Search

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: 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]

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]

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]

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]

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]

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]

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]

Background: No specific clinical rating scale currently exists for Lewy body dementia (LBD). Clinical rating scales developed for other diseases are therefore used instead for LBD clinical trials. However, these scales are not optimized for LBD and may not sufficiently reflect the complex array of LBD‐related phenomenology, making it more difficult to interpret outcome data from LBD clinical trials. Method: A working group comprised of 14 members bridging various international LBD‐focused research groups was convened to develop the first iteration of the LBD‐DRS with a focus on inclusion of key LBD related symptom domains, ensuring that any scale is mapped to regulatory expectations, and an emphasis on being patient‐centered. This draft was then subsequently presented to a broader stakeholder group (»50 participants) at the International Lewy body Dementia Conference in June 2022 for further feedback, leading to a further iteration of the scale. Result: The LBD‐DRS has been designed to capture ratings of the frequency and severity of symptoms across the key domains relevant to LBD – cognitive, neuropsychiatric, motor, autonomic and sleep – as well as the functional impact and perceived burden of symptoms for patients and their care partners. An international Delphi exercise is now planned with many LBD‐relevant stakeholders, which will be coupled with workgroup engagement (for example, with patient‐caregiver groups) to further develop the scale with the resulting final draft anticipated for pilot use in the near future. Conclusions: In this presentation we will elaborate on the development of the scale, key areas that it will cover as well as challenge points and next steps. Upon completion of the development and refinement of the LBD‐DRS, we propose that this scale will have utility as valid and LBD specific outcome measure in LBD clinical trials. [ABSTRACT FROM AUTHOR]

Background: Reviews of randomized clinical trials (RCTs) in Dementia with Lewy bodies (DLB) are essential for informing ongoing research efforts of symptomatic therapies and potentially disease‐modifying therapies (DMTs). Methods: We performed a Systematic Review of DLB drug development by examining 3 international registries: ClinicalTrials.gov, the European Union Drug Regulating Authorities Clinical Trials Database, and the International Clinical Trials Registry Platform, to identify drugs in trials in DLB. We analyzed recruitment status, the disease stage and diagnostic groups included in clinical trials, number of trials participants and treatment exposure, use of repurposed agents per clinical trial phase, description of outcome measures for primary endpoints, use of biomarkers for inclusion and/or outcome measures, sponsorship, and global distribution. Results: We found 25 agents in 40 trials assessing symptomatic treatments and disease modifying therapies for DLB: 7 Phase 3, 31 Phase 2, and 2 Phase 1 trials. We found an active pipeline for drug development in DLB, with most ongoing clinical trials in phase 2. We identified a recent trend towards including participants at the prodromal stages, although more than half of active clinical trials will enroll mild to moderate dementia patients. Additionally, repurposed agents are frequently tested representing 65% of clinical trials. Conclusion: To accelerate DLB drug development there is a need for more clinical trials, increased diagnosis at earlier stages of the disease, disease‐specific outcome measures and biomarkers, as well as augmenting global representation and including more diverse populations. [ABSTRACT FROM AUTHOR]

The term Lewy body disease (LBD) encompasses a spectrum of neurodegenerative conditions, particularly Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), associated with abnormal deposits of alpha‐synuclein in the brain and representing up to 20% of all neurocognitive disorders in memory clinics. Mild cognitive impairment or mild dementia precede or concur with Parkinsonism in the early stages of DLB and in a third of patients with PD at diagnosis. However, when Parkinsonism is slightly detectable, the differential diagnosis from other dementing conditions, such as Alzheimer's disease (AD), may be challenging. For this reason, neuroimaging and electrophysiological biomarkers, divided into indicative or supportive based on their diagnostic performance over or below 80%, assist the clinical reasoning to increase the likelihood that MCI/early dementia is associated with LB. The European Intersociety Consensus Diagnostic Task Force recommends prioritizing the Dopamine transporter (DaT)‐SPECT imaging to investigate nigro‐striatal degeneration as the first biomarker (sensitivity 76%, specificity 88%), and suggests subsequently [123I]‐MIBG cardiac scintigraphy to evaluate the postganglionic sympathetic denervation in those cases (about a quarter) where DaT‐SPECT is negative but DLB is still clinically possible (AD pathology is estimated to be underlying in about 86% of these cases). In the absence of well‐validated techniques to establish the presence of brain alpha‐synuclein aggregates in vivo, the proposed sequence of biomarkers will provide the most accurate and cost‐effective biomarker‐based diagnosis of LBD. [ABSTRACT FROM AUTHOR]

