Search

ObjectiveCognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their interrelations and combined effects on functional outcome have not been elucidated. We investigated the associations between cognitive and motor functions and their interactions and mediating effects on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH).MethodsParticipants of the Helsinki Small Vessel Disease Study (n=152) were assessed according to an extensive clinical, neuropsychological and MRI protocol. Cognitive composite scores for global cognition, processing speed, executive functions and memory were constructed from multiple tests within each domain. Physical examination included measures of gait speed, balance (single-leg-stance) and functional mobility (timed-up-and-go test). IADL was evaluated with a proxy-based Amsterdam IADL questionnaire and quality of life with a self-report EUROHIS-Qol index. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Sets of linear regression analyses were used to model the associations between motor and cognitive performances, WMH and GM volumes, and IADL and quality of life.ResultsDomain-specific cognitive and motor functions 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 IADL, but not on quality of life. In particular, low cognitive scores together with decline in the timed-up-and-go test and gait speed were strongly related to impaired IADL. 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.ConclusionThe 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 the individual effects of each of the two impairments. WMH and brain atrophy contribute to disability through cognitive and motor impairment.

Background and ObjectivesDecline in everyday functioning is a key clinical change in Alzheimer disease and related disorders (ADRD). An important challenge remains the determination of what constitutes a clinically meaningful change in everyday functioning. We aimed to investigate this by establishing the minimal important change (MIC): the smallest amount of change that has a meaningful effect on patients' lives. We retrospectively investigated meaningful change in a memory clinic cohort.MethodsIn the first, qualitative part of the study, community-recruited informal caregivers of patients with ADRD and memory clinic clinicians completed a survey in which they judged various situations representing changes in everyday functioning. Their judgments of meaningful change were used to determine thresholds for MIC, both for decline and improvement, on the Amsterdam Instrumental Activities of Daily Living (IADL) Questionnaire. In the second, quantitative part, we applied these values in an independent longitudinal cohort study of unselected memory clinic patients.ResultsMIC thresholds were established at the average threshold of caregivers (N = 1,629; 62.4 ± 9.5 years; 77% female) and clinicians (N = 13): −2.2 points for clinically meaningful decline and +5.0 points for clinically meaningful improvement. Memory clinic patients (N = 230; 64.3 ± 7.7 years; 39% female; 60% dementia diagnosis) were followed for 1 year, 102 (45%) of whom showed a decline larger than the MIC, after a mean of 6.7 ± 3.5 months. Patients with a dementia diagnosis and more atrophy of the medial temporal lobe had larger odds (odds ratio [OR] = 3.4, 95% CI [1.5–7.8] and OR = 5.0, 95% CI [1.2–20.0], respectively) for passing the MIC threshold for decline than those with subjective cognitive complaints and no atrophy.DiscussionWe were able to operationalize clinically meaningful decline in IADL by determining the MIC. The usefulness of the MIC was supported by our findings from the clinical sample that nearly half of a sample of unselected memory clinic patients showed a meaningful decline in less than a year. Disease stage and medial temporal atrophy were predictors of functional decline greater than the MIC. Our findings provide guidance in interpreting changes in IADL and may help evaluate treatment effects and monitor disease progression.

Objective:Commonly used measures of instrumental activities of daily living (IADL) do not capture activities for a technologically advancing society. This study aimed to adapt the proxy/informant-based Amsterdam IADL Questionnaire (A-IADL-Q) for use in the UK and develop a self-report version.Design:An iterative mixed method cross-cultural adaptation of the A-IADL-Q and the development of a self-report version involving a three-step design: (1) interviews and focus groups with lay and professional stakeholders to assess face and content validity; (2) a questionnaire to measure item relevance to older adults in the U.K.; (3) a pilot of the adapted questionnaire in people with cognitive impairment.Setting:Community settings in the UK.Participants:One hundred and forty-eight participants took part across the three steps: (1) 14 dementia professionals; 8 people with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or dementia due to Alzheimer’s disease; and 6 relatives of people with MCI or dementia; (2) 92 older adults without cognitive impairment; and (3) 28 people with SCD or MCI.Measurements:The cultural relevance and applicability of the A-IADL-Q scale items were assessed using a 6-point Likert scale. Cognitive and functional performance was measured using a battery of cognitive and functional measures.Results:Iterative modifications to the scale resulted in a 55-item adapted version appropriate for UK use (A-IADL-Q-UK). Pilot data revealed that the new and revised items performed well. Four new items correlated with the weighted average score (Kendall’s Tau −.388, −.445, −.497, −.569). An exploratory analysis of convergent validity found correlations in the expected direction with cognitive and functional measures.Conclusion:The A-IADL-Q-UK provides a measurement of functional decline for use in the UK that captures culturally relevant activities. A new self-report version has been developed and is ready for testing. Further evaluation of the A-IADL-Q-UK for construct validity is now needed.

