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Estimates of the risk of dementia in Parkinson's disease (PDD) vary widely. We aimed to review the incidence of PDD and in a meta‐analysis estimate the pooled annual incidence and relative risk of PDD while also exploring factors that may contribute to heterogeneity between studies. Preferred Reporting Items for Systematic reviews and Meta‐Analyses guidelines were followed and MEDLINE and EMBASE were searched for articles reporting the number of cases of dementia in a population, followed longitudinally, with a minimum of 100 dementia‐free Parkinson's disease (PD) patients at baseline. Meta‐analyses and meta‐regressions were used to estimate the pooled incidence rate of PDD and the relative risk of PDD versus healthy controls (HC). A total of 32 studies were identified, 25 reporting the incidence of PDD and 10 reporting the relative risk of PDD versus HC. The pooled incidence rate of PDD was 4.45 (95% confidence interval [CI], 3.91–4.99) per 100 person‐years at risk, equating to a 4.5% annual risk of dementia in a PD prevalent population. The relative risk of PDD was estimated to be 3.25 (95% CI, 2.62–4.03) times greater than HC. Factors contributing to study heterogeneity and disparities in the estimated risk of PDD include the age of patients, year of recruitment, and study location. Significant gaps remain with no studies identified in several geographical regions. Future studies should stratify by age and standardize reporting to reduce overall heterogeneity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Anxiety and depression are common non‐motor symptoms in Parkinson's disease (PD) but remain under‐recognized and under‐treated. Objectives: To evaluate functional outcomes associated with baseline anxiety or depression and effects related to the initiation of new psychiatric treatment. Methods: We analyzed 7 years of data from patients with de novo PD enrolled in the Parkinson's Progression Markers Initiative. Longitudinal regression models evaluated the association between baseline anxiety and depression with Schwab and England (SE) and MDS‐UPDRS total scores over time. Cox proportional hazard models assessed effects of baseline anxiety and depression on time to initiation of dopaminergic therapy. Piecewise linear regression models examined the association of treatment initiation for anxiety and depression with SE and MDS‐UPDRS. Results: 490 participants with baseline depression and anxiety data were included. Anxiety and depression were associated with lower SE (anxiety: β = −1.31, P = 0.038, depression: β = −1.96, P = 0.012, co‐morbid: β = −2.70, P = 0.003) and higher MDS‐UPDRS scores (anxiety: β = 5.37, P < 0.001, depression: β = 9.17, P < 0.001, co‐morbid: β = 10.50, P < 0.001) longitudinally. Anxiety was associated with faster time to dopamine replacement therapy initiation (HR 1.30, 95% CI 1.03–1.66, P = 0.03). 16 participants with anxiety initiated treatment for anxiety, which was associated with subsequent lower levodopa daily dose (slope change = −218.49, P = 0.018). 10 participants with depression initiated treatment of depression, which was associated with reduced MDS‐UPDRS total scores (slope change = −8.3, P < 0.001) and higher SE scores (slope change = 5.99, P = 0.004). Conclusions: Anxiety and depression at PD onset are associated with multiple negative longitudinal trajectories. However, preliminary findings suggest that anxiety and depression treatment may be linked with improved motor and non‐motor outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Wrist‐worn actigraphy can be an objective tool to assess sleep and other behavioral and psychological symptoms in dementia (BPSD). We investigated the feasibility of using wearable actigraphy in agitated late‐stage dementia patients. METHODS: Agitated, late‐stage Alzheimer's dementia care home residents in Greater London area (n = 29; 14 females, mean age ± SD: 80.8 ± 8.2; 93.1% White) were recruited to wear an actigraphy watch for 4 weeks. Wearing time was extracted to evaluate compliance, and factors influencing compliance were explored. RESULTS: A high watch‐acceptance (96.6%) and compliance rate (88.0%) was noted. Non‐compliance was not associated with age or BPSD symptomatology. However, participants with "better" cognitive function (R = 0.42, p = 0.022) and during nightshift (F1.240, 33.475 = 8.075, p = 0.005) were less compliant. Female participants were also marginally less compliant (F1, 26 = 3.790, p = 0.062). DISCUSSIONS: Wrist‐worn actigraphy appears acceptable and feasible in late‐stage agitated dementia patients. Accommodating the needs of both the patients and their carers may further improve compliance. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

INTRODUCTION: iWHELD is a digital person‐centered care program for people with dementia in nursing homes adapted for remote delivery during the COVID‐19 pandemic. METHODS: A 16‐week two‐arm cluster‐randomized controlled trial in 149 UK nursing homes compared iWHELD with treatment as usual (TAU). Primary outcome was the overall quality of life with secondary outcomes of agitation and psychotropic use. RESULTS: iWHELD conferred benefit to quality of life on the primary (F = 4.3, p = 0.04) and secondary measures of quality of life (F = 6.45, p = 0.01) and reduced psychotropic medication use (χ2 = 4.08, p = 0.04) with no worsening of agitation. Benefit was seen in participants who contracted COVID‐19, those with agitation at baseline, and those taking psychotropic medications. DISCUSSION: iWHELD confers benefits to quality of life and key measures of well‐being, can be delivered during the challenging conditions of a pandemic, and should be considered for use alongside any emerging pharmacological treatment for neuropsychiatric symptoms. Highlights: iWHELD is the only remote, digital delivery nursing home training programme for dementia careiWHELD improved quality of life in people with dementia and reduced antipsychotic use without worsening of agitationResidents who contracted Covid‐19 during the study also experienced benefits from iWHELDiWHELD offers a valuable, pandemic‐safe tool for improving dementia care [ABSTRACT FROM AUTHOR]

Background: Synapse pathology has been linked to excitotoxicity and glutamate receptor dysregulation (such as AMPAR) in Alzheimer´s Disease (AD) progression. Of the core cerebrospinal fluid (CSF) AD biomarkers for amyloid, tau pathology and neurodegeneration (A/T/N), T/N status is proposed to reflect levels of neuronal plasticity, but fluid biomarkers for precision interventions in subgroups with increased excitotoxicity are lacking. Herein, we assess group differences of 19 CSF synapse markers including the AMPAR‐modulating NPTX, in both cognitively normal (CN) and Mild Cognitive Impairment (MCI) with either A+/T‐/N‐ and A+/T or N+ (A+/T/N+) as compared to CN A‐/T‐/N‐ and assess relationships with verbal memory recall and hippocampal volume. Methods: A/T/N was determined using the CSF Aβ42/40 ratio, p‐tau181 and total‐tau in predementia AD cases (n = 194) and CN participants with normal AD biomarkers (n = 145) in the Dementia Disease Initiation cohort. CSF synapse marker concentrations were determined using mass‐spectrometry (table 1) and ELISA for GAP‐43. Adjusted for age and sex, we compared marker concentrations between CN cases (A+/T‐/N‐ n = 20; A+/T/N+ n = 40) and MCI cases (A+/T‐/N‐ n = 25;A+/T/N+ n = 109) with CN A‐/T‐/N‐ (n = 145) as the reference group. Associations to verbal memory recall and brain imaging were performed in the total sample and respective A/T/N groups adjusted for covariates. Results p<.01 were considered significant. Results: Top markers based on between‐group results are reported (Table 1 & figure 1‐2 for all markers). Compared to CN A‐/T‐/N‐, 14‐3‐3 ζ/δ concentrations were higher in all A+/T/N+ groups (p<.001), but unaltered in A+/T‐/N‐ groups. In A+/T‐/N‐, NPTX2 concentrations were lower in MCI (p<.001) but not in CN. In A+/T/N+, NPTX2 was higher in CN (p<.001) but not in MCI. 14‐3‐3 ζ/δ was associated with worse memory in the total sample (p<.001) but not in the A+ groups. Lower NPTX2 was associated with worse memory in the total sample (p<.001) and in both A+ groups (p<.01; p<001). Neither 14‐3‐3 ζ/δ nor NPTX2 were significantly associated with hippocampal volume (figure 2). Conclusion: Overall, increased 14‐3‐3 ζ/δ was most closely associated with worse memory recall. Lower NPTX2 was linked to poorer cognitive status within A+ groups, suggesting links to AMPAR dysregulation and excitotoxicity. [ABSTRACT FROM AUTHOR]

