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Background: Cognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their combined effects on functional outcome have not been elucidated. This study investigated the interactions and mediating effects of cognitive and motor functions on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH). Methods: Participants of the Helsinki Small Vessel Disease Study (n = 152) were assessed according to an extensive clinical, physical, neuropsychological and MRI protocol. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Results: Cognitive (global cognition, executive functions, processing speed, memory) and motor functions (gait speed, single‐leg stance, timed up‐and‐go) had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on informant‐evaluated IADL, but not on self‐evaluated quality of life. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up‐and‐go performance. Conclusion: The results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than their individual effects. Patients with both impairments are at disproportionate risk for poor outcome. WMH and brain atrophy contribute to disability through cognitive and motor impairment. [ABSTRACT FROM AUTHOR]

Efficient identification of cognitive decline and Alzheimer's disease (AD) risk in early stages of the AD disease continuum is a critical unmet need. Subjective cognitive decline is increasingly recognized as an early symptomatic stage of AD. Dyadic cognitive report, including subjective cognitive complaints (SCC) from a participant and an informant/study partner who knows the participant well, represents an accurate, reliable, and efficient source of data for assessing risk. However, the separate and combined contributions of self- and study partner report, and the dynamic relationship between the two, remains unclear. The Subjective Cognitive Decline Professional Interest Area within the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment convened a working group focused on dyadic patterns of subjective report. Group members identified aspects of dyadic-report information important to the AD research field, gaps in knowledge, and recommendations. By reviewing existing data on this topic, we found evidence that dyadic measures are associated with objective measures of cognition and provide unique information in preclinical and prodromal AD about disease stage and progression and AD biomarker status. External factors including dyad (participant-study partner pair) relationship and sociocultural factors contribute to these associations. We recommend greater dyad report use in research settings to identify AD risk. Priority areas for future research include (1) elucidation of the contributions of demographic and sociocultural factors, dyad type, and dyad relationship to dyad report; (2) exploration of agreement and discordance between self- and study partner report across theADsyndromic and disease continuum; (3) identification of domains (e.g., memory, executive function, neuropsychiatric) that predict AD risk outcomes and differentiate cognitive impairment due to AD from other impairment; (4) development of best practices for study partner engagement; (5) exploration of study partner report as AD clinical trial endpoints; (6) continued development, validation, and optimization, of study partner report instruments tailored to the goals of the research and population. [ABSTRACT FROM AUTHOR]

Background: For the item analysis project of the Subjective Cognitive Decline Initiative (SCD‐I) Working Group, we have pooled item level data from North American, European, and Australian cognitive aging studies. As a step toward developing a questionnaire that can be used across settings and studies, we examined similarly worded groups of items and compared their psychometric quality. Method: Item‐level subjective cognitive data were combined from 21 studies (>18,000 participants). Unidimensional models consistent with item response theory captured a general subjective cognition factor using ADNI as the reference sample. Other studies were calibrated by using parameter constraints on common items. We characterized the measurement properties of 648 items from 35 measures utilized in the contributing studies. Next, we identified 20 groups of items (median items per group=6) with overlapping content from our previous study (Rabin et al., 2015), and plotted their item information curves, reflecting the items' ability to discriminate between trait scores at different levels of the subjective cognition factor score. We then considered items with the highest peak information across groupings and identified commonalities in key features such as terminology of item stems, temporal referents, and response options. Result: We present instrument characteristics (Table 1) and item information curves for 6 groupings (Figure 1). For items with the greatest information, we observed trends for the following features: clarity and directness of language of stem, utilization of current as opposed to other time referents, assessment of ability/level of difficulty rather than change over time or frequency of problem (Table 2). Conclusion: We identified key linguistic/structural features of subjective cognitive functioning items with the greatest contributions to measurement precision. We next plan to analyze all item groupings in our test bank to facilitate construction of a measure with high quality items from cognitive domains of interest (e.g., memory, language, executive functioning). Ultimately, we hope to derive a subjective cognitive screening tool that enables reliable identification of subtle cognitive changes in clinically normal individuals. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer's Association (NIA-AA) research framework. Method: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models. Results: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p <.001). Word List Delayed Recall (β = −.22, p <.05) and Trail Making Test (β = 6.2, p <.05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p <.001) and 4 (β = −2.23, p <.001). Conclusions: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD. [ABSTRACT FROM AUTHOR]

