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Abstract Background Sarcopenia is associated with multiple adverse outcomes. Traditional methods to determine low muscle mass for the diagnosis of sarcopenia are mainly based on dual‐energy X‐ray absorptiometry (DXA), whole‐body magnetic resonance imaging (MRI) and bioelectrical impedance analysis. These tests are not always available and are rather time consuming and expensive. However, many brain and head diseases require a head MRI. In this study, we aim to provide a more accessible way to detect sarcopenia by comparing the traditional method of DXA lean mass estimation versus the tongue and masseter muscle mass assessed in a standard brain MRI. Methods The H70 study is a longitudinal study of older people living in Gothenburg, Sweden. In this cross‐sectional analysis, from 1203 participants aged 70 years at baseline, we included 495 with clinical data and MRI images available. We used the appendicular lean soft tissue index (ALSTI) in DXA images as our reference measure of lean mass. Images from the masseter and tongue were analysed and segmented using 3D Slicer. For the statistical analysis, the Spearman correlation coefficient was used, and concordance was estimated with the Kappa coefficient. Results The final sample consisted of 495 participants, of which 52.3% were females. We found a significant correlation coefficient between both tongue (0.26) and masseter (0.33) with ALSTI (P

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

Abstract Introduction Plasma tests have demonstrated high diagnostic accuracy for identifying Alzheimer's disease pathology. To facilitate the transition to clinical utility, we assessed whether plasma storage duration and temperature affect the biomarker concentrations. Methods Plasma samples from 13 participants were stored at +4°C and +18°C. Concentrations of six biomarkers were measured after 2, 4, 6, 8, 10, and 24 h by single molecule array assays. Results Phosphorylated tau 181 (p‐tau181), phosphorylated tau 231 (p‐tau231), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) concentrations were unchanged both when stored at +4°C and +18°C. Amyloid‐β 40 (Aβ40) and amyloid‐β 42 (Aβ42) concentrations were stable for 24 h at +4°C but declined when stored at +18°C for longer than 6 h. This decline did not affect the Aβ42/Aβ40 ratio. Discussion Plasma samples can be stored for 24 h at +4°C or +18°C and result in valid assay results for p‐tau181, p‐tau231, Aβ42/Aβ40 ratio, GFAP, and NfL. HIGHLIGHTS Plasma samples were stored for 24 h at +4°C and +18°C, mimicking clinical practice. Concentrations for Alzheimer's disease biomarkers were measured at six time‐points. p‐tau181, p‐tau231, NfL, and GFAP concentrations were unchanged during the experiment. Storage at +18°C affected Aβ40 and Aβ42 concentrations while storage at +4°C did not. The Aβ42/Aβ40 ratio was unaffected. These plasma tests seem suitable for use in general practice.

Abstract Introduction Late‐life onset psychosis is associated with faster progression to dementia in cognitively normal people, but little is known about its relationship with cognitive impairment in advance of dementia. Methods Clinical and genetic data from 2750 people ≥50 years of age without dementia were analyzed. Incident cognitive impairment was operationalized using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and psychosis was rated using the Mild Behavioral Impairment Checklist (henceforth MBI‐psychosis). The whole sample was analyzed before stratification on apolipoprotein E (APOE) ε4 status. Results In Cox proportional hazards models, MBI‐psychosis had a higher hazard for cognitive impairment relative to the No Psychosis group (hazard ratio [HR]: 3.6, 95% confidence interval [CI]: 2.2–6, p < 0.0001). The hazard for MBI‐psychosis was higher in APOE ε4 carriers and there was an interaction between the two (HR for interaction: 3.4, 95% CI: 1.2–9.8, p = 0.02). Discussion Psychosis assessment in the MBI framework is associated with incident cognitive impairment in advance of dementia. These symptoms may be particularly important in the context of APOE genotype.