Background: Among promising markers for neurodegenerative disorders, electroencephalogram (EEG) represents a non‐invasive and potentially portable alternative. Standardized methods for preprocessing may contribute to less inter‐observer variability, while pooling multi‐centric EEG data may provide more generalizable results. We aim to formulate a reproducible pipeline for group‐level classification (of Parkinson's Disease ‐PD‐) based on various features of resting‐state EEG recordings (rsEEG) collected in multi‐site studies. Methods: We used four datasets (acquired in Colombia, Finland, and the USA) consisting of 169 subjects (84 PD; 85 non‐PD healthy controls). Our workflow included rsEEG raw files standardization, preprocessing, spectral bandpowers and multiple entropy features extraction on sensor space, harmonization of multi‐site features, and group‐level multiclass classification using supervised machine learning methods. Center/scanner‐related variability effects in the extracted features were harmonized using the ComBat approach and its variants 1. Finally, sequential feature selection (SFS) and binary classification (Non‐PD vs. PD) was conducted using XGradientBoosting 2. The full workflow is detailed in Figure 1. Results: t‐distributed stochastic neighbor embedded (tSNE) plots showed that center‐related variability in spectral features was reduced after harmonization using the ComBat method and its bootstrapped variant, Figure 2. SFS of rsEEG features was performed on 224 harmonized features, showing the highest performance when alpha, pre‐alpha, and slow‐theta bands were considered for subsequent classification. The XGradientBoosting classifier showed an AUC of 0.826 in separating PD from non‐PD, Figure 3. Conclusions: In multicenter studies, the harmonization of rsEEG features at the sensor space using ComBat can contribute to controlling batch effects. XGradientBoosting with rsEEG features and SFS performed well in classifying non‐PD vs. PD. Intended to be a practical tool for group‐level analysis of neurodegenerative disorders based on sensor space rsEEG features, our workflow is openly available at (https://github.com/alberto‐jj/raw%5fto%5fclassification) and can be easily adapted to multi‐class classification and regression tasks. References 1. Da‐ano, R., et al. Sci. Rep. 10, 10 (2020). 2. Moguilner, S., et al. J. Neural Eng. 19, 046048 (2022). [ABSTRACT FROM AUTHOR]

Background: Gait is a complex everyday activity that depends upon supraspinal activity and a host of cognitive functions such as attention and executive functions. As cognition declines in neurodegenerative diseases, the interaction and competition for neuronal resources during motor‐cognitive dual‐tasking (e.g., walking while talking) might be a sensitive measure of subtle functional impairments in early Alzheimer's disease (AD). Here, we aim to identify gait deficits due to neuronal competition across the AD spectrum. Method: This investigation is part of the ongoing Remote Assessment of Disease and Relapse – Alzheimer's Disease (RADAR‐AD) study. We attached three inertial measurement units (accelerometer and gyroscope) to both feet and one hip to assess dual task effects (DTE) assessing gait performance with/without concurrent serial subtraction‐by‐1 task in four groups: 1) amyloid negative healthy controls (HC, N = 59); and 2) amyloid positive preclinical AD (PreAD, N = 30); 3) prodromal AD (ProAD, N = 51); and 4) mild‐to‐moderate AD dementia (MildAD, N = 44) (Table 1). We furthermore investigated associations of DTE with observer‐reported cognition. Result: Group comparisons showed that dual‐tasking induced lower cadence and increased stance, which were significantly different between HC and ProAD. Several DTE measures of variability differed significantly between PreAD and MildAD, with variability in the path length separating best between PreAD and ProAD (Table 2, Figure 1). DTE measures were associated with observer‐rated divided attention only in the MildAD group. Conclusion: Neuronal competition as assessed with motor‐cognitive dual‐tasking, specifically the DTE variability, might reflect functional deficits already in early AD, and could be a valuable additional measure to detect early impairments not captured by cognitive or motor tests alone. Future studies should implement an adaptive cognitive load to improve sensitivity/specificity in early AD stages and investigate the use of sensor technologies in predicting and monitoring changes in gait and fall prevention in later stages of the disease. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid (DHA) is an essential omega‐3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA‐containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α‐synuclein‐containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post‐mortem samples from the parietal cortex of 25 DLB patients and 17 age‐matched controls were processed for phospholipidomics analyses using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA‐phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA‐phospholipid species were subsequently validated with further LC–MS/MS measurements. Of the DHA‐containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta‐amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α‐synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets. [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]

Background: RADAR‐AD is a European project in the context of the Innovative Medicine Initiative (IMI) focusing on the earlier identification of patients at risk for developing Alzheimer's Disease (AD) via a panel of remote monitoring technologies (RMTs), including smartphone apps and wearable devices. Method: We examined the ability of 6 RMTs (Altoida, Axivity, Banking app, Fitbit, Physilog, and Mezurio) to distinguish between healthy controls (HC) and disease stages of preclinical (PreAD), prodromal (ProAD), and mild to moderate Alzheimer's disease (MildAD) based on 175 patients (interim analysis). We trained three machine learning classifiers (Logistic Regression, Random Forest, and XGBoost) in a pairwise setting (HC vs. PreAD, HC vs. ProAD, HC vs. MildAD, PreAD vs. ProAD, and ProAD vs. MildAD). Since the interim dataset is still limited, we performed repeated, stratified nested cross‐validation to get a robust performance estimate. Each classifier was trained with the features of the different devices and a set of baseline variables. The latter include a patient's gender, age, years of education, and body mass index (BMI) when physical conditions might play a role (Axivitiy, Fitbit, Physilog). In addition, we checked whether specific patterns of the study groups allowed discrimination of the different study groups based on the baseline variables alone. Therefore, we trained one Logistic Regression model with these variables and compared the performance of the other three models with this baseline. The models trained with the baseline and questionnaire‐based data served as the reference value in our benchmark that represents how well the discrimination of the different groups works with clinical tests. Result: Our preliminary data show that RMTs can identify patients already in a prodromal disease stage (AUC ∼69%, Figure 1). Furthermore, the pairwise combination of data from a banking app and an app monitoring functional cognitive abilities via an augmented reality game slightly increased our model's discriminative ability (Altoida ‐ Banking, Figure 2). The overall best performance was achieved when combining RMTs with the Amsterdam I‐ADL questionnaire. Conclusion: Our results demonstrate the potential of RMTs and the Amsterdam I‐ADL questionnaire for identifying patients in prodromal stage in primary care settings. [ABSTRACT FROM AUTHOR]

Background: Current evidence suggests an association between sarcopenia and multiple negative outcomes. Traditional methods to diagnose sarcopenia are based on dual‐energy X‐ray absorptiometry (DXA) and whole body magnetic resonance imaging. These tests are complicated, time‐consuming and expensive. We aim to bring a more accessible way to diagnose sarcopenia, making its detection easier in a neurological and dementia setting where brain MRI are regularly ordered. Therefore, we aim to compare the traditional methods of muscle mass and function vs. muscle quantification using the tongue and the masseter muscle in a standard brain MRI to diagnose sarcopenia in clinical settings. Method: The H70 study, is a longitudinal study of people born in the Gothenburg area of Sweden aged 70 at baseline. We included 791 participants with available clinical data and MRI. DXA and bioimpedance analyses were used as reference measures. Images were analyzed using 3Dslicer.(figure 1) Adjusted speermarRo coefficients were calculated to assess the correlation between the gold standard (DXA) and the muscle mass of the tongue and masseters. Result: There was a higher prevalence of women (55,7%). When comparing the different tests to assess muscle mass, we found significant and positive coefficient between both tongue and masseter. Total lean tissue mass (DXA) & Tongue volume (Cm3) Rho = 0,375, total lean tissue mass (DXA) & Total masseter volume (Cm3) Rho = 0,326. < 0.001. (table1,2 Figure 2.) Conclusion: There is a significant positive correlation between total lean tissue mass using DXA and muscle mass calculated with MRI measuring tongue and masseter. Clinical longitudinal Implications of these measurements will be tested in further steps of this research and exposed at the conference. [ABSTRACT FROM AUTHOR]