Purpose: Being able to function independently in society is an important aspect of quality of life. This ability goes beyond self-care, requires higher order cognitive functioning, and is typically measured with instrumental activities of daily living (IADL) questionnaires. Cognitive deficits are frequently observed in brain tumour patients, however, IADL is almost never assessed because no valid and reliable IADL measure is available for this patient group. Therefore, this measure is currently being developed. Methods: This international multicentre study followed European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group module development guidelines. Three out of four phases are completed: phases (I) generation of items, (II) construction of the item list, and (III) pre-testing. This paper reports the item selection procedures and preliminary psychometric properties of the questionnaire. Brain tumour patients (gliomas and brain metastases), their informal caregivers, and health care professionals (HCPs) were included. Results: Phase I (n = 44 patient-proxy dyads and 26 HCPs) generated 59 relevant and important activities. In phase II, the activities were converted into items. In phase III (n = 85 dyads), the 59 items were pre-tested. Item selection procedures resulted in 32 items. Exploratory factor analysis revealed a preliminary dimensional structure consisting of five scales with acceptable to excellent internal consistency (α = 0.73–0.94) and two single items. For three scales, patients with cognitive impairments had significantly more IADL problems than patients without impairments. Conclusion: A phase IV validation study is needed to confirm the psychometric properties of the EORTC IADL-BN32 questionnaire in a larger international sample. [ABSTRACT FROM AUTHOR]

Background: Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in non‐demented older individuals is mixed. The multidomain FINGER study1 found small positive effects on cognition among older people at risk for dementia. As part of the World‐Wide FINGERS initiative to replicate and build on these results, FINGER‐NL aims to investigate the effectiveness of a 2‐year high versus low intensive multidomain lifestyle intervention on cognitive functioning in Dutch older at‐risk individuals. Method: FINGER‐NL is a Dutch multi‐center, randomized, controlled, multidomain lifestyle intervention trial aiming to include 1,206 adults at risk for cognitive decline. Adults aged 60‐80 years with at least 3 modifiable dementia risk factors (based on 'LIfestyle for BRAin Health' (LIBRA))2 and either a family history of dementia or self‐reported cognitive decline are eligible for inclusion. Participants are randomized (1:1 ratio) to either a high (HI‐group) or low‐intensity (LI‐group) intervention group. The multi‐domain intervention comprises a combination of 7 lifestyle components (physical exercise, cognitive training, cardiovascular risk management, nutritional counseling (with a specific focus on the MIND diet), sleep counseling, stress management, social activities) and 1 nutritional product (Souvenaid, 125ml). The HI‐group receives a personalized, supervised and hybrid intervention consisting of group meetings and individual sessions guided by a lifestyle coach. The LI‐group receives online lifestyle‐related health education. Primary outcome is 2‐year change from baseline on the cognitive composite score covering processing speed, executive function and memory. Secondary outcomes including changes in specific cognitive domains, instrumental activities of daily living, LIBRA score, and lifestyle component specific outcomes. For recruitment, we use the Dutch Brain Research Registry.3 Result: Participant recruitment started in January 2022. So far, 2405 people were interested, 1711 individuals have been screened for eligibility, 949 underwent baseline testing and 880 participants (73% of target sample) have been randomized and started with the intervention. The intervention is well‐accepted based on drop‐out rate (0.5%) and use of the online intervention portal. We expect to finalize randomization in Q2 of 2023 and complete the two‐year trial in 2025. Conclusion: Results so far show that FINGER‐NL is well on track, the intervention is well‐accepted and the trial will reach its inclusion target. [ABSTRACT FROM AUTHOR]