Introduction. In the context of the development of pharmaceutical interventions, expectations and experiences of participants are essential. Their insights may be particularly helpful to address the challenges of recruiting and retaining participants for Alzheimer’s disease (AD) clinical trials. We examined clinical trial participants’ experiences to optimize trial design in Alzheimer’s disease (AD). Method. In this mixed-methods study, we included adults who participated in sponsor-initiated AD trials at Brain Research Center, a clinical trial organization in the Netherlands. Participants (N = 71, age 69 ± 6.5, 54%F, 19 cognitively normal (CN), 19 Mild Cognitive Impairment (MCI) and 33 AD dementia) first completed an online survey. Next, a subsample (N = 12; 8 = CN, 4 = MCI) participated in focus groups to gain in-depth insight into their views on optimizing trial design. Audio recordings from focus group interviews were transcribed verbatim and analysed by thematic content analysis by two independent researchers. Results. To benefit future generations was most frequently (34%) reported as a motive for enrolment. The lumbar puncture (40%) and memory assessments (15%) were most often experienced as being of high burden. Structurally receiving individualized test results and smaller chance to get placebo, increased willingness to participate. Two main themes emerged from the focus groups: “trials design”, such as follow-up visit(s) after participating, and “trial center”, including the relevance of a professional and empathic staff. Conclusion. Relevant factors include expectation management and careful planning of high burden assessments, provision of individual feedback and prioritizing professionalism and empathy throughout conduct of the trial. Our findings provide insight into participants’ priorities to increase willingness to participate and can be used to optimize trial success.

BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users .OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health.DESIGN: 30-day user test; multi-method.SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne).PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female).MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews.RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health.CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

Highlights • We examined the markers that optimally predict progression from normal to MCI. • A LASSO Cox model was used to determine the minimum set of markers. • Entorhinal thickness, Aβ burden, default network connectivity, and hippocampal volume predicted progression. • These markers may enhance risk stratification in clinically normal adults., Objective To identify a parsimonious set of markers that optimally predicts subsequent clinical progression from normal to mild cognitive impairment (MCI). Methods 250 clinically normal adults (mean age = 73.6 years, SD = 6.0) from the Harvard Aging Brain Study were assessed at baseline on a wide set of markers, including magnetic resonance imaging markers of gray matter thickness and volume, white matter lesions, fractional anisotropy, resting state functional connectivity, positron emission tomography markers of glucose metabolism and β-amyloid (Aβ) burden, and a measure of vascular risk. Participants were also tested annually on a battery of clinical and cognitive tests (median follow-up = 5.0 years, SD = 1.66). We applied least absolute shrinkage and selection operator (LASSO) Cox models to determine the minimum set of non-redundant markers that predicts subsequent clinical progression from normal to MCI, adjusting for age, sex, and education. Results 23 participants (9.2%) progressed to MCI over the study period (mean years of follow-up to diagnosis = 3.96, SD = 1.89). Progression was predicted by several brain markers, including reduced entorhinal thickness (hazard ratio, HR = 1.73), greater Aβ burden (HR = 1.58), lower default network connectivity (HR = 1.42), and smaller hippocampal volume (HR = 1.30). When cognitive test scores were added to the model, the aforementioned neuroimaging markers remained significant and lower striatum volume as well as lower scores on baseline memory and processing speed tests additionally contributed to progression. Conclusion Among a large set of brain, vascular and cognitive markers, a subset of markers independently predicted progression from normal to MCI. These markers may enhance risk stratification by identifying clinically normal individuals who are most likely to develop clinical symptoms and would likely benefit most from therapeutic intervention.