Background: A psychiatric‐onset prodrome is increasingly recognised in Dementia with Lewy Bodies (DLB) and while late‐onset psychosis is associated with increased risk of developing dementia, it is not clear what proportion of patients with psychotic disorders go onto develop DLB. Among patients with late onset psychosis, we aimed to identify the proportion who developed DLB and to characterise the clinical features and characteristics of those who convert to DLB. Method: Anonymised data collected between 2006‐2021 was retrieved from clinical records from a large London mental health service for patients who were ≥50 years when first diagnosed with a psychotic disorder. Patients with dementia diagnoses >3 months later were identified and a natural language processing (NLP) algorithm was used to identify patients with probable DLB, with two of the core features (visual hallucinations, parkinsonism, fluctuations or sleep disturbance) identified in the free text at the time of dementia diagnosis. Predictors of progression to DLB were investigated including demographic factors, Health of the National Outcome scale for older people (HoNOS65+) and key clinical features at the time of psychosis diagnosis identified with NLP. Result: In 3784 patients with late onset psychosis, 321 (8.5%) received a diagnosis of dementia from mental health services during the follow‐up period (mean time to dementia diagnosis 3.66±3.13 years). A high percentage (30.5%, n = 98) of those who developed dementia met criteria for probable DLB. Presence of hallucinations, falls, parkinsonism, fluctuations or drowsiness at the time of late onset psychosis diagnosis was associated with an increased relative risk of later developing probable DLB. Adjusted multivariate Cox proportional hazard models suggested that older age and higher scores on HoNOS cognitive and hallucinatory items at baseline were significant predictors of faster progression to DLB. Conclusion: DLB is overrepresented in patients with late‐onset psychosis who later develop dementia; a psychiatric prodrome in dementia should give a high index of suspicion for DLB. In patients with late‐onset psychosis, risk factors for future progression to DLB include cognitive impairment, older age, hallucinations, falls, fluctuations, parkinsonism and drowsiness. Where these hallmarks are present at the time of psychosis, close follow up could facilitate the earlier identification of DLB. [ABSTRACT FROM AUTHOR]

Background: Remote monitoring technologies (RMTs), such as smartphone apps and smartwatches, are changing the way functional and cognitive performance are measured in Alzheimer's disease (AD). Due to their sensitivity, objectivity, and the option of long‐term and continuous measurement, RMTs have the potential to detect a subtle decline in the earliest stages of AD. Here, we present the results of the European RADAR‐AD project (Remote Assessment of Disease and Relapse – Alzheimer's disease), which aims to test feasibility, acceptability and validity of RMT measures across all stages of AD, from cognitively normal to mild dementia. Method: Four study groups (amyloid negative healthy controls, and amyloid positive preclinical AD, prodromal AD, mild‐to‐moderate AD) were included in this cross‐sectional study (N = 175). During 8 weeks, participants wore two activity trackers (Fitbit and Axivity) measuring physical activity, heart rate and sleep continuously, and used two interactive smartphone apps (Mezurio and Altoida's research algorithm: DNS‐MCI) measuring cognition daily/weekly. At baseline, participants underwent extensive neuropsychological, physical examinations, and did two sensor‐based tests (banking app and walk test). Features were extracted for all RMTs (Figure 1) and compared across groups using ANCOVA, with adjustment for relevant confounders. This study is part of an ongoing investigation into high‐end multimodal analyses for real‐world functional performance of continuous RMT data streams. Result: Compliance was high, but decreased with cognitive impairment (feasibility). User experience did not differ between groups but was lower for smartwatches compared to interactive smartphone apps (Table 1) (acceptability). Various individual sensors discriminated symptomatic AD participants from asymptomatic participants (p<0.05), for example the two active apps, but did not discriminate preclinical AD from healthy controls (Table 1) (validity). Conclusion: The RADAR‐AD study provides unique insights in the feasibility, acceptability, and validity of remote monitoring of functional abilities in AD and their potential to differentiate between syndromic stages. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999) and their associated partners. www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Background: Remote monitoring technologies (RMTs), such as smartphone apps, smartwatches, and in‐home sensors, are rapidly changing the way functional and cognitive performance is measured in Alzheimer's disease (AD) patients. Here, we present results from the European RADAR‐AD study on the use of multimodal data streams for the identification of functional deficits across all syndromic stages of AD. Method: Four study groups (Healthy controls (HC), preclinical AD (pre. AD), prodromal AD (pro. AD), and mild AD) were included in this cross‐sectional study. The RMT features (gait measures from Timed up and Go (TUG), Dual Task Effect (DTE) using physilog, acoustic features from Speech task in Mezurio, neurocognitive function using Altoida, managing finances with Banking app) with in‐clinic neuropsychological (NP) tests, activities of daily living with Amsterdam IADL and demographics (age, gender, education years) were analyzed for different combinations of the multimodal digital biomarker of disease stage in AD across different pairwise comparisons. The analysis includes data from 175 participants (HC = 67, Pre.AD = 26, Pro.AD = 50, Mild AD = 32) collected for 8 weeks. An extreme gradient boosting (XGBoost) machine learning model was trained to obtain a multimodal biomarker of AD disease stage with repeated cross‐validation (5‐fold with 4 repeats) (Figure 1). This investigation is part of the ongoing RADAR‐AD study. Result: The multimodal combination of RMTs achieved a mean AUC of > 0.60 in all pairwise comparisons with a mean AUC > 0.65 for HC vs (Pre.AD, Pro.AD and Mild) (Figures 2 and 3). The addition of NP tests increases the performance considerably across all pairwise comparisons except HC vs Pre.AD. Conclusion: Our results highlight the advantage of combining RMTs to identify functional deficits in the early stage of AD. In particular, in prodromal and mild AD patients, a combined signal shows much more strength compared to individual tests. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Background: Brain small vessel disease (SVD) increases Alzheimer's disease (AD) risk. Impaired amyloid β (Aβ) clearance is linked to amyloid plaque formation and cerebral amyloid angiopathy (CAA). Aβ1‐40 is deposited in vessel walls, and Aβ with a C‐terminal 34' cut‐point is produced by perivascular cells. Evidence for SVD‐AD interactions in early AD is elusive, but incipient CAA putatively increases susceptibility for amyloid‐related imaging abnormalities (ARIA) in AD patients. Here we compare the SVD MRI marker "peak width of skeletonized mean diffusivity" (PSMD) to cerebrospinal fluid (CSF) Aβ species and the neurodegeneration marker Neurofilament light chain (Nfl), assessing links between SVD and AD pathologies and Aβ species as potential markers for incipient CAA. Method: Cross‐sectional data from the Dementia Disease Initiation (DDI) cohort were available, comprising (n = 112) cognitively normal (CN) and (n = 115) cases with mild cognitive impairment (MCI) (n = 227). CSF markers for AD A/T/N‐staging identified 134 cases with negative markers (A‐/T‐/N‐), 21 with amyloid positive markers (A+/T‐/N‐) and 72 with amyloid and tau‐positive markers (A+/T or N+) (see table 1 for sample descriptives). Multiple linear regression models were used with PSMD by lobe as the dependent variable, and NfL, Aβ1‐40 (MesoScale), Aβx‐34 (Bioventix, Pre Diagnostic) (separately) and interactions with A/T/N group as independent variables. Variables were log‐transformed and standardized. Result: Higher Nfl was related to higher PSMD independently of the Aβ species in all lobes. Although Nfl correlated with Aβ1‐40 (figure 1), no multicollinearity was observed in the model. In A+, lower Aβ markers were related to higher PSMD in all lobes, but particularly for the temporal lobe (figure 2). Aβx‐34 showed more robust relationships with PSMD in both A+ groups particularly in the temporal lobes (A+/T‐/N‐ b =.62, p = <.001, A+/T or N+ b =.52, p<.001) than Aβ1‐40. (A+/T‐/N‐ b =.66, p = <.01, A+/T or N+ b =.33, p<.001). Neither t‐ nor p‐tau measures were associated with PSMD (not shown). Conclusion: Nfl independently related to PSMD, possibly reflecting amyloid‐independent neurodegeneration. CSF Aβx‐34 was in particular tightly linked to increased temporal lobe PSMD even in A+/T‐/N‐, pointing to early AD‐related SVD. This supports further evaluation of Aβx‐34 as a marker for CAA and susceptibility marker for ARIA. [ABSTRACT FROM AUTHOR]