Background: A potential explanation for the limited success of past therapeutic trials for Alzheimer's disease (AD) lies in disease heterogeneity. We set out to pool and jointly analyze data from completed trials using a hypothesis‐free machine learning approach, aiming to identify participant characteristics related to increased responsiveness to treatment. Considering methodological difficulties, we also aim to describe the pooling and analytical process. Method: We requested data from fifteen completed phase I–III trials investigating several compounds in AD individuals and were granted access to six trial datasets using compounds LY450139 (semagacestat), GSK933776, and BI409306 (with donepezil) with 2,397 participants (73.3±7.8 years old, 55% female, Table 1), through the Vivli platform. Causal Forest analyses, a machine learning technique that extracts a minimal subset of patient characteristics that can explain heterogeneity in outcomes, were used with change on (1) ADAS‐Cog and (2) MMSE as outcome, accounting for treatment group (placebo vs. compound). Result: The included trial datasets showed considerable differences in available variables and data structure, constraining the amount of data that may be used in joint analysis. We were able to pool and analyze twenty‐seven characteristics shared across trial datasets in the model, covering demographics, vital signs, MRI volumetrics, baseline cognitive and functional performance, apolipoprotein ε4‐carriership and drug compound. Causal forest analyses did not reveal heterogeneity in pooled treatment effects on ADAS‐Cog (estimate for differential forest prediction: ‐2.25, p = 0.96) or MMSE (‐2.97, p = 0.98), indicating that these patient characteristics were not predictive for increased responsiveness to treatment. Stratifying by compound, similar results were found. Conclusion: We took an innovative approach and provided a methodological basis to examine heterogeneity in treatment effects by pooling existing trial datasets. Our results imply that responsiveness to treatment may not be well‐explained by the patient characteristics to our disposal, or that different compounds should be investigated. More research into other factors possibly related to treatment response is needed, e.g., fluid biomarkers and genetics. Based on our experience, we recommend that trial sponsors improve collaboration and data access, as we work towards personalized medicine by identifying which therapeutic approach works best for whom. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) are increasingly recognized as non‐cognitive manifestation of Alzheimer's disease (AD). However, the relationship between AD‐related pathology and NPS remains unclear. We aimed to investigate the cross‐sectional association between Alzheimer biomarkers and neuropsychiatric symptoms (NPS) in individuals with subjective cognitive decline (SCD) presenting at a memory clinic. In addition, we evaluated personality traits and education as potentially modifying factors of this association. Method: We included 346 individuals with SCD (age: 62.9±7.8) from the SCIENCe cohort, including 92 amyloid positive participants (age: 66.4±7.0, Female: 44.6%, MMSE: 28.5±1.3) and 254 amyloid negative participants (age: 61.6±7.7, Female: 40.6%, MMSE: 28.6±1.3). Amyloid status was determined by amyloid PET or CSF biomarkers according to visual read or established cut points. Neuropsychiatric symptoms were assessed using the Geriatric Depression Scale (GDS; n = 282), the Center for Epidemiological Studies‐Depression (CES‐D; n = 225), the Hospital Anxiety and Depression Scale – anxiety subscale (HADS‐A; n = 225) and the Neuropsychiatric Inventory Questionnaire (NPI‐Q; n = 198). We used linear regression analyses, adjusted for age and sex, to assess the association between amyloid status and NPS. In secondary analyses, we tested for interactions between amyloid status and (1) neuroticism (Dutch Personality Questionnaire), (2) somatization, (Four‐Dimensional Symptom Questionnaire), and (3) educational level (Dutch Verhage scale). Result: Amyloid status was not associated with GDS, CES‐D, HADS‐A and NPI‐Q scores in univariable analyses. When we evaluated effect modification, we found an interaction between amyloid status and neuroticism in the association with NPI‐Q (p<0.05), indicating a positive association between amyloid status and NPS in participants with a low level of neuroticism (β: 2.56±2.24), and a negative association in participants with a high level of neuroticism (β: ‐4.09±3.23). Conclusion: In this cross‐sectional analysis in individuals with SCD, amyloid status was hardly associated with neuropsychiatric symptoms. In future studies, we focus on amyloid status as determinant of change in NPS over time. [ABSTRACT FROM AUTHOR]