The behavioral variant of Alzheimer’s disease (bvAD) is characterized by early and predominant behavioral changes, resembling the clinical profile of the behavioral variant of frontotemporal dementia (bvFTD). Social cognition deficits form hallmark features in bvFTD and altered biometric responses to socioemotional cues have been observed in bvFTD. However, little is known about social cognition and its biometric signature in bvAD. In this explorative study, we investigated all levels of social cognition (i.e., level-1: perception, level-2: interpretation and level-3: reasoning), using the Ekman 60 faces test (level-1), Interpersonal Reactivity Index (IRI) and empathy eliciting videos (level-2), the Social Norms Questionnaire (SNQ) and moral dilemmas (level-3), while measuring eyemovements and galvanic skin response (GSR). We compared 12 patients with bvAD with patients with bvFTD (n=14), typical AD (tAD, n=13) and controls (n=15), using ANCOVAs and post hoc testing, adjusting for age and sex. Regardingperception, bvAD (40.1±8.6) showed lower scores on the Ekman test compared to controls (50.1±4.6, p0.05), but bvAD (18.7±9.5%) and bvFTD (19.4±14.3%) spent significantly less dwell time on the mouth when viewing the faces than controls (30.4±10.6%, pempathy, bvAD (11.3±4.6) exhibited lower scores on the IRIPerspective Takingsubscale compared with controls (15±3.4, p=0.02) and similar scores to bvFTD (8.7±5.6, p=0.19) and tAD (13.0±3.2, p=0.43). The GSR to empathy eliciting videos did not differ between groups (all p>0.05). Regardingknowledge of social norms, bvAD (16.0±1.6) and bvFTD (15.2±2.2) showed lower scores on the SNQ than tAD (17.8±2.1, both pmoral reasoning, no differences among the groups were observed in responses to moral dilemmas (all p>0.05), while only bvFTD (0.9±1.1) showed a lower GSR during the personal condition compared with controls (3.2±3.3 peaks per minute, p=0.02). In conclusion, bvAD showed a similar though milder social cognition profile and a similar eyetracking signature compared with bvFTD and greater social cognition impairments and divergent eyemovement patterns compared with tAD. Our results suggest that bvAD and bvFTD show reduced attention to salient features during facial expression perception, potentially contributing to their emotion recognition deficits. These social cognition and biometric measures provide important insights into the basis of behavioral changes in bvAD, and might be valuable for its clinical diagnosis.

The global fight against Alzheimer’s disease (AD) poses unique challenges for the field of neuropsychology. Along with the increased focus on early detection of AD pathophysiology, characterizing the earliest clinical stage of the disease has become a priority. We believe this is an important time for neuropsychology to consider how our approach to the characterization of cognitive impairment can be improved to detect subtle cognitive changes during early-stage AD. The present article aims to provide a critical examination of how we define and measure cognitive status in the context of aging and AD. First, we discuss pitfalls of current methods for defining cognitive impairment within the context of research shifting to earlier (pre)symptomatic disease stages. Next, we introduce a shift towards a more continuous approach for identifying early markers of cognitive decline and characterizing progression and discuss how this may be facilitated by novel assessment approaches. Finally, we summarize potential implications and challenges of characterizing cognitive status using a continuous approach.

INTRODUCTIONImpaired awareness in dementia due to Alzheimer’s disease and related disorders, made study partner-report the preferred method of measuring interference in ‘instrumental activities of daily living’ (IADL). However, with a shifting focus towards earlier disease stages and prevention, the question arises whether self-report might be equally or even more appropriate. This study aims to investigate how participant and study partner report IADL perform in a community-based volunteer population without dementia, and which factors relate to differences between participant and study partner report.METHODSParticipants (N=3288; 18–97 years, 70.4% females) and their study partners (N=1213; 18–88 years, 45.8% females) were recruited from the Dutch brain research registry. IADL was measured using the Amsterdam IADL Questionnaire. Concordance between participant and study partner-reported IADL difficulties was examined using intraclass correlation coefficient (ICC). Multinomial logistic regressions were used to investigate which demographic, cognitive and psychosocial factors related to participant and study partner differences, by looking at the over- and underreport of IADL difficulties by the participant, relative to their study partner.RESULTSThe vast majority of A-IADL-Q scores represented no difficulties for both participants (87.9%) and study partners (89.4%). Concordance between participants and study partners was moderate (ICC=.55, 95%CI=[.51, .59]), 24.5% (N=297) of participants overreported their IADL difficulties compared to study partners, and 17.8% (N=216) underreported difficulties. The presence of depressive symptoms (odds ratio (OR)=1.31, 95%CI=[1.12, 1.54]), as well as memory complaints (OR=2.45, 95%CI=[1.80, 3.34]), increased the odds of participants overreporting their IADL difficulties. Higher IADL ratings decreased the odds of participant underreport (OR=0.71, 95%CI=[0.67, 0.74]).CONCLUSIONIn this sample of community-based volunteers, the majority of participants and study partners reported no major IADL difficulties. Differences between participant and study partner were, however, quite prevalent, with subjective factors indicative of increased report of IADL difficulties by the participant in particular. These findings suggest that self- and study partner-report measures may not be interchangeable, and that the level of awareness needs to be taken into account, even in cognitively healthy individuals.