Introduction: Operationalized research criteria for mild cognitive impairment with Lewy bodies (MCI‐LB) were published in 2020. The aim of this systematic review and meta‐analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI‐LB set out in the criteria. Methods: MEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI‐LB. Results: Fifty‐seven articles were included. The meta‐analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta‐iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers. Discussion: The available evidence largely supports the current diagnostic criteria for MCI‐LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research. Highlights: A meta‐analysis of the diagnostic features of MCI‐LB was carried out.The four core clinical features were more common in MCI‐LB than MCI‐AD/stable MCI.Neuropsychiatric and autonomic features were also more common in MCI‐LB.More evidence is needed for the proposed biomarkers.FDG‐PET and quantitative EEG show promise as diagnostic biomarkers in MCI‐LB. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are very common in Lewy body dementias (LBD), but their aetiology is poorly understood. In a post‐mortem study we aimed to characterise the contribution of neuropathological substrates to some of the most common NPS in dementia. Method: Participants who passed away between 2004 and 2021 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies. Neuropathological data was collected for Lewy body neuropathology (LBD Braak score), neurofibrillary tangles (NFT Braak score), amyloid‐β burden (CERAD‐NP), TDP‐43, lacunar infarcts, cerebral amyloid angiopathy and hyaline atherosclerosis. Post‐mortem interviews were used to collect information regarding neuropsychiatric and cognitive status using the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). A total of 948 cases were classified according to neuropathological assessment: (1) No pathology (NP) (n = 678); (2) Alzheimer's Disease (AD) (n = 183); (3) LBD (n = 57); (4) AD+LBD (n = 30). Result: Multinomial logistic regression models comparing LBD, AD and AD+LBD to NP, adjusted for age, ethnicity, sex, and education level, showed significantly higher odds of hallucination and delusions across all groups compared to NP with the relative risk of hallucinations most elevated in AD+LBD cases (RRR = 19.3,[95%CI = 8.00‐46.3], p<0.001). All groups had increased risk of higher NPI scores relative to NP, but the greatest increase was for AD+LBD (RRR = 1.04, [95%CI = 1.02‐1.06], p<0.001). There were significantly greater risk of agitation and apathy in AD and AD+LBD groups relative to NP. (Table 1) Additionally, hallucinations were associated with higher Lewy body Braak scores (OR = 1.30, 95%CI = 1.13‐1.49, p<0.001). Higher NFT Braak scores were associated with depression (OR = 1.28, 95%CI = 1.09‐1.50, p<0.001), agitation (OR = 1.30, 95% CI = 1.07‐1.57, p = 0.009) and overall NPI score (IRR = 1.15, 95%CI = 1.05‐1.27, p = 0.004). Lacunar infarcts were associated with delusions (OR = 4.68, 95%CI = 1.12‐19.5, p = 0.03). More frequent neuritic plaques was inversely associated with apathy (OR = 0.70, 95%CI = 0.52‐0.93, p = 0.01). Cerebral amyloid angiopathy, hyaline atherosclerosis, and TDP‐43 did not associate with any of the neuropsychiatric symptoms in the multivariable logistic models. (Table 2) Conclusion: Lewy body pathology was the most significant contributor to the aetiology of hallucinations, while NFT were important contributors to depression and agitation in dementia. Supporting the dual importance of these pathologies, subjects with AD and LBD co‐pathology showed the greatest burden of NPS. [ABSTRACT FROM AUTHOR]

Introduction: Etiological diagnosis of neurocognitive disorders of middle‐old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results. Methods: Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions. Results: We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI‐mild dementia), and detailed pre‐assessment screening (clinical‐neuropsychological evaluations, brain imaging, and blood tests). Discussion: The Delphi consensus on these assumptions set the stage for the development of the first pan‐European workflow for biomarkers' use in the etiological diagnosis of middle‐old age neurocognitive disorders at MCI‐mild dementia stages. Highlights: Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe.A consensus of experts will define a workflow for the rational use of biomarkers.The diagnostic workflow will be patient‐centered and based on clinical presentation.The workflow will be updated as new evidence accrues. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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 FROM AUTHOR]

Cognitive differences in memory, information processing speed (IPS), and executive functions (EF), are common in autistic and high autistic trait populations. Despite memory, IPS and EF being sensitive to age‐related change, little is known about the cognitive profile of older adults with high autistic traits. This study explores cross‐sectional memory, IPS and EF task performance in a large sample of older adults in the online PROTECT cohort (n = 22,285, aged 50–80 years), grouped by high vs. low autistic traits. Approximately 1% of PROTECT participants (n = 325) endorsed high autistic traits [henceforth Autism Spectrum Trait (AST) group]. Differences between AST and age‐, gender‐, and education‐matched comparison older adults (COA; n = 11,744) were explored on memory, IPS and EF tasks and questionnaires administered online. AST had lower performance than COA on tasks measuring memory, working memory, sustained attention, and information processing. No group differences were observed in simple attention or verbal reasoning. A similar pattern of results was observed when controlling for age, and current depression and anxiety symptoms. In addition, AST self‐reported more cognitive decline than COA, but this difference was not significant when controlling for current depression symptoms, or when using informant‐report. These findings suggest that autistic traits are associated with cognitive function in middle‐aged and later life. Older adults with high autistic traits experienced more performance difficulties in a range of memory, IPS and EF tasks compared with the low autistic traits comparison group. Further longitudinal work is needed to examine age‐related change in both older autistic and autistic trait populations. Lay Summary: Little is known about the cognitive profile of middle‐aged and older autistic or high autistic trait adults. Using data from the PROTECT cohort and a well‐validated online cognitive assessment platform, the findings from the current study suggest that higher autistic traits are associated with worse cognitive functioning throughout later adulthood. This suggests that older adults with high autistic traits may require additional support as they age. [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies (DLB) is clinically defined by the presence of visual hallucinations, fluctuations, rapid eye movement (REM) sleep behavioral disorder, and parkinsonism. Neuropathologically, it is characterized by the presence of Lewy pathology. However, neuropathological studies have demonstrated the high prevalence of coexistent Alzheimer's disease, TAR DNA‐binding protein 43 (TDP‐43), and cerebrovascular pathologic cases. Due to their high prevalence and clinical impact on DLB individuals, clinical trials should account for these co‐pathologies in their design and selection and the interpretation of biomarkers values and outcomes. Here we discuss the frequency of the different co‐pathologies in DLB and their cross‐sectional and longitudinal clinical impact. We then evaluate the utility and possible applications of disease‐specific and disease‐nonspecific biomarkers and how co‐pathologies can impact these biomarkers. We propose a framework for integrating multi‐modal biomarker fingerprints and step‐wise selection and assessment of DLB individuals for clinical trials, monitoring target engagement, and interpreting outcomes in the setting of co‐pathologies. [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic disorders (CMD) and Mild Cognitive Impairment (MCI) have been associated with an increased risk of developing dementia. However, brain glucose metabolism has not been compared between patients with CMD and MCI, and little is known about its associations with global cognitive performance. Here we examined regional brain 18F – FDG uptake in patients with CMD and MCI, and analyzed its potential associations with global cognitive performance. Methods: 55 patients with increased risk for developing dementia were recruited (MCI = 22; CMD = 33) in this cross‐sectional study. As a measure of brain glucose metabolism, PET/CT was performed and the mean uptake value in brain regions of interest (ROI) was obtained and standardized by whole brain uptake. Global cognitive performance was examined using the Mini‐Mental State Examination (MMSE). Group differences in brain metabolism and cognitive performance were examined. We conducted separate linear regression models considering standardized MMSE as the dependent variable, and mean 18F – FDG uptake in each of the ROI (and its CMD/MCI group‐interactions) as independent variables. Our models were adjusted by age, gender, years of education, and presence of at least one APOE e4 allele, and corrected for multiple testing with the False Discovery Ratio (FDR < 0.01). Results: The CMD and MCI groups were comparable in age, gender, education, and mean 18F‐FDG uptake across all the ROIs, but significantly different in MMSE (Table 1). Adjusted models for global cognitive performance showed significant group interactions with the mean 18F – FDG uptake in bilateral caudate and hippocampus, as well as in left‐hemisphere amygdala, cuneus, fusiform gyrus, and opercular part of the inferior frontal gyrus. Thus, significant negative associations of 18F – FDG uptake in the above ROIs and cognitive performance was observed in the MCI group (Figure 1 & Table 2). Conclusions: In MCI patients, reduced global cognitive performance was significantly associated with high brain glucose metabolism in bilateral caudate and hippocampus, and with the left fusiform gyrus, cuneus, and inferior frontal gyrus (opercular part). These asymmetric associations between high metabolism and low cognitive performance could suggest compensatory effects in MCI patients but further research is needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Background: CSF and imaging biomarkers are needed for the etiological diagnosis of neurocognitive disorders, but evidence is incomplete on their rational use in the clinic. Since October 2020, a European task force has been defining an evidence‐based diagnostic workflow, where incomplete evidence is filled by the opinion of experts. Herein, we report the preliminary results through January 2022. Method: A Delphi method was used to reach consensus. Eleven pertinent European scientific societies delegated two panelists each to join Delphi rounds and voting. Consensus was set at 70% of consistent responses. Result: In the 5 voting rounds completed so far, panelists defined clinical setting (specialist outpatient service) and stage of application (prodromal and mild dementia) of the workflow, patients' age window of biomarkers use (strongly encouraged below 70 years and of limited usefulness over 85). Workflow is configurated to be patient‐centered and structured on three levels of assessment (W): W1, definition of clinical profiles based on the combined results of MRI, neuropsychology, blood tests; W2, choice of first‐line biomarkers according to the main clinical suspicion (i.e., FDG‐PET for frontotemporal lobar degeneration and motor tauopathies, dopamine SPECT/PET for Lewy body spectrum disorders, and CSF biomarkers either for Alzheimer's disease or in cases with inconclusive neuropsychological and/or MRI findings, whereas no biomarker was indicated in suspected vascular cognitive impairment); W3, selection of a second‐line biomarker when results of first‐line biomarkers are inconsistent with diagnostic hypothesis (i.e., not typical FDG‐PET pattern) or uninformative (i.e., borderline CSF amyloid results) or not sufficient to rule out other etiologies (i.e., amyloid‐positive and tau‐negative CSF results) or when a diagnosis remains possible despite a negative first‐line biomarker (e.g., normal dopamine SPECT/PET in suspected prodromal dementia with Lewy bodies). Conclusion: The task force is currently defining the second‐line biomarkers of W3 and the project it set to deliver the final algorithm by June 2022. The workflow will promote consistency in diagnosing neurocognitive disorders across countries, and rational use of resources. The initiative has an impact in preparing clinicians to work in the upcoming clinical space where etiological disease‐modifying drugs are expected to be available. [ABSTRACT FROM AUTHOR]