Background: Reduced learning is an early sign of memory impairment and relevant in the context of Alzheimer's disease. The Visual Association Test (VAT) is a brief visual associative memory task comprising two sets (A and B) of six interactive pictures (e.g., a monkey holding an umbrella). We hypothesized that the VAT may be able to elicit learning deficits on set B when administered directly following set A, particularly in patients with Alzheimer's disease‐related episodic memory deficits. We related learning on the VAT to medial temporal lobe atrophy (MTA) and amyloid‐β positivity. Method: We selected 3,599 patients (63.9±8.9 years, 41% female) who completed two VAT sets. Patients had subjective cognitive decline (n = 1,369, 38%), mild cognitive impairment (n = 756, 21%), Alzheimer's disease dementia (n = 856, 24%), or other types of dementia (n = 618, 17%). Average MTA scores of both hemispheres from magnetic resonance imaging were available for all; amyloid‐β status was obtained from cerebrospinal fluid or positron emission tomography for n = 2,769 (77%). We modeled learning curves on both VAT sets using linear mixed models, including an interaction with amyloid‐β status. Using logistic regressions, we analyzed the relationship between learning of associations on both sets (either all associations on both sets, or all associations on the first, but not the second set) and MTA, as well as amyloid‐β status. Result: Most patients learned all associations on both sets (n = 2,442, 68%). Patients who learned all associations on the first, but not the second set (n = 640, 18%) were more likely to have higher MTA scores and to be amyloid‐β positive than those who learned all associations (Table 1). Figure 1 shows learning curves on both sets of the VAT, stratified by amyloid‐β status. Less steep learning curves seem to suggest that amyloid‐β positive patients benefited less from completing a first set than amyloid‐β negative patients. Conclusion: We observed reduced learning on the second set, with those who did not learn all associations on both sets having more medial temporal lobe atrophy and more often being amyloid‐β positive. The VAT may be a useful, simple tool to assess early episodic memory deficits in the presence of Alzheimer's disease pathology. [ABSTRACT FROM AUTHOR]

Background: As cognitive assessments can be burdensome to patients, new approaches are emerging to assess symptomatic changes in Alzheimer's Disease (AD). Since typing on smartphones requires a variety of cognitive functions, passively and remotely collected typing behaviour has the potential to provide day‐to‐day insights into cognitive decline in AD. We investigated therefore the feasibility and reliability of a keyboard application for smartphones (Neurokeys) that passively collects keystroke dynamics (KD) to monitor cognition in people with preclinical and clinical AD. Method: Participants with preclinical AD (N = 8) and patients with a clinical AD diagnosis (N = 8, Table 1) were included from the Amsterdam Dementia Cohort. Participants used Neurokeys for 28 consecutive days in the context of the 'A Personalized Medicine Approach for Alzheimer's Disease' (ABOARD)‐project. The retention rate (active users on day 28) and the average number of daily keystrokes were calculated to determine feasibility. KD were aggregated into two commonly investigated features: time between keystrokes (flight‐time) and duration of a keystroke (hold‐time), which were standardized into z‐scores. Intra‐class correlations (ICC) between first and last 14 days of data collection for both features were determined to assess reliability. Finally, KD features were correlated to scores on the Mini‐Mental State Examination (MMSE) to explore the association between KD and global cognition. Results: The retention rate was 93.75% for all participants (Figure 1). Participants with preclinical AD used the keyboard for 26.25±2.12 days with 653.67±305.61 keystrokes each day, and clinical AD patients used the keyboard for 22.63±4.10 days with 409.44±288.73 daily keystrokes. For all participants, the ICC for flight‐time and hold‐time are 0.85 and 0.89 respectively. MMSE is negatively correlated with flight‐time (r = ‐0.68, p = 0.003), but not with hold‐time (r = ‐0.20, p = 0.45, Figure 2). Conclusion: The number of daily keystrokes is sufficient to obtain reliable KD features in preclinical and clinical AD. The results show that people with better global cognition type faster, indicating that passive logging of keystrokes can be a feasible measure for cognition in AD. To elaborate on these first findings, a larger validation study can further explore the utility of smartphone interactions and aid the development of digital biomarkers in AD. [ABSTRACT FROM AUTHOR]