Background: Along with memory problems and functional impairment, people with Alzheimer's dementia often suffer from behavioural and psychological symptoms of dementia (BPSD), such as hallucinations, delusions, anxiety and agitation. Current used medications have modest benefits and significant side effects. Promising evidence suggests that cannabidiol (CBD) a non‐psychoactive and non‐addictive substance present in the cannabis plant extract may be useful in treating these symptoms. We conducted a randomised, double‐blind, placebo‐controlled trial of CBD for AD patients with BPSD. However, it is also important to seek to explore the views of potential participants through qualitative research methods about their acceptance of such interventions and participating in such trials especially during the COVID‐19 pandemic period. Methods: AD patients with BPSD were recruited within a single site, South London and Maudsley NHS trust, UK. We carried out semi structured quality interview for participants and their carers who were randomised and received treatment within the feasibility trial. The purpose of the qualitative interviews was to explore participants' experiences of taking part in the trial including what encouraged them to take part, their views on the intervention and how they are finding the trial in general. Results: Both AD participants (n = 15) and their carers (14) were interviewed. Only five AD participants could reasonably participate due to their symptoms. All the carers completed the interview. The key motivator for participating in the trial identified was to derive health benefits from the intervention (100% carers), and 43% also had altruistic motivation to help other people and research. Of the 5 AD patients, 4 had altruistic motivation and one said for health benefits. There were no concerns taking CBD orally in little capsule form. All the participants expressed positive experience with adequate information, thorough and flexible assessments (face to face and virtual), being visited at home or taxis arranged for hospital visits. Conclusions: The findings demonstrate good acceptability and compliance for CBD among elderly with AD and BPSD. Health benefit was the key motivator for enrolling in the clinical trial facilitated by appropriate arrangements for participation. Learnings from this study would help plan further trials for this cohort. [ABSTRACT FROM AUTHOR]

Background: Late‐life onset psychosis assessed in the Mild Behavioral Impairment framework (MBI‐psychosis) is a risk factor for dementia and known to be associated with impaired reasoning and memory in people without dementia. There is evidence that psychotic symptoms across diagnostic boundaries share some common genetic and neuropsychological correlates. In this study we aimed to determine whether MBI‐psychosis is associated cognitive deficits typically associated with other psychoses. To do this, we examined the relationship between MBI‐psychosis and scores on a specialised decision making and risk‐taking test, the Cambridge Gambling Task (CGT), performance on which is impaired in people with earlier life psychotic syndromes. Method: 476 participants were drawn from the online PROTECT registry on the basis of the Mild Behavioural Impairment Checklist (MBI‐C) ratings indicating psychosis and invited to complete the Cambridge Gambling Task. The association between performance on six CGT outcome measures, assessing elements of risk taking and decision making, and MBI‐psychosis was tested using linear regression (controlling for age, sex and education level). Result: Overall, there was little evidence of a substantial impact of MBI‐psychosis on CGT scores. Our study was powered to detect medium effect sizes. We found modest evidence of higher risk taking associated with more severe MBI‐psychosis scores (β = ‐0.1, SE = 0.05, p = 0.04) but this did not survive multiple testing correction. Conclusion: This is the first time a specialist decision making and risk‐taking test has been conducted in MBI‐psychosis. Although MBI‐psychosis is associated with a range of cognitive impairments in later‐life and dementia risk it appears that any shared neuropsychological basis with other psychoses is limited (though we cannot rule out a small non‐clinically significant effect size). This has possible implications for the diagnostic classification of later‐life onset mild psychotic symptoms. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Parkinson's disease dementia (PDD) are termed Lewy body diseases (LBDs). These neurodegenerative diseases are classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LB). Whilst pathologically similar, symptomatic staging is different. Previous genome wide association studies (GWAS) have identified classic Alzheimer's disease (AD) and PD loci as risk loci in DLB. Therefore, we have used polygenic risk score (PRS) analysis to investigate the contribution of AD and PD variants in the LBDs. Method: DNA was extracted from bulk brain tissue from 481 individuals (162 controls, 95 DLB, 156 PDD and 68 PD) and genotyped on the Illumina global screening array. After a strict quality control and imputation pipeline, PRSs for multiple relevant traits using reference GWAS summary statistics were calculated using PRSice2. Result: Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. All groups, including controls are stratified for age and concomitant AD pathology. Assessing multiple PRSs for association with pathological development and clinical outcomes we have identified the contribution of genetic risk from related neurodegenerative and neuropsychiatric disorders in our cohort of PD, PDD and DLB samples. Conclusion: We have collated a well powered study cohort to interrogate the genetic basis of the Lewy body dementias and the relative contribution of AD and PD risk loci in the LBDs. We are currently generating methylation quantitative trait loci (mQTLs) for this dataset using previously generated matched DNA methylation data in the brain. [ABSTRACT FROM AUTHOR]