Objectives: It is believed that inadequate environmental light, especially in facilities such as care homes, contribute to the diurnal changes of behavioural and psychological symptoms of dementia (BPSD) historically referred to as "sundowning syndrome". Conceptual models of sundowning phenomena have shifted emphasis from the role of light in vision (image forming) to its role in circadian rhythm modulation. However, the grounds for this change are unclear and the evidence on which it is based has not been examined comprehensively.Methods: We have searched literature on sundowning syndrome and its association with light and studies evaluating BPSD, behavioural rhythm and environmental light in care homes in four databases (PubMed, Web of Science, Embase and Cochrane Library) from inception to 31 January 2021.Results: Of the nine studies investigating light, behavioural rhythm and BPSD in care homes identified, we found evidence that insufficient natural light exposure was associated with worsening of BPSD and disrupted activity rhythm but it was not clear whether this related to image forming or disrupted circadian rhythm. There was a paucity of evidence in relation to the role of low levels of light for image forming in the context of a specific BPSD symptom: visual hallucinations. We also found literature on the possible role of light outside the visible spectrum influencing cognition. Based on the evidence, we proposed a new model integrating different components of light in BPSD and sundowning syndrome that combines its image forming and circadian roles.Conclusions: Inadequate light may be a risk factor for BPSD and sundowning syndrome for dementia patients through a range of different mechanisms. It is recommended that multiple neuro-endocrinological and socio-environmental factors relevant to light such as adjusting the environmental setting, increasing light exposure, and scheduling activities should be considered when treating dementia patients with BPSD. [ABSTRACT FROM AUTHOR]

Background and Aims: In older adults with dementia, low body mass index (BMI) is associated with higher mortality and other adverse health outcomes. BMI or nutritional status trajectories from diagnosis have not yet been well described in dementia, especially in people with Lewy body dementia (LBD); a group that has a poorer prognosis. With this study, we aimed to evaluate the BMI trajectory in people diagnosed with mild LBD and Alzheimer's disease (AD). Methods: The Dementia Study of Western Norway is a cohort study with annual assessments. Five‐year measurements of BMI from 196 patients (LBD = 85 and AD = 111) diagnosed with mild dementia were analyzed using adjusted linear mixed‐effects models. Results: There were no differences between LBD and AD in baseline BMI, age, or mini‐mental status examination (MMSE). During the follow‐up, we observed a significant decrease in BMI in the LBD group across the study period (estimation [Est.]: −0.63, SE: 0.14; p < 0.001). By contrast, there was no significant change in BMI trajectory associated with AD diagnosis (Est.: 0.05, SE: 0.15; p = 0.730). Further, the introduction of an interaction term between diagnosis and time in the study showed that this difference (BMI trajectories) was significant (Est.: −0.63, SE: 0.14; p < 0.001). In addition, there was a significant interaction between MMSE total score and the follow‐up time; the lower the MMSE, the lower the BMI (Est.: 0.01, SE: 0.01; p = 0.044). Conclusion: In LBD, BMI significantly decreased with disease progression. In addition, low cognitive performance was associated with a reduction in BMI. These results highlight the importance of BMI evaluation in people with dementia, particularly patients diagnosed with LBD, and suggest that patients with LBD could be targeted for dietary intervention to maintain body weight. [ABSTRACT FROM AUTHOR]

Background: Higher physical activity is associated with better global cognition and a lower risk of dementia (Rojer et al., 2021). Using questionnaires to assess physical activity is difficult in an Alzheimer's disease (AD) population, since questionnaires rely on retrospective subjective recall. Wearables measure physical activity objectively and continuously. A variety exists, with some delivering raw high‐frequency research‐grade movement data, others providing summary variables only. The aim of this study is to compare simple activity metrics from two activity trackers monitoring physical activity in AD, and relate these to standard questionnaires. Method: Participants in the RADAR‐AD study (Remote Assessment of Disease and Relapse – Alzheimer's Disease) were asked to wear two activity trackers (dominant hand: Axivity AX3, non‐dominant hand: Fitbit Charge 3) for 8 weeks. Features calculated from the Axivity's raw accelerometer data were: acceleration magnitude, time spent in sedentary, light, moderate‐to‐vigorous activity, and sleeping. Fitbit features included: step count and heart rate. Self‐reported activity levels (Godin Leisure Time Questionnaire), depression (Geriatric Depression Scale), social functioning (Social Functioning Scale), global cognition (Mini‐Mental State Examination), partner‐reported function (ADCS‐ADL) and neuropsychiatric symptoms (Neuropsychiatric Inventory) were assessed and related to activity levels using regression models. Result: We included amyloid negative controls (n = 36) and amyloid positive preclinical (n = 13), prodromal (n = 15) and mild‐to‐moderate (n = 10) AD participants (Table 1). Expected associations were found between sedentary activity time and age, and between self‐reported activity and both moderate‐to‐vigorous activity time and step count (Table 2, Figure 1). Small group sizes currently make further comparisons of exploratory value only. Conclusion: Wearable devices have the potential to accurately capture clinically relevant aspects of daily activity and function of interest in AD population. On‐going research in the RADAR‐AD study will focus on developing disease‐specific methods of feature extraction based on raw movement data, and combining features from multiple devices, to explore this further. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999).www.imi.europa.eu. This communication reflects the views of the RADAR-AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [ABSTRACT FROM AUTHOR]

Background: Unlike traditional pen‐and‐paper clinical assessments, remote monitoring technologies (RMTs) can assess participants' function continuously and objectively during activities of daily living. Despite the potential of RMTs to assess function or assist early disease detection, there is skepticism that age or impairment may render participants unable or unwilling to comply with complex RMT protocols. The 8‐week RADAR‐AD study protocol asks Alzheimer's disease (AD) patients in all disease stages to wear, amongst others, two activity trackers (Axivity, Fitbit), a wearable camera (Autographer), and use an active smartphone app (Mezurio), with a daily schedule totaling over 400 separate tasks and a parallel schedule for caregivers. This abstract presents preliminary compliance data and participant feedback. Method: We included amyloid negative control participants (n=47) and amyloid positive preclinical (n=16), prodromal (n=19) and mild‐to‐moderate (n=16) AD participants (Table 1), based on MMSE and CDR scores, in 8 European countries. Metrics based on device data were calculated for participant commitment (study duration completion percentage or wear time) and compliance (task completion percentage). Patient experiences were monitored using bi‐weekly semi‐structured phone interviews. Result: Mezurio average commitment and compliance were 90% and 85% respectively (Table 2) and were comparable across diagnostic groups. Wear time of Axivity, Fitbit and wearable camera was high (>86%), with 48% of those offered adopting the optional wearable camera (Table 2). Participant feedback was positive, with relatively few problems reported (Figure 1). Conclusion: RADAR‐AD shows that age and impairment are not necessarily barriers to successful deployment of complex RMT study protocols. We acknowledge that our high commitment and compliance rates benefitted from an active rapport between researchers, participants and care givers, which may not be reproducible in every scenario. Nevertheless, this study shows that AD patients are able and willing to comply and engage with technology. This work has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (grant No 806999). www.imi.europa.eu. This communication reflects the views of the RADAR‐AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. [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]

Introduction: Artificial intelligence (AI) systems leveraging speech and language changes could support timely detection of Alzheimer's disease (AD). Methods: The AMYPRED study (NCT04828122) recruited 133 subjects with an established amyloid beta (Aβ) biomarker (66 Aβ+, 67 Aβ–) and clinical status (71 cognitively unimpaired [CU], 62 mild cognitive impairment [MCI] or mild AD). Daily story recall tasks were administered via smartphones and analyzed with an AI system to predict MCI/mild AD and Aβ positivity. Results: Eighty‐six percent of participants (115/133) completed remote assessments. The AI system predicted MCI/mild AD (area under the curve [AUC] = 0.85, ±0.07) but not Aβ (AUC = 0.62 ±0.11) in the full sample, and predicted Aβ in clinical subsamples (MCI/mild AD: AUC = 0.78 ±0.14; CU: AUC = 0.74 ±0.13) on short story variants (immediate recall). Long stories and delayed retellings delivered broadly similar results. Discussion: Speech‐based testing offers simple and accessible screening for early‐stage AD. [ABSTRACT FROM AUTHOR]

Background: Sporadic Alzheimer's disease (AD) and Down syndrome related AD (DSAD) share a common neuropathologic picture, with hallmark amyloid plaques and neurofibrillary tangles. The key constituents, amyloid beta (Abeta) and tau, respectively, define the biomarker picture shared between sporadic AD, DSAD and autosomal dominant AD. Small Abeta oligomers and fragments such as Abeta 1‐42 and pyroglutamate Abeta3‐42 (pGlu‐Abeta3‐42) are key for disease initiation and neurotoxicity. ACI‐24 is a liposomal vaccine targeting Abeta. Initial clinical data demonstrated safety and pharmacodynamic response, both in sporadic AD and people with DS. Preclinical data recently demonstrated that a new, optimized formulation of ACI‐24 (ACI‐24.060) has significantly improved immunogenicity against key toxic species, i.e., Abeta oligomers, Abeta 1‐42 and pGlu‐Abeta3‐42. Method: Recent clinical trials evaluating monoclonal antibodies targeting Abeta in AD have successfully employed translational biomarkers, including amyloid PET, as surrogate markers to predict clinical benefit. These biomarkers can now be more effectively used in clinical trials for both patient selection and demonstrating treatment efficacy. Result: The ABATE study's (NCT05462106) innovative translational clinical trial design evaluates the effects of ACI‐24.060 in sporadic AD (Part 1) and in people with DS (Part2). The biomarker‐based design with multiple interim analyses, enables (I) early assessment of safety and immunogenicity, (II) appropriate dose selection using readouts on translational biomarkers including amyloid PET, (III) the safe transition into the DS population and (IV) informed transition into pivotal studies. The use of these shared biomarkers in predictable and pre‐specified trajectories allows effective cross‐learnings between sporadic AD and DSAD and has been enabled by the recent results with anti‐Abeta monoclonal antibodies, strongly enabling this translational approach for an amyloid immunotherapy. Initial safety and immunogenicity data will be presented. Conclusion: The field of biomarker‐based translational medicine has been mobilized by the clinical evaluation of targeting of toxic abeta fragments and aggregates in monoclonal antibody trials. As shown we are utilizing these advances in an innovative clinical trial design for an efficient, evidence‐based translational medicine approach to test ACI‐24.060 as a novel Abeta vaccine candidate. This approach allows the parallel investigation of ACI‐24.060 for the treatment and prevention of both sporadic AD and DSAD. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic led to serious health implications for older adults who may have already significant comorbidities. In addition to the risk related to COVID‐19, self‐isolation and limited social contact may have led to psychosocial impacts, such as increased boredom, frustration, depression and anxiety. These stressors may have had increased effects on other key health outcomes, including worse general well‐being, and diminished quality of life. Therefore, finding techniques to boost older adults' ability to manage these stressors is vital for better planning of unsettled events of similar nature. Method: A feasibility study assessing a 6‐week online technology assisted compassion training (T‐ACTS) for older adults (Age 60+ without a diagnosis of dementia, access to internet) living in the UK during the COVID‐19 pandemic. T‐ACTS builds on the Raise Your Resilience intervention by Treichler et al., (2020) [1] with weekly one‐to‐one online sessions by research therapists on empathy, self‐compassion, social connections, acts of kindness, gratitude, self‐efficacy, and positive ageing. Key activities included relaxation, gratitude journaling, and positive social engagement. The data reported on feasibility, demographics and mental health using the Patient Health Questionnaire at pre‐ and post‐intervention. McNemar test reported the difference in depression pre‐and post‐intervention. Result: Forty‐seven participants gave consent, 35 participants entered the intervention, 25 participants (100% Caucasians, 64% females with age 76/5.74 mean/SD) completed the 6 week intervention; and 10 participants withdrew at different timepoints. Reasons for withdrawals included eligibility (1), IT difficulties (1), intervention content (1), engagement (5) and availability (2). There was a significant difference in levels of depression; pre and post intervention (p = 0.014). Around 70% of the participants found the programme enjoyful very‐much so; 30% some‐what enjoyful. Forty‐three percent found the intervention very‐much useful for setting personal goals, with 57% some‐what useful. Activities that were useful included relaxation exercises, gratitude journaling and acts of kindness. Conclusion: The T‐ACTS intervention demonstrates feasibility of pragmatic online interventions to improve mental health in older adults, suggesting high potential for further evaluation in a larger sample and implementation for older adults. Future studies are warranted for assessing benefits to other key health outcomes such anxiety and general wellbeing. [ABSTRACT FROM AUTHOR]

Background: Measuring and monitoring behaviour is difficult in people living with later stage Alzheimer's disease and specific behavioural symptoms such as agitation and aggression (AA). Currently, subjective information given by these patients is highly susceptible to inaccurate recall, clinicians rely on answers provided by care givers, which can be biased and lack fine‐grain temporal detail. Although actigraphy watches have been useful tools for research, little is known about the feasibility of their use in agitated dementia participants and on the factors influencing watch compliance. Method: People diagnosed with Alzheimer's disease and significant AA symptoms living in care homes were asked to wear an actigraphy watch (GENEactiv Original) for 4 consecutive weeks. Demographic data, Functional Assessment Staging Tool (FAST) score, behavioural symptom pattern and severity were recorded using the Neuropsychiatric Inventory Nursing Home Version (NPI‐NH). Watch‐recorded wearing time and activity data were used to evaluate adherence. Care home staff were interviewed to explore factors influencing watch wearing by participants and to develop solutions to improve compliance. Result: We recruited 28 participants (14 female) and found wearing the watch feasible overall. No statistical compliance difference was found between different groups based on age, FAST score, agitation pattern or severity; however, a significant gender difference was found with male participants being more adherent (Table). Participants were more compliant in weeks 3‐4, and first week adherence predicted overall adherence (Figure). Factors influencing compliance include the design and appearance of the watch, previous watch wearing habit, and the perceived purpose of the study. Using documents easily readable to participants and care givers to facilitate understanding of the study and to communicate challenging clinical scenarios appeared to enhance adherence. Conclusion: Wearing an actigraphy watch for behavioural monitoring was feasible for moderate to severe Alzheimer's disease patients with AA symptoms in care home settings. Gender‐specific design and appearance should be considered when selecting the actigraphy watch. For dementia studies planning to use an actigraphy watch, compliance can be improved by incorporating a short lead‐in phase to establish a watch wearing routine and by providing reader‐friendly documents about the watch purpose to communicate with participants and care givers. [ABSTRACT FROM AUTHOR]

Background: Visual hallucinations (VH) phenomenology in Lewy Body Disease (LBD) is heterogenous, including minor phenomena (passage, presence, illusions) and complex hallucinations. Neural substrates and mechanisms involved are still unclear. Here we investigated grey matter (GM) alterations associated with minor (MVH) and complex VH (CVH). Method: LBD patients (n = 28) with VH and Healthy controls (HC‐n = 20) underwent MRI. We administered the North East Visual Hallucinations Interview (NEVHI), a semi‐structured interview assessing the phenomenology of VH, their duration and frequency. VH were clustered in MVH and CVH and treated as a patient's trait. First we compared GM volume of LBD and HC. Then, multiple regressions were performed to disclose alterations associated with the duration, frequency and severity of MVH and CVH, including the opposite VH domain, total intracranial volume (TIV) and MMSE as nuisance regressors. Result: We found a decreased GM volume in the bilateral fusiform gyrus (FG), in the left posterior cingulate and in the right inferior frontal gyrus in LBD compared to HC. We also found that CVH duration was negatively associated with GM volume in the left FG. We did not find any association with MVH phenomenology. Conclusion: LBD patients showed GM alterations in ventral‐visual‐stream, default‐mode‐network and inhibitory regions compared to HC. Although the LBD versus HC comparison is not specific to VH, the regions identified have been implicated in VH in previous studies suggesting they may represent structural hallmarks of functional alterations in networks contributing to VH. When the association with VH phenomenology was tested, we did not find GM alterations associated with MVH. It is likely that these phenomena might be not associated with structural alterations but with functional alterations within visual networks. CVH were instead associated with decreased GM in FG. The atrophy in the FG may lead to a spontaneous activation of this region that sustain CVH duration, accounting for VH content (D'Antonio et al., 2022). These alterations may represent the predisposing condition to VH in LBD. According to the hodotopic model, VH phenomenology may help identify brain regions implicated and might reveal the substrates for cortical region/network dysfunctions occurring during VH state (ffytche et al., 2008). [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) co‐pathology is a common feature in dementia with Lewy bodies (DLB) and associated with a more rapid decline. Here, we aimed to evaluate plasma biomarkers as alternatives for CSF biomarkers for the detection of amyloid pathology, and for their diagnostic and prognostic value in DLB. Method: Plasma Aβ42/40, GFAP, NfL, pTau181 and pTau231, were measured by SIMOA in patients with DLB (n = 342), AD (n = 131), and healthy controls (n = 89) from the E‐DLB consortium cohort. Associations of biomarkers with CSF Aβ42 status were assessed with ANCOVA corrected for age and sex. ROC analyses were performed to assess biomarker's performance for amyloid detection and differential diagnosis. Associations of biomarkers with cognitive impairment and decline were determined by linear regression and mixed effects models. Result: Altered Aβ42/40 (β = ‐0.0076, 95%CI:‐0.0137 to ‐0.0016, p<.05), pTau181 (β = 0.2503, 95%CI: 0.0555 to 0.4451, p<.05) and pTau231 levels (β = 0.2269, 95%CI:0.0347 to 0.4191, p<.05) were associated with amyloid pathology in DLB, as assessed by CSF Aβ42. The combination of these biomarkers differentiated amyloid normal from abnormal DLB patients with an AUC of 0.728 (sensitivity = 64.6%, specificity = 75.0%). pTau181 best differentiated these groups as a single marker (AUC = 0.700, sensitivity = 62.5%, specificity = 73.1%). The combination of Aβ42/40, NfL and pTau231 differentiated DLB from AD with an AUC of 0.726 (sensitivity = 73.3%, specificity = 68.8%). In DLB, increased GFAP (β = ‐8.9, 95%CI:‐11.7 to ‐6.1, p<.001), NfL (β = ‐7.2, 95%CI:‐10.0 to ‐4.4, p<.001), pTau181 (β = ‐2.6, 95%CI:‐4.0 to ‐1.2, p<.001) and pTau231 (β = ‐2.4, 95%CI:‐3.7 to ‐1.2, p<.001) were associated with lower baseline MMSE scores and increased GFAP (annual change of ‐2.1 MMSE points (95%CI:‐2.9 to ‐1.3, p<.001) and NfL (annual change of ‐2.1 MMSE points (95%CI:‐3.0 to ‐1.3, p<.001) predicted faster cognitive decline. Conclusion: Plasma Aβ42/40, pTau181 and pTau231 were associated with amyloid abnormality in DLB. Their utility for differential diagnosis and identifying amyloid pathology in DLB was modest. Our findings suggest a prognostic value of GFAP and NfL for cognitive decline in DLB. [ABSTRACT FROM AUTHOR]

Objectives: Physical exercise may benefit people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, randomised controlled trials (RCTs) of exercise have shown conflicting findings and it is unclear if positive outcomes are comparable to a commonly used cholinesterase inhibitor, donepezil. Methods: Embase, Medline, PsycINFO, PsycARTICLES, SCOPUS were searched for RCTs of physical activity compared to a control condition, and donepezil compared to placebo in people with AD and MCI. Effect sizes were calculated from pre‐ and post‐MMSE and ADAS‐Cog scores and pooled using a random effects meta‐analysis. Results: Ninteen RCTs were included in the exercise meta‐analysis (AD, N = 524; MCI, N = 1269). Physical exercise improved MMSE scores in AD (Hedges' g = 0.46) and MCI groups (g = 0.63). For the MCI group, exercise appeared to have a stronger effect for those with lower MMSE scores at baseline (p = 0.022). 18 RCTs were included in the donepezil meta‐analysis (AD, N = 2984, MCI, N = 1559). In people with AD, donepezil improved cognition (MMSE g = 0.23; ADAS‐Cog, g = −0.17) but there was no evidence of improved cognition in MCI. Conclusions: Physical exercise improved cognition in both AD and MCI groups. Where comparisons were possible, the effect size for physical exercise was generally comparable to donepezil. These results strengthen the evidence base for exercise as an effective intervention in AD and MCI, and future clinical trials should examine exercise type, intensity and frequency, in addition to cholinesterase inhibitors to determine the most effective interventions for AD and MCI. Key points: Randomised controlled trials have suggested that physical activity has beneficial effects in Alzheimer's disease (AD) and Mild cognitive impairment, however it is not known how efficacious this intervention is compared to medicationTo our knowledge this is the first meta‐analysis to compare the effects of physical activity to donepezil (a commonly used medication in AD) in these two clinical populationsWhere direct comparisons were possible, the effects of physical activity were comparable to those exerted by donepezil [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion: P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD. [ABSTRACT FROM AUTHOR]