Background: The prevalence of amyloid‐beta (Aβ) pathology increases at higher ages in non‐demented individuals1. With anti‐amyloid‐beta therapies on the horizon and the growing number of elderly in our population, a clear perception of the association between accumulated Aβ pathology, APOE genotype and cognitive performance in the oldest‐old is warranted. Methods: In 93 post‐mortem brains donated by participants of the Dutch 100‐plus Study, who self‐reported to be cognitively healthy at inclusion, we evaluated: 1) the spatiotemporal Aβ spread using Thal phases2; and 2) Aβ load in frontal, parietal, temporal and occipital cortices using a quantitative image analysis method. Spread and load of Aβ pathology were compared between different APOE groups (ɛ2/2 and ɛ2/3 (n = 20); ɛ3/3 (n = 65); ɛ2/4 and ɛ3/4 (n = 8)). Post‐mortem Aβ measurements were correlated to ante‐mortem test scores on a comprehensive neuropsychological test battery3 and a composite z‐score for global cognitive performance. Median age at death was 103.3 (interquartile range (IQR): 102.3‐104.9) and median time between neuropsychological assessment and brain donation amounted 0.61 years (IQR: 0.28‐0.93). Results: Notably, only 10% of the centenarians had not accumulated Aβ pathology. APOE ɛ2/2 and ɛ2/3 carriers had lower Aβ load (median frontal AB load = 0.30%, IQR: 0.02‐6.15), but not spread, compared to APOE ɛ2/4 and ɛ3/4 carriers (median frontal AB load = 5.08%, IQR: 2.13‐30.71) (p = 0.041), but not compared to ɛ3/3 carriers (median frontal AB load = 2.19%, IQR:0.23‐7.54) (p = 0.245). Higher Aβ load in all four analyzed regions associated with lower performance on the Digit Span Backward test (rfrontal = ‐0.29, rparietal = ‐0.29, rtemporal = ‐0.28, roccipital = ‐0.32, FDR corrected p<0.05) and the Clock Drawing test (rfrontal = ‐0.40, rparietal = ‐0.29, rtemporal = ‐0.29, roccipital = ‐0.33, FDR corrected p<0.05), which assess executive‐ and visuospatial‐functioning. Moreover, higher Aβ load in the frontal cortex correlated with lower performance on the Mini Mental State Examination (MMSE) (r = ‐0.24, p = 0.049) and a seperate composite score of global cognitive performance (r = ‐0.28, p = 0.019). Conclusion: Although Aβ pathology seems nearly inevitable at extreme ages, our results suggest that Aβ load, rather than Aβ spread, affects cognitive performance in the oldest‐old 1 https://doi.org/10.1002/alz.12899 2 https://doi.org/10.1212/wnl.58.12.1791 3 https://doi.org/10.1007/s10654-018-0451-3 [ABSTRACT FROM AUTHOR]

Introduction: Non‐pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. Methods: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. Results: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. Discussion: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area. [ABSTRACT FROM AUTHOR]