Search

Background: Genome-wide association studies demonstrate that Alzheimer's disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility. Methods: Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58–76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; NEFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features. Results: We observed marked reductions in autobiographical recollection (Cohen's d = − 1.66; PFDR = 0.014) and midline structure (cingulate) thickness (Cohen's d = − 1.55, PFDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = − 0.002, P = 0.011), supporting the validity of our approach. Conclusions: These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk. [ABSTRACT FROM AUTHOR]

Background: While the gender/sex differences in neuropsychiatric symptoms in dementia population are well described, gender/sex differences in mild behavioral impairment (MBI) in dementia-free populations and the relationship to cognitive performance and to subsequent cognitive decline have not been studied.Objective: We aimed to explore gender/sex differences in the association of MBI with the level of cognitive performance and its rate of decline in a dementia-free cohort.Methods: We studied 8,181 older adults enrolled in the online PROTECT UK Study. MBI was assessed using the MBI Checklist and cognition was measured by digit span, paired associate learning, spatial working memory, and verbal reasoning. Statistical analysis was conducted using linear regression models and linear mixed-effects models.Results: Out of 8,181 individuals (median age 63 years, 73% females), 11% of females and 14% of males had MBI syndrome. Females exhibited less often symptoms of decreased motivation (45% versus 36% in males), impulse dyscontrol (40% versus 44% in males; p = 0.001) and social inappropriateness (12% versus 15%; p < 0.001), while they showed more often symptoms of emotional dysregulation (45% versus 36%; p < 0.001). The associations of MBI domains with some measures of cognitive performance and decline were stronger in males than females, with the exception of the association of emotional dysregulation with the rate of cognitive decline in verbal reasoning, which was present exclusively in females.Conclusion: MBI may influence cognition to a greater extent in males than in females. We propose that predictors and biomarkers of dementia should consider gender/sex as an effect modifier. [ABSTRACT FROM AUTHOR]

Psychosis is a common and distressing symptom in people with Alzheimer disease, and few safe and effective treatments are available. However, new approaches to symptom assessment and treatment are beginning to drive the field forward. New nosological perspectives have been provided by incorporating the emergence of psychotic symptoms in older adults - even in advance of dementia - into epidemiological and neurobiological frameworks as well as into diagnostic and research criteria such as the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment. Here, we highlight the latest findings in genomics, neuroimaging and neurobiology that are informing approaches to drug discovery and repurposing. Current pharmacological and non-pharmacological treatment options are discussed, with a focus on safety and precision medicine. We also explore trial data for pimavanserin, a novel agent that shows promise for the treatment of psychosis in people with dementia, and discuss existing agents that might be useful but need further exploration such as escitalopram, lithium, cholinesterase inhibitors and vitamin D. Although the assessment and management of psychosis in people with dementia remain challenging, new opportunities are providing direction and hope to the field. [ABSTRACT FROM AUTHOR]

Background: Late-life onset neuropsychiatric symptoms are established risk factors for dementia. The mild behavioral impairment (MBI) diagnostic framework was designed to standardize assessment to determine dementia risk better. In this Mini Review, we summarize the emerging clinical and biomarker evidence, which suggests that for some, MBI is a marker of preclinical Alzheimer's disease. Main: MBI is generally more common in those with greater cognitive impairment. In community and clinical samples, frequency is around 10–15%. Mounting evidence in cognitively normal samples links MBI symptoms with known AD biomarkers for amyloid, tau, and neurodegeneration, as well as AD risk genes. Clinical studies have found detectable differences in cognition associated with MBI in cognitively unimpaired people. Conclusion: The emerging evidence from biomarker and clinical studies suggests MBI can be an early manifestation of underlying neurodegenerative disease. Future research must now further validate MBI to improve identification of those at the very earliest stages of disease. [ABSTRACT FROM AUTHOR]

Psychotic symptoms are a common and debilitating feature of Alzheimer's disease (AD) and are associated with a more rapid course of decline. Current evidence from postmortem and neuroimaging studies implicates frontal, temporal, and parietal lobes, with reported disruptions in monoaminergic pathways. However, the molecular mechanisms underlying this remain unclear. In the present study, we investigated methylomic variation associated with AD psychosis in 3 key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex, and superior temporal gyrus) in postmortem brain samples from 29 AD donors with psychosis and 18 matched AD donors without psychosis. We identified psychosis-associated methylomic changes in a number of loci, with these genes being enriched in known schizophrenia-associated genetic and epigenetic variants. One of these known loci resided in the AS3MT gene—previously implicated in schizophrenia in a large GWAS meta-analysis. We used bisulfite-pyrosequencing to confirm hypomethylation across 4 neighboring CpG sites in the ASM3T gene. Finally, our regional analysis nominated multiple CpG sites in TBX15 and WT1 , which are genes that have been previously implicated in AD. Thus one potential implication from our study is whether psychosis-associated variation drives reported associations in AD case-control studies. • Psychosis is common in AD and has a negative impact on the course of the disease. • We compared genomewide DNA methylation in AD donors with and without psychosis. • The top-ranked genes were enriched for known schizophrenia GWAS and EWAS loci. • We observed 2 significant differentially methylated regions with multiple CpGs. • AD + P-associated methylation of AS3MT gene was replicated by pyrosequencing. [ABSTRACT FROM AUTHOR]

Introduction: Visual hallucinations (VH) have a significant impact on quality of life for people with Parkinson's disease (PD). A major reason for this is the well‐established link with cognitive impairment, but there is still a need for more longitudinal studies examining the specific cognitive domains which may be affected. The aim of this study was to profile decline in cognition associated with VH in a cohort of 69 individuals with PD over 1 year. Method: Visual hallucinations assessments were carried out every 3 months. Executive function and episodic memory were assessed at baseline and 1 year. All evaluations were performed via phone interviews. The presence or absence of VH was categorized based on the entirety of the year's data (i.e., no episodes and >0 episodes). We also defined a persistent VH group who had VH present at more than one time point and compared these with a no‐VH group and a group with transient VH (i.e., only one episode). Results: Linear mixed‐effect models showed that VH were associated with more rapid overall cognitive decline (−0.26, t = −2.39, p =.02), which was driven by executive function (−0.28, t = −2.48, p =.02). Persistent VH were associated with decline in executive function (−0.33, t = −2.4, p =.02), while no relationship was found for non‐persistent VH, suggesting that persistent VH be the major driver of this relationship. Conclusion: This finding brings greater clarity to the relationship between cognitive decline and VH in PD. Future research should examine the robustness of this phenotype for biomarkers studies and treatment interventions. [ABSTRACT FROM AUTHOR]

To establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease. Two-arm randomized controlled trial of the START program. Remote online trial in adults older than 50 taking part from home. The trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array. START conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype. The 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way. [ABSTRACT FROM AUTHOR]

New work building on the results of genome-wide association studies in Alzheimer disease has identified molecular mechanisms that are shared with some psychiatric disorders. The study leveraged 'omics data and has the realistic potential to elucidate unknown disease mechanisms; however, a lack of information about neuropsychiatric symptoms in the participants with Alzheimer disease limits the conclusions. [ABSTRACT FROM AUTHOR]

Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition - or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results. [ABSTRACT FROM AUTHOR]

In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors - for example, autonomic dysfunction - that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis. [ABSTRACT FROM AUTHOR]

Introduction There is evidence that neurofibrillary tangle (NFT) burden is associated with psychotic symptoms in Alzheimer disease (AD). However, it is not clear whether this association is direct or mediated through the increased cognitive impairment associated with NFTs. Methods We sought to determine whether the extended MAPT haplotype was associated with the worsening of delusions and hallucinations in a combined cohort of 95 patients who participated in 2 clinical trials of treatment with memantine. Results After controlling for baseline dementia severity, exposure to memantine, and antipsychotics, analysis shows that carriers of at least one H2 allele had a 5.4-fold ( P = .03) increased risk of worsening hallucinations. There was some evidence of association with worsening delusions but only in analysis by allele. Conclusion These results are the first to indicate that the H2 allele of the extended MAPT haplotype negatively affects the course of psychotic symptoms in AD independently of disease severity. It will be important for future research to examine MAPT transcription in people with AD with and without psychotic symptoms to understand the exact mechanisms underlying these findings. [ABSTRACT FROM AUTHOR]

Background: Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally. Methods: Data were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003–2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions). Results: Of 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aβ42 (standardized β [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aβ42/40 (p = 0.01); higher p-tau (9.67% [3.96–15.70%]; p = 0.001), t-tau (7.71% [2.70–12.97%]; p = 0.002), p-tau/Aβ42 (p < 0.001), and t-tau/Aβ42 (p = 0.001). NPSnotMBI was associated only with lower Aβ42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99–6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49–1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aβ40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia. Conclusions: These findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes cognitive impairment but it remains contested regarding which cognitive domains are most affected. Further, moderate-severe TBI is known to be deleterious, but studies of mild TBI (mTBI) show a greater mix of negative and positive findings. This study examines the longer-term cognitive effects of TBI severity and number of mTBIs in later life. We examined a subset (n = 15,764) of the PROTECT study, a cohort assessing risk factors for cognitive decline (ages between 50 and 90 years). Participants completed cognitive assessments annually for 4 years. Cognitive tests were grouped using a principal components analysis (PCA) into working memory, episodic memory, attention, processing speed, and executive function. Lifetime TBI severity and number were retrospectively recalled by participants using the Brain Injury Screening Questionnaire (BISQ). Linear mixed models (LMMs) examined the effect of severity of head injury (non-TBI head strike, mTBI, and moderate-severe TBI) and number of mTBI at baseline and over time. mTBI was considered as a continuous and categorical variable (groups: 0 mTBI, 1 mTBI, 2 mTBIs, 3 mTBIs, and 4+ mTBIs). Of the participants 5725 (36.3%) reported at least one mTBI and 510 (3.2%) at least one moderate-severe TBI, whereas 3711 (23.5%) had suffered at worst a non-TBI head strike and 5818 (32.9%) reported no head injuries. The participants had suffered their last reported head injury an average (standard deviation, SD) of 29.6 (20.0) years prior to the study. Regarding outcomes, there was no worsening in longitudinal cognitive trajectories over the study duration but at baseline there were significant cognitive deficits associated with TBI. At baseline, compared with those without head injury, individuals reporting at least one moderate-severe TBI had significantly poorer attention (B = −0.163, p< 0.001), executive scores (B = −0.151, p = 0.004), and processing speed (B = −0.075, p = 0.033). Those who had suffered at least a single mTBI also demonstrated significantly poorer attention scores at baseline compared with the no head injury group (B = −0.052, p = 0.001). Compared with those with no mTBI, those in the 3 mTBI group manifested poorer baseline executive function (B = −0.149, p = 0.025) and attention scores (B = −0.085, p = 0.015). At baseline, those who had suffered four or more mTBIs demonstrated poorer attention (B = −0.135, p < 0.001), processing speed (B = −0.072, p = 0.009), and working memory (B = −0.052, p = 0.036), compared with those reporting no mTBI. TBI is associated with fixed, dose, and severity-dependent cognitive deficits. The most sensitive cognitive domains are attention and executive function, with approximately double the effect compared with processing speed and working memory. Post-TBI cognitive rehabilitation should be targeted appropriately to domain-specific effects. Significant long-term cognitive deficits were associated with three or more lifetime mTBIs, a critical consideration when counseling individuals post-TBI about continuing high-risk activities. [ABSTRACT FROM AUTHOR]

Background/Aims: Cognitive impairment is a well-established correlate of psychotic symptoms in Alzheimer's disease (AD-P). We review whether this relationship has confounded previous genetic association studies of 5HTTLPR and AD-P. Methods: We reviewed all studies on 5HTTLPR and conducted a semi-quantitative analysis. Results: Three out of 4 studies with low MMSE reported a significant association, while 1 out of 4 with high MMSE reported a significant association. Conclusions: Variation in cognitive impairment in past studies has contributed to the inconsistency in findings. The findings presented here bring a greater clarity to our understanding of the role of 5HTTLPR in AD-P. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: We sought to determine whether the COMT val158met polymorphism (rs4680) is associated with delusions and hallucinations in people with dementia with Lewy bodies (DLB) and Parkinson''s disease dementia (PDD). A total of 218 individuals, recruited from centres in Norway, Sweden and the UK were included in this study; 121 with clinically or neuropathologically diagnosed DLB/PDD and 97 age-matched, cognitively normal controls. 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''s disease, the Neuropsychiatric Inventory or the Present Behavioural Examination. Severity of cognitive impairment was measured using the Mini Mental State Examination (MMSE). Both controls and participants with dementia were genotyped for rs4680. In contrast to previous findings, analysis by logistic regression failed to find any associations between rs4680 and psychotic symptoms. Larger studies in well characterised cohorts are warranted in order to investigate this relationship further. [Copyright &y& Elsevier]

Neuropsychiatric symptoms affect most patients with dementia over the course of the disease. They include a wide variety of symptoms from apathy and depression to psychosis, irritability, impulsivity and agitation. These symptoms are associated with significant distress to the patient and caregivers, as well as more rapid progression of dementia, institutionalisation and higher mortality. The first-line management of the neuropsychiatric symptoms of dementia should be non-pharmacological. If medications are required, antipsychotics are commonly chosen. Second-generation antipsychotics such as risperidone, olanzapine, quetiapine and aripiprazole are prescribed more often than first-generation antipsychotics, such as haloperidol. The aim of this review is to provide an update on findings on adverse outcomes and clinical implications of antipsychotic use in dementia. These medications may increase mortality and can be associated with adverse events including pneumonia, cerebrovascular events, parkinsonian symptoms or higher rates of venous thromboembolism. Risks related to antipsychotic use in dementia are moderated by a number of modifiable and non-modifiable factors such as co-prescribing of other medications, medical and psychiatric co-morbidities, and demographics such as age and sex, making individualised treatment decisions challenging. Antipsychotics have further been associated with an increased risk of reliance on long-term care and institutionalisation, and they might not be cost-effective for healthcare systems. Many of these risks can potentially be mitigated by close physical health monitoring of antipsychotic treatment, as well as early withdrawal of pharmacotherapy when clinically possible. [ABSTRACT FROM AUTHOR]

Physical inactivity in mid-life is a modifiable risk factor for dementia. Mild behavioral impairment (MBI) is a marker of potential neurodegenerative disease. We investigated the association between physical activity and MBI. Baseline data from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT) were used. Four categories of weekly physical activity (cardiovascular, mind-body, strength training, and physical labour) were derived from the Community Healthy Activities Model Program for Seniors questionnaire. MBI was measured using the MBI-Checklist. Multivariable negative binomial regressions modelled the association between the standardized physical activity duration and MBI severity, adjusted for age, sex, education, marital status, ethno cultural origin, occupation, hypertension, dyslipidemia, mobility, and body mass index. Every 1 SD increase in cardiovascular activity was associated with 8.42% lower MBI severity. In contrast, every 1 SD increase in physical labor duration was associated with 5.64% greater MBI severity. These associations were neither moderated by the frequency engaging in each physical activity nor by sex. Cardiovascular physical activity in older persons may reduce levels of non-cognitive dementia markers like MBI, comparable to effects seen in cognition, potentially modulating dementia risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Key points: Playing a musical instrument was associated with significantly better working memory and executive function.Singing and overall musical ability was associated with more favourable cognition.Engagement with musical activities should be considered as part of public health initiatives to promote a protective lifestyle for brain health. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Key points: This study assessed the association between self‐reported short (<6 h) and long (>9 h) sleep duration and sleep fragmentation (3 or more nightly awakenings) in cognitive function.Univariate linear regression analysis indicated that short and long sleep duration, and sleep fragmentation impaired cognitive processes such as working memory, verbal reasoning (VR) and episodic memory in individuals aged 50+, even when including other established risk factors for dementia and cognitive decline, such as low educational level, hearing loss, traumatic brain injury, hypertension, diabetes, alcohol consumption, obesity, smoking, depression, social isolation, and physical inactivity.Both sleep duration and sleep fragmentation are highlighted as potential risk factors for reduced cognitive function and might be a possible target for interventions to maintain cognitive health in ageing. [ABSTRACT FROM AUTHOR]

Suicide has been identified as a leading cause of premature death in autistic populations. Elevated autistic traits have also been associated with higher rates of self-harm, suicidal ideation, and suicidal self-harm in the general population, but this has yet to be examined in older age. Using baseline cross-sectional data from the PROTECT study, middle-age and older adults with high autistic traits (n = 276) had significantly higher rates of suicidal ideation, deliberate self-harm, and suicidal self-harm than an age/sex-matched comparison group (n = 10,495). These differences represented a 5- to 6-fold increase in likelihood for self-harming and suicidality. These findings, which remained when controlling for depression symptoms, suggest that middle-age and older adults with high autistic traits may be particularly at risk of self-harm and suicidal behaviours. [ABSTRACT FROM AUTHOR]

A major concern with COVID‐19 was the impact it would have on individual health, the routine use of healthcare services, and physical activities, especially for older adults with comorbidities. To address this, we studied the association between these variables for older adults during the pandemic. To explore what policy instruments might be effective in mitigating the negative impacts, we investigated the effects of a shielding notice for those identified as vulnerable by the government and social media given it has been an important source for disseminating information of COVID‐19. We employed a UK sample with 3,807 participants aged ≥50 from an online survey administered during May and June 2020. Based on numbers of comorbidities, we separated the sample into a higher comorbidity group with those in the upper quartile of the sample (n = 829) and a lower comorbidity group with the remainder (n = 2,978). Statistical methods include chi‐squared analyses and cross‐sectional regressions. We found that individuals with higher comorbidities were more likely to have poorer self‐reported health and mental health and to receive a shielding notice from the government compared to those without (p < 0.05). Decreases in physical activities were associated with poorer self‐reported health and the increases were associated with better self‐reported health; on the other hand, the decreases were associated with poorer mental health, but the increases did not link to better mental health. Examination of the effects of policy instruments shows that a shielding notice was positively associated with primary care use. The notice generated greater reliance on telephone/video consultations compared to in‐person consultations, but the impacts were less strong for people with higher comorbidities. Frequent use of social media raised the probability of increasing physical activities and reduced that of decreasing physical activities, implying social media being an effective tool in promoting physical activities during the lockdown and subsequent restrictions. [ABSTRACT FROM AUTHOR]

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials. [ABSTRACT FROM AUTHOR]

Background: In the absence of disease-modifying treatments, identifying potential psychosocial risk factors for dementia is paramount. Depression and anxiety have been identified as potential risk factors. Studies however have yielded mixed findings, lending possibility to the fact that potential constellations of co-occurring depression and anxiety symptoms may better explain the link between affective symptoms and cognitive decline.Methods: Data from participants (aged 50 and above) of the PROTECT study was used. Latent Class Analysis (LCA) was conducted on 21,684 participants with baseline anxiety and depression measures. Multiple linear regressions models, using a subset of these participants (N = 6136) who had complete cognition data at baseline and at 2-year follow-up, were conducted to assess for associations between class membership and longitudinal changes in cognition.Results: The LCA identified a 5-class solution: "No Symptoms", "Sleep", "Sleep and Worry", "Sleep and Anhedonia", and "Co-morbid Depression and Anxiety". Class membership was significantly associated with longitudinal change in cognition. Furthermore, this association differed across different cognitive measures.Limitations: Limitations included significant attrition and a generally healthy sample which may impact generalisability.Conclusions: Substantial heterogeneity in affective symptoms could explain previous inconsistent findings concerning the association between affective symptoms and cognition. Clinicians should not focus solely on total symptom scores on a single affective domain, but instead on the presence and patterns of symptoms (even if sub-clinical) on measures across multiple affective domains. Identifying particular subgroups that are at greater risk of poor cognitive outcomes may support targeted prevention work. [ABSTRACT FROM AUTHOR]

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. Key points: Using data from PROTECT, a large healthy ageing cohort, approximately 30% of middle‐aged and older adults with high autistic traits reported severe trauma in childhood/adulthood compared to less than 8% of a low autistic trait comparison groupMiddle‐aged and older adults with high autistic traits also reported elevated current PTSD symptoms when compared to the low autistic trait comparison groupAn interaction was observed between autistic traits and trauma severity; the effect of level of trauma on PTSD symptoms was significantly greater for those with high autistic traits vs. low autistic traitsMiddle‐aged and older adults with high autistic traits—especially those who have experienced severe trauma ‐ may need additional support to mitigate this vulnerability to poor mental health later in life [ABSTRACT FROM AUTHOR]

Objectives The mental and physical health profile of autistic people has been studied in adolescence and adulthood, with elevated rates of most conditions being reported. However, this has been little studied taking a dimensional approach to autistic traits and in older age. Methods A total of 20,220 adults aged 50–81 years from the PROTECT study reported whether they experienced persistent sociocommunicative traits characteristic of autism. Approximately 1%, 276 individuals, were identified as endorsing elevated autistic traits in childhood and currently, henceforth the "Autism Spectrum Trait" (AST) group. An age- and gender-matched comparison group was formed of 10,495 individuals who did not endorse any autistic behavioral traits, henceforth the "Control Older Adults" (COA) group. Differences between AST and COA groups were explored in self-reported psychiatric diagnoses, self-reported symptoms of current depression and anxiety, and self-reported physical health diagnoses. Associations were also examined between autistic traits and health across the whole sample. Results The AST group reported significantly elevated rates of psychiatric diagnoses compared to the COA group. Additionally, the AST group showed significantly higher self-reported symptoms of current depression and anxiety than the COA group. However, few differences were observed in individual physical health conditions, and no differences in total co-occurring physical diagnoses between groups. Similar associations between autistic traits and health were also found taking a dimensional approach across the whole sample. Discussion These findings suggest that older adults with elevated autistic traits may be at greater risk of poorer mental, but not physical, health in later life. Future studies should incorporate polygenic scores to elucidate the possible genetic links between the propensity to autism/high autistic traits and to psychiatric conditions, and to explore whether those with elevated autistic traits experience particular barriers to mental health care. [ABSTRACT FROM AUTHOR]

Background: Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice.Objective: To establish research criteria for the diagnosis of psychosis in AD.Methods: The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria.Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers.Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Up to 90 % of people living with dementia in care homes experience one or more behaviours that staff may describe as challenging to support (BSC). Of these agitation is the most common and difficult to manage. The presence of agitation is associated with fewer visits from relatives, poorer quality of life and social isolation. It is recommended that agitation is treated through psychosocial interventions. Dementia Care Mapping™ (DCM™) is an established, widely used observational tool and practice development cycle, for ensuring a systematic approach to providing person-centred care. There is a body of practice-based literature and experience to suggests that DCM™ is potentially effective but limited robust evidence for its effectiveness, and no examination of its cost-effectiveness, as a UK health care intervention. Therefore, a definitive randomised controlled trial (RCT) of DCM™ in the UK is urgently needed.Methods/design: A pragmatic, multi-centre, cluster-randomised controlled trial of Dementia Care Mapping (DCM™) plus Usual Care (UC) versus UC alone, where UC is the normal care delivered within the care home following a minimum level of dementia awareness training. The trial will take place in residential, nursing and dementia-specialist care homes across West Yorkshire, Oxfordshire and London, with residents with dementia. A random sample of 50 care homes will be selected within which a minimum of 750 residents will be registered. Care homes will be randomised in an allocation ratio of 3:2 to receive either intervention or control. Outcome measures will be obtained at 6 and 16 months following randomisation. The primary outcome is agitation as measured by the Cohen-Mansfield Agitation Inventory, at 16 months post randomisation. Key secondary outcomes are other BSC and quality of life. There will be an integral cost-effectiveness analysis and a process evaluation.Discussion: The protocol was refined following a pilot of trial procedures. Changes include replacement of a questionnaire, whose wording caused some residents distress, to an adapted version specifically designed for use in care homes, a change to the randomisation stratification factors, adaption in how the staff measures are collected to encourage greater compliance, and additional reminders to intervention homes of when mapping cycles are due, via text message.Trial Registration: Current Controlled Trials ISRCTN82288852 . Registered on 16 January 2014. Full protocol version and date: v7.1: 18 December 2015. [ABSTRACT FROM AUTHOR]

Background Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. Methods The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. Results There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI –1.80–2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI –0.35–8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI –1.68–11.70; P = .05) and 3.63 (95% CI –1.40–8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks. Discussion This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk. [ABSTRACT FROM AUTHOR]

Background Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. Methods The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. Results There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI –1.80–2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI –0.35–8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI –1.68–11.70; P = .05) and 3.63 (95% CI –1.40–8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks. Discussion This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk. [ABSTRACT FROM AUTHOR]