Abstract Objective To determine the evolution of numerous neuropsychiatric symptoms and cognitive abilities in Parkinson disease from disease onset. Methods Prospectively collected, longitudinal (untreated, disease onset to year 5), observational data from Parkinson's Progression Markers Initiative annual visits was used to evaluate prevalence, correlates, and treatment of 10 neuropsychiatric symptoms and cognitive impairment in Parkinson disease participants and matched healthy controls. Results Of 423 Parkinson disease participants evaluated at baseline, 315 (74.5%) were assessed at year 5. Eight neuropsychiatric symptoms studied increased in absolute prevalence by 6.2–20.9% at year 5 relative to baseline, and cognitive impairment increased by 2.7–6.2%. In comparison, the frequency of neuropsychiatric symptoms in healthy controls remained stable or declined over time. Antidepressant and anxiolytic/hypnotic use in Parkinson disease were common at baseline and increased over time (18% to 27% for the former; 13% to 24% for the latter); antipsychotic and cognitive‐enhancing medication use was uncommon throughout (2% and 5% of patients at year 5); and potentially harmful anticholinergic medication use was common and increased over time. At year 5 the cross‐sectional prevalence for having three or more neuropsychiatric disorders/cognitive impairment was 56% for Parkinson disease participants versus 13% for healthy controls, and by then seven of the examined disorders had either occurred or been treated at some time point in the majority of Parkinson disease patients. Principal component analysis suggested an affective disorder subtype only. Interpretation Neuropsychiatric features in Parkinson disease are common from the onset, increase over time, are frequently comorbid, and fluctuate in severity.

Abstract Background Identifying predictors of incident cognitive impairment (CI), one of the most problematic long‐term outcomes, in Parkinson's disease (PD) is highly relevant for personalized medicine and prognostic counseling. The Nonmotor Symptoms Scale (NMSS) provides a global clinical assessment of a range of NMS, reflecting NMS burden (NMSB), and thus may assist in the identification of an “at‐risk” CI group based on overall NMSB cutoff scores. Methods To investigate whether specific patterns of PD NMS profiles predict incident CI, we performed a retrospective longitudinal study on a convenience sample of 541 nondemented PD patients taking part in the Nonmotor Longitudinal International Study (NILS) cohort, with Mini‐Mental State Examination (MMSE), NMSS, and Scales for Outcomes in PD Motor Scale (SCOPA Motor) scores at baseline and last follow‐up (mean 3.2 years) being available. Results PD patients with incident CI (i.e., MMSE score ≤ 25) at last follow‐up (n = 107) had severe overall NMSB level, significantly worse NMSS hallucinations/perceptual problems and higher NMSS attention/memory scores at baseline. Patients with CI also were older and with more advanced disease, but with no differences in disease duration, dopamine replacement therapy, sex, and comorbid depression, anxiety, and sleep disorders. Conclusions Our findings suggest that a comprehensive baseline measure of NMS and in particular hallucinations and perceptual problems assessed with a validated single instrument can be used to predict incident CI in PD. This approach provides a simple, holistic strategy to predict future CI in this population.

Abstract Introduction A phase 2b clinical trial, HEADWAY‐DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB). Methods HEADWAY‐DLB was a multinational, double‐blind, randomized, placebo‐controlled study. Two hundred sixty‐nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale–Part III (UPDRS‐III). Results Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS‐III (35 mg/day: P = .1580, 70 mg/day: P = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo. Discussion Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY‐DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.

Abstract Dementia with Lewy bodies (DLB) research has seen a significant growth in international collaboration over the last three decades. However, researchers face a challenge in identifying large and diverse samples capable of powering longitudinal studies and clinical trials. The DLB research community has begun to focus efforts on supporting the development and harmonization of consortia, while also continuing to forge networks within which data and findings can be shared. This article describes the current state of DLB research collaborations on each continent. We discuss several established DLB cohorts, many of whom have adopted a common framework, and identify emerging collaborative initiatives that hold the potential to expand DLB networks and diversify research cohorts. Our findings identify geographical areas into which the global DLB networks should seek to expand, and we propose strategies, such as the creation of data‐sharing platforms and the harmonization of protocols, which may further potentiate international collaboration.

Abstract Background The neuropsychiatric syndrome mild behavioral impairment (MBI) describes an at‐risk state for dementia and may be a useful screening tool for sample enrichment. We hypothesized that stratifying a cognitively normal sample on MBI status would enhance the association between genetic risk for Alzheimer's disease (AD) and cognition. Methods Data from 4458 participants over age 50 without dementia was analyzed. A cognitive composite score was constructed and the MBI Checklist was used to stratify those with MBI and those without. Polygenic scores for AD were generated using summary statistics from the IGAP study. Results AD genetic risk was associated with worse cognition in the MBI group but not in the no MBI group (MBI: β = –0.09, 95% confidence interval: –0.13 to –0.03, P = 0.002, R2 = 0.003). The strongest association was in those with more severe MBI aged ≥65. Conclusions MBI is an important feature of aging; screening on MBI may be a useful sample enrichment strategy for clinical research.

Abstract Introduction Neuropsychiatric symptoms (NPS) in dementia are associated with poor cognitive outcomes in longitudinal studies. Whether this is due to differences in symptom burden between persons (BP) or changes within persons (WP) is unknown. Methods Patients with mild Alzheimer's disease (AD, n = 111) and Lewy‐body dementia (LBD, n = 85) were assessed annually for 8 years. We modelled the association between NPS assessed by the Neuropsychiatric Inventory (NPI) and Mini‐Mental State Examinations (MMSE) using Tobit mixed‐effects model with NPS as individual means over time (BP) and its deviance (WP). Results The association between higher NPS and poorer cognitive outcomes was mostly due to BP differences for the NPI‐total score, and in particular for delusions, hallucinations, agitation, aberrant motor behavior, and apathy scores. Discussion The NPS trait (BP) effect on cognitive decline is considerably stronger than the state effect (WP). Clinically, long‐term rather than episodic NPS better identifies patients with poor cognitive outcomes.

Abstract Introduction Sensitive neuropsychological tests are needed to improve power for clinical trials in early Alzheimer's disease (AD). Methods To develop a neuropsychological composite (FLAME – Factors of Longitudinal Attention, Memory and Executive Function), we assessed, 10,714 participants over the age of 50 from PROTECT with validated computerized assessments for 2 years. A factorial analysis was completed to identify the key cognitive factors in all participants, and further analyses examined sensitivity to change in people with stage 2/3 early Alzheimer's disease (AD) according to the US Food and Drug Administration (FDA) framework. Results The FLAME composite score (speed of attention, accuracy of attention, memory, and executive function) distinguished between normal cognition and stage 2/3 early AD at baseline, and was sensitive to cognitive and global/functional decline over 2 years, with the potential to improve power for clinical trials. Discussion FLAME is sensitive to change, providing a straightforward approach to reduce sample size for RCTs in early AD. Conclusion FLAME is a useful computerized neuropsychology composite with utility for clinical trials focusing on cognition.

Abstract 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.

The caregiver-care receiver relationship (mutuality) in Parkinson’s disease (PD) and its association with motor and non-motors symptoms, health-related quality of life (HRQoL), and caregiver burden have not fully been investigated. The aim of our study was to explore if (1) the level of mutuality perceived by PD-patients and PD-partners differs, (2) different factors are associated with perceived mutuality by PD-patients and PD-partners, and (3) mutuality is associated with PD-patients health-related quality of life (HRQoL) and caregiver burden. We collected data on motor signs (UPDRS III), non-motor manifestations (NMSQuest), PD-patients’ cognition (IQCODE), mutuality scale (MS), PD-patients’ HRQoL (PDQ8), and caregiver burden (CB) from 51 PD dyads. Predictors were identified using multivariate regression analyses. Overall, the dyads rated their own mutuality as high with no significant difference between the dyads except for the dimension of reciprocity. PD-patients’ MS score (p=.001) and NMSQuest (p ≤ .001) were significant predictors of PDQ8. Strongest predictor of CB was PD-partners’ MS score (

Dementia is an evolving challenge in society, and no disease-modifying treatment exists. Diagnosis can be demanding and MR imaging may aid as a noninvasive method to increase prediction accuracy. We explored the use of 2D local binary pattern (LBP) extracted from FLAIR and T1 MR images of the brain combined with a Random Forest classifier in an attempt to discern patients with Alzheimer's disease (AD), Lewy body dementia (LBD), and normal controls (NC). Analysis was conducted in areas with white matter lesions (WML) and all of white matter (WM). Results from 10-fold nested cross validation are reported as mean accuracy, precision, and recall with standard deviation in brackets. The best result we achieved was in the two-class problem NC versus AD + LBD with total accuracy of 0.98 (0.04). In the three-class problem AD versus LBD versus NC and the two-class problem AD versus LBD, we achieved 0.87 (0.08) and 0.74 (0.16), respectively. The performance using 3DT1 images was notably better than when using FLAIR images. The results from the WM region gave similar results as in the WML region. Our study demonstrates that LBP texture analysis in brain MR images can be successfully used for computer based dementia diagnosis.