BACKGROUND Neurocognitive deficits are common among brain tumour patients, and may impact on patient awareness of deficits in instrumental activities in daily life (IADL). This study aimed to examine differences between patient-reported and proxy-reported assessments of the patient’s performance of IADL, and whether the level of (dis)agreement is associated with neurocognitive deficits. MATERIAL AND METHODS A phase III EORTC questionnaire measuring IADL in brain tumour patients (EORTC IADL-BN32) and six neurocognitive test measures were administered as part of a larger multicentre international study designed to develop a brain tumour specific IADL questionnaire. Bland-Altman plots and Mann-Whitney U tests were used to evaluated patient- and proxy-reported IADL on a group level. Subsequently, Mann-Whitney U tests were performed to compare patient-proxy difference scores (patient IADL score - their proxy IADL score) between patients who were considered clearly neurocognitively impaired (≥2 neurocognitive test measures; ≤2.0 SD below healthy controls) and patients who were not. Furthermore, multinomial logistic regression analyses were performed to examined which sociodemgraphic, clinical, and particularly neurocognitive variables were independently associated with patients and proxies differing in their evaluation of patient’s IADL. RESULTS Patients (N=81) and proxies (N=81), on group level, did not significantly differ on either the IADL individual item or scale scores. However, significant differences were found on patient-proxy difference scores between patients who were (N=37) and were not (N=44) considered clearly neurocognitively impaired for 10/32 individual items and one of the scales (i.e. Scale 4: Administrative tasks), all showing that the proxies of clearly neurocognitively impaired patients reported more problems relative to the patients themselves, compared to proxies of patients not clearly neurocognitively impaired. Furthermore, for each scale, a neurocognitive variable, either impaired information processing speed, cognitive flexibility, verbal fluency or the number of neurocognitive test measures impaired, was found to be independently associated with proxies reporting more problems. For 4/5 scales, a clinical variable was additionally independently associated with proxies reporting more problems. Only one variable was independently associated with patient reporting more problems, namely being in active treatment was found to be associated with patients reporting more problems on Scale 4: Administrative tasks. CONCLUSION Results imply a consistent trend of clearly neurocognitively impaired patients underreporting problems with IADL compared to their proxies. It would therefore be advised to administer both the patient- and proxy-version of the EORTC IADL-BN32, particularly if neurocognitive deficits are presumed.

Neuropsychological test scores in people with MS (PwMS) do not fully reflect cognitive functioning in daily life. Therefore, we developed a questionnaire based on instrumental activities of daily living (IADL), using the Amsterdam IADL-Q© for Alzheimer’s disease as starting point. Forty-eight items were evaluated on relevance and clarity by (inter)national experts (n = 30), PwMS (n = 61) and proxies (n = 30). Consequently, four items were omitted, two items were merged and seven items were added. Fifty items were included in the IADL questionnaire specific to cognitive functioning in MS (the MS-IADL-Q). Future studies are warranted to assess the psychometric properties of the MS-IADL-Q.

Background: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. Objectives: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. Design, Setting, Participants: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). Measurements: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. Results: Independent of Aß status, participants were more likely to report ‘Yes’ or ‘Maybe’ compared to the study partners for nearly all CFI items. Older age (r= 0.06, p

ObjectiveTo investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.MethodsIndividuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a “placebo” and “treatment” group and subsequently computed group differences on the CDR–sum of boxes (CDR-SB), Alzheimer’s Disease Assessment Scale–cognitive subscale–13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.ResultsIndividual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).ConclusionsIndividuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.

Impairment in instrumental activities of daily living (IADