review the incidence, treatment and genetics of psychosis in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). RECENT FINDINGS: Psychosis in Alzheimer's disease (AD) has an incidence of ~ 10% per year. There is limited evidence regarding psychological interventions. Pharmacological management has focused on atypical antipsychotics, balancing modest benefits with evidence of long-term harms. The 5HT2A inverse agonist pimavanserin appears to confer benefit in PD psychosis with initial evidence of benefit in AD. Cholinesterase inhibitors give modest benefits in DLB psychosis. The utility of muscarinic agonists, lithium, glutamatergic and noradrenergic modulators needs further study. Recent work has confirmed the importance of psychosis in MCI as well as AD. The lack of evidence regarding psychological therapies is an urgent knowledge gap, but there is encouraging evidence for emerging pharmacological treatments. Genetics will provide an opportunity for precision medicine and new treatment targets.

Profile of mild behavioral impairment and factor structure of the Mild Behavioral Impairment Checklist in cognitively normal older adults.

OBJECTIVES: In this large population study, we set out to examine the profile of mild behavioral impairment (MBI) by using the Mild Behavioral Impairment Checklist (MBI-C) and to explore its factor structure when employed as a self-reported and informant-rated tool. DESIGN: This was a population-based cohort study. SETTING: Participants were recruited from the Platform for Research Online to Investigate Genetics and Cognition in Aging study (https://www.protect-exeter.org.uk). PARTICIPANTS: A total of 5,742 participant-informant dyads participated in the study. MEASUREMENTS: Both participants and informants completed the MBI-C. The factor structure of the MBI-C was evaluated by exploratory factor analysis. RESULTS: The most common MBI-C items, as rated by self-reported and informants, related to affective dysregulation (mood/anxiety symptoms), being present in 34% and 38% of the sample, respectively. The least common items were those relating to abnormal thoughts and perception (psychotic symptoms) (present in 3% and 6% of the sample, respectively). Only weak correlations were observed between self-reported and informant-reported MBI-C responses. Exploratory factor analysis for both sets of respondent answers indicated that a five-factor solution for the MBI-C was appropriate, reflecting the hypothesized structure of the MBI-C. CONCLUSION: This is the largest and most detailed report on the frequency of MBI symptoms in a nondementia sample. The full spectrum of MBI symptoms was present in our sample, whether rated by self-reported or informant report. However, we show that the MBI-C performs differently in self-reported versus informant-reported situations, which may have important implications for the use of the questionnaire in clinic and research.

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) tool - ERRATUM.

The above article (Griffiths et al., 2019) published with an incorrect abstract.The correct abstract is as follows. OBJECTIVES: Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. DESIGN: Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. SETTING: Fifty care homes in England. PARTICIPANTS: Residents (N = 726) with dementia. MEASUREMENTS: Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. RESULTS: The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer's disease (ß = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). CONCLUSIONS: The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia.

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) tool.

OBJECTIVES: Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. DESIGN: Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. SETTING: Fifty care homes in England. PARTICIPANTS: Residents (N = 726) with dementia. MEASUREMENTS: Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. RESULTS: The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer's disease (ß = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). CONCLUSIONS: The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia.

Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults.

OBJECTIVE: Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) that represent an at-risk state for incident cognitive decline and dementia in people with mild cognitive impairment (MCI). We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment. METHODS: A total of 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function, and working memory at baseline and 1 year. MBI was ascertained using self-administration of the Mild Behavioral Impairment Checklist at 1 year, and participants were grouped according to MBI status: No Symptoms, Intermediate NPS and MBI. All assessments were completed online, and data analyzed using mixed-effects model repeated measures analysis of covariance. RESULTS: A total of 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over 1 year in the four composite cognitive scores measuring attentional intensity (F [2,8578] = 3.97; p = 0.019), sustained attention (F [2,8578] = 18.63; p <0.0001), attentional fluctuation (F [2,8578] = 10.13; p <0.0001) and working memory (F [2,9895] = 13.1; p <0.0001). CONCLUSION: Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.

Current practice and challenges in night-time care for people with dementia living in care homes: a qualitative study.

OBJECTIVE: To explore the current practices and challenges in night-time care for people with dementia living in care homes in the UK. METHODS: Focus group discussions (FGD) were held with care staff and family carers from five care homes in South London. To supplement the FGD data, an online survey was circulated to family carers (n = 16), and informal interviews were conducted with night-time care staff and nurses (n = 19). The questions for the online survey were designed to specifically explore the themes that emerged from the FGD. RESULTS: Thematic analysis revealed eight key themes in the management of sleep disturbance in people with dementia living in care homes: current night-time care practices, dissonance in perceived causes of sleep disturbances, inconsistencies in treatment options, insufficient staffing levels, working relationships between shifts, nurse burden and responsibility, communication as a critical challenge, connecting with residents and one overarching theme of balance. CONCLUSIONS: The findings of this study highlight the need for an evidence-based sleep disturbance management programme designed for use in care homes and informed by stakeholders. The key themes identified represent the major barriers to good quality care and areas which future programmes will need to address to improve the quality of night-time care in care homes. There are clearly opportunities for future examination of non-pharmacological night-time care management programmes for use in the population. Copyright © 2017 John Wiley & Sons, Ltd.

Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: Review and meta-analyses.

Heterozygous mutations in glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBA mutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta-analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta-analysis demonstrated that GBA mutations are associated with a 2.4-fold increased risk of cognitive impairment. In addition, our novel meta-analyses of psychosis and depression showed a 1.8- and 2.2-fold increased risk respectively associated with GBA mutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBA carriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBA mutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBA mutations increase risk for PD and DLB and influence disease course.

Determining the association of the 5HTTLPR polymorphism with delusions and hallucinations in Lewy body dementias.

OBJECTIVES: To determine whether the 5HTTLPR serotonin transporter polymorphism is associated with delusions and hallucinations in people with dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). DESIGN: Prospective cohort study. PARTICIPANTS: A total of 187 individuals, recruited from centres in Norway, Sweden, and the United Kingdom were included in this study; 97 with clinically or neuropathologically diagnosed DLB/PDD and 90 cognitively normal individuals as a comparison group. MEASUREMENTS: All participants with dementia underwent serial evaluation of neuropsychiatric symptoms to assess the presence of persistent delusions and hallucinations using the Columbia University Scale for Psychopathology in Alzheimer disease, the Neuropsychiatric Inventory, or the Present Behavioural Examination. Severity of cognitive impairment was measured using the Mini Mental State Examination (MMSE). Individuals were genotyped for the 5HTTLPR polymorphism. RESULTS: Logistic regression demonstrated that homozygosity for the L/L genotype and lower MMSE were associated with an increased risk for delusions (odds ratio: 11.5 and 1.16, respectively). Neither was significantly associated with hallucinations. CONCLUSIONS: This study is the first to demonstrate the 5HTTLPR polymorphism is associated with delusions in Lewy body dementias, with important implications regarding the mechanisms underlying this symptom across the AD/DLB/PDD spectrum. Further studies are warranted to investigate this relationship further and examine treatment opportunities.