Objectives: We aim to study the effects of the prescription of benzodiazepines and antidepressants on cognitive and functional decline in older adults living with Alzheimer's disease (AD) and Lewy body dementia (LBD) over a 5‐year follow‐up. Methods: This is a longitudinal analysis of a Norwegian cohort study entitled "The Dementia Study of Western Norway" (DemVest). We included 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed annually for 5 years. Three prescription groups were defined: only benzodiazepines (BZD), only antidepressants (ADep), and the combination of benzodiazepines and antidepressants (BZD‐ADep). Linear mixed‐effects models were conducted to analyze the effect of the defined groups on the outcomes. The outcomes were functional decline, measured by the Rapid Disability Rating Scale—2, and cognition measured with the Mini‐Mental State Examination. Results: Prescription of the combination of benzodiazepines and antidepressants in LBD was associated with faster functional decline. In AD, the prescription of BZD and BZD‐ADep was associated with greater functional deterioration. ADep alone did not show positive or negative significant associations with the studied outcomes. Conclusions: BZD and especially the combination of BZD and ADep are associated with functional decline in AD and LBD and should be used cautiously. Key Points: Combination of benzodiazepines and antidepressants in Lewy body dementia was associated with faster functional declineBenzodiazepines and the combination of benzodiazepines and antidepressants in Alzheimer's disease were associated with greater functional deteriorationThe consumption of antidepressants alone did not show positive or negative significant associations with cognitive or functional decline [ABSTRACT FROM AUTHOR]

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, placebocontrolled 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 FROM AUTHOR]

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 FROM AUTHOR]

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 FROM AUTHOR]

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 onMBI 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 FROM AUTHOR]

Background: The phenomenology of visual hallucinations (VH) in Lewy Body Disease (LBD) is heterogenous including minor phenomena (passage, presence, illusions) and complex hallucinations. Underlying mechanisms are largely unknown and here we investigated whether distinct neural networks underpin minor (MVH) and complex VH (CVH). Method: LBD patients (n=17 DLB, n=10 PDD; mean age=76.5±6.5; mean MMSE=20.2±5.7, male=16; 59.2%) with VH underwent resting state fMRI and the North East Visual Hallucinations Interview (NEVHI) to assess the phenomenology, duration and frequency of VH. Using multiple regression models, we performed a seed‐to‐seed functional connectivity (FC) analysis to identify specific nodes associated with i) duration, ii) frequency and iii) severity of MVH (controlling for CVH and MMSE) or CVH (controlling for MVH and MMSE). Result: The severity, frequency and duration of MVH was negatively associated with FC between early visual areas (EVA) and regions of the ventral visual stream, and positively associated with FC between EVA and regions of the dorsal visual stream that may reflect the phenomenology of passage and presence. Furthermore, the duration of MVH was negatively associated with FC between the brainstem and EVA that may be linked to LBD brainstem neuropathology and positively associated with FC between areas of the dorsal visual stream (Table 1). The severity and duration of CVH was negatively associated with FC between areas of the ventral visual stream and positively associated with FC between lingual gyrus and supramarginal gyrus, within the salience network, that may relate to the complexity of the hallucination content. The frequency of CVH was negatively associated with FC between areas of the default mode network and the salience network (i.e. supramarginal gyrus) that may reflect attentional dysregulation (Table 2). Conclusion: Functional alterations in distinct visual and attentional networks underpin VH in LBD according to their phenomenology, showing a greater involvement of the brainstem and dorsal visual stream for MVH, and of the ventral visual stream and attentional networks for CVH. These findings can be interpreted according to the hodotopic hypothesis of VH (ffytche et al. 2008) and may reflect a link between VH phenomenology and the neuropathological progression of Braak stage (ffytche et al. 2017). [ABSTRACT FROM AUTHOR]

Background: This study aims to compare the progression of motor and cognitive decline in dementia with Lewy bodies (DLB) compared with Parkinson's disease (PD) using a large multicentre international consortium with up to 15 years of follow‐up. Method: Longitudinal data from 12 cohorts of patients with PD and DLB were included. The PD cohort (n=1108) included newly diagnosed patients from large, on‐going studies. The DLB cohort (n=290) included patients with probable DLB from the European DLB consortium (Table 1). The Mini Mental State Examination (MMSE) was used to explore cognitive functioning and UPDRS‐III for motor impairment. The differences in the rate of progression of MMSE and UPDRS‐III were analyzed with Linear Mixed Effects Model (LMEM) adjusted for baseline variables, with interactions for time. We used square root transformation of the number of errors to obtain an MMSE variable with normal distribution. Result: Both DLB and PD groups presented motor and cognitive decline. The MMSE (figure 1A) showed a mean annual worsening of 2.35 points (95% CI 1.67‐3.03) for DLB patients and 1.05 points (95% CI 0.62‐1.47) for PD patients (P <0.001). In PD the rate of decline increased with time and from the tenth year, the annual rate of decline of the transformed MMSE scores matched the rate in the DLB group. While DLB patients had lower UPDRS‐III scores at baseline, the rate of decline in UPDRS‐III (figure 1B) scores was faster in DLB compared to PD (P <0.001). The annual increase in UPDRS III in DLB was 5.8 points (95% CI 5.71‐5.90), while in PD it was 1.9 points (95% CI 1.76‐1.97). Conclusion: Our findings suggest that patients with DLB experience not only more rapid cognitive decline, but also accelerated motor deterioration compared to patients with PD. After ten years of follow‐up (and 12.9 years from the onset of symptoms), PD patients reach DLB's degree of yearly cognitive decline. This is the first large study to compare the natural history of PD and DLB and provides important information about the prognosis of these diseases. [ABSTRACT FROM AUTHOR]

Background: The potential role of the amygdala for neuropsychiatric symptoms (NPS) in dementia is not well known, especially in dementia with Lewy bodies (DLB). Cross‐sectional studies have proposed the associations between amygdala volume and NPS in Alzheimer’s Disease (AD). However, less is known about the association between amygdala volume and longitudinal trajectories of NPS. We aimed to analyze the association between amygdala volume and the longitudinal trajectories of NPS in AD and DLB. Method: 89 patients with mild dementia were included (AD = 55; DLB =34) in this secondary analysis of a longitudinal cohort study. Baseline amygdala volume was segmented from structural magnetic resonance images (sMRI) using a semi‐automatic method (Freesurfer 6.0). NPS were assessed annually over five years with the Neuropsychiatric Inventory (NPI) frequency × severity item‐scores. NPI item‐scores ≥ 4 were considered clinically relevant symptoms. Mixed‐effects logistic regression models were conducted in the whole sample and then in AD and DLB separately. Amygdala volume was included as a predictor of each NPS (i.e. NPI item‐score ≥ 4) over time. The models were adjusted for key demographic variables and diagnostic, as well as for center of sMRI acquisition and cognition. Result: The cohort characteristics are shown in Table 1. Intracranial volume‐normalized amygdala volumes were comparable between AD and DLB patients. After correcting adjusted models for multiple testing, a lower odds of apathy scores ≥ 4 over time was found in patients with larger amygdala volume at baseline (OR:0.36; 95% CI: 0.21 – 0.64; p < 0.001; FDR = 0.002), with no significant effects of diagnostic (OR: 1.11; 95%CI: 0.56 – 2.17; p = 0.769; FDR = 0.846), Figure 1. The subgroup analyses showed significant results for apathy in both DLB and AD: (DLB (OR: 0.37; 95% CI: 0.16 – 0.87; p = 0.023) and AD (OR: 0.35; 95% CI: 0.15 – 0.79; p = 0.012). Conclusion: Smaller amygdala volumes in people with mild dementia were associated with a higher risk of clinically relevant apathy, in both AD and DLB patients, during the 5 years study period. This association between apathy and amygdala might reflect damage in circuits underlying behavioral and cognitive avoidance. [ABSTRACT FROM AUTHOR]