Background: PROTECT Norge, a fully digital platform, aims to help determine the role of defined genetic, lifestyle and environmental factors on cognition, health and wellbeing in people 50+. Annual questionnaires on demographics, medical conditions and medication use, mental health and lifestyle are completed online. The current study aims to assess whether potentially modifiable risk factors for dementia as presented by the Lancet Commission by Livingston and colleagues (2020) are related to cognitive performance in cognitively healthy people aged 50 and above. Method: A total of 2349 participants completed the PROTECT Cognitive Test System, an online cognitive battery containing six tasks which assess visual episodic memory, spatial and working memory, verbal reasoning, visual attention and task switching. The following risk factors were included in our analysis: physical activity, alcohol use, smoking, social isolation, age, BMI, education, depression, high blood pressure, head trauma and hearing loss. Multiple hierarchical regression analysis was performed. Separate analyses were conducted with the average performance across three sessions for each of the six cognitive measures as the dependent variable. Independent variables were included into the model in a hierarchy based on known risk factors for dementia. Result: Results show that age was associated with reduced cognitive performance for all tasks (p<0.001). In addition, for the digit span test, the risk factors were found to influence the test score were: smoking and previously diagnosed stroke. For the paired associate learning task, the only additional significant risk factor appeared to be gender, with male gender associated with poorer performance. For the grammatical reasoning task, the risk factors associated with lower scores were lower education, older age and smoking. For the switching Stroop test, the risk factors of lower scores were older age, smoking and previously diagnosed depression. For Trail‐making B test, the risk factors of lower scores were age, stroke and the history of heart disease. Conclusion: These preliminary results may improve our understanding of potentially modifiable risk factors for dementia and could inform the design and delivery of interventional trials as a mean to protect cognition in later life and to prevent or slow progression of cognitive decline. [ABSTRACT FROM AUTHOR]

Background: While the last two decades have seen important advances in the in vivo detection of Alzheimer's disease (AD) pathology (i.e. β‐amyloid [Aβ] and Tau) using biomarkers (PET‐ and CSF‐based), the global use of these measures is quite limited due to high costs, insufficient availability and their invasive nature. Interest in blood‐based biomarkers for AD is growing due their greater accessibility and lower cost. We here aimed to investigate the relationship between ultrasensitive plasma‐based measures for AD and both cross‐sectional and longitudinal brain atrophy. Methods: We evaluated cross‐sectional plasma samples for 307 participants (100 cognitively unimpaired (CU) elderly, and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) and 106 AD) from the European multicentre AddNeuroMed cohort. Single molecule array (Simoa) assays were performed for NfL, T‐tau, Aβ42, Aβ40 and GFAp. P‐tau181 was measured using an in‐house Simoa assay. Associations with longitudinal MRI (baseline, 3‐months, 12‐months) were performed using linear mixed models (adjusted for age, sex, education, APOE ε4 status, and interval between plasma and MRI). Three predefined MRI markers were selected: hippocampal volume (adjusted for intracranial volume), cortical thickness within a temporal meta‐ROI encompassing regions susceptible to AD (mean thickness in the bilateral entorhinal, inferior/middle temporal, and fusiform cortices) and whole‐brain cortical thickness. Results: Cross‐sectionally, P‐tau181 and whole‐brain cortical thickness were the only significant association for CU. In CI subjects, Aβ42/Aβ40 and P‐tau181 were significantly associated with hippocampal volume and temporal meta‐ROI/whole‐brain cortical thickness (Table 1). Longitudinally, increased baseline P‐tau181 was associated with all three MRI measures in both CU and CI subjects (Table 1). Low Aβ42/Aβ40 was also associated with all three MRI measures, though only in CI subjects. Further analyses will associate these plasma measures at the voxel level. Conclusion: These results suggest that plasma‐based measurements of Aβ42/Aβ40 and P‐tau181 are associated with cross‐sectional atrophy levels and, more importantly, can predict brain atrophy over time, both in patients with AD and in CU elderly individuals. These findings add to a growing number of studies suggesting that these markers hold great promise, both as diagnostic tools as well as in research and clinical trials. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is the second‐most common neurodegenerative disorder that affects 2–3% of the population ≥ 65 years of age and may belong to cognitive deficits and dementia in 50% of cases. Disease with Lewy Bodies (DLB) is emerging as another important cause of dementia in pathological aging. PD and DLB are both due to intra‐neuronal Lewy bodies and are characterized not only by motor dysfunctions but also by cognitive and/or psychiatric symptoms. An open issue is the extent to which these diseases are distinct entities. In this respect, here we compared cortical sources of resting state eyes‐closed electroencephalographic (rsEEG) rhythms in PD and DLB patients having visual hallucinations. Method: Clinical and rsEEG rhythms in demographic matched PD (N = 93), DLB (N = 46), Alzheimer's disease dementia (AD, N= 70) and healthy elderly (Nold, N = 60) subjects were available from an international archive. Pathological groups were matched for cognitive status. Individual alpha frequency peak was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were considered. The eLORETA freeware estimated rsEEG cortical sources. Result: As a confirmation of previous studies, compared to the Nold subjects, the AD, LBD, and PD patients showed higher widespread delta source activities and lower posterior alpha source activities. Specifically, posterior alpha source activities were more abnormal in the AD than the LBD and PD groups, while widespread delta source activities were more abnormal in the PD and DLB than the AD group. As novel results, in relation to the LBD and PD patients without visual hallucinations and the control groups (Nold, AD), those with visual hallucinations were characterized by higher parietal delta source activities (LBD, Figure 1) and parieto‐occipital alpha sources activities (PD, Figure 2). Conclusion: These novel results suggest that in LBD and PD patients resting in the quiet wakefulness, abnormalities in cortical neural synchronization at delta and alpha frequencies in parietal cortex are differently related to visual hallucinations despite the essence of alpha‐synucleinopathy. [ABSTRACT FROM AUTHOR]

Background: Implementation of evidence‐based training into real world practice in nursing home settings is a major challenge. Digital approaches provide real potential to addressing the barriers, particularly over the difficult period of the COVID‐19 pandemic. Method: iWHELD is a first‐of‐its‐kind digital programme evolving the principles of the WHELD intervention combining person centred care, social interaction, and antipsychotic review, combining virtual coaching with a digital resource for nursing homes. The intervention utilising a Dementia Champion model supported by live virtual coaching set within a digital resource hub and peer networking platform was compared to usual care in a 16‐week randomised control cluster study of 741 people with dementia across 149 nursing homes in the UK. The initial outcomes evaluated are the use of antipsychotic drugs and neuropsychiatric symptoms (using the Neuropsychiatric Inventory NH). Result: 36/72 (53%) of nursing homes allocated to the active treatment arm engaged successfully with the digital intervention, with 563 residents completing the treatment period. The average age of residents was 84.5 years, 71% were female, and there were no significant differences between treatment arms. There was a significant reduction in antipsychotic use in the digital iWHELD treatment group from 49% to 31% compared to no change in the group receiving usual care (p = 0.046). Initial analysis of neuropsychiatric symptoms indicates a non‐significant improvement in the intervention group compared to those receiving usual care. Conclusion: The current RCT using an online programme with live virtual coaching delivered through a Dementia Champion achieved better than 50% engagement, which compares favourably with previous studies of digital interventions in other therapeutic areas. The intervention also achieved significant reductions in antipsychotic use without any worsening of neuropsychiatric symptoms, and provides an important potential approach to safely reducing the rise in antipsychotic use in nursing home residents with dementia that has become a major challenge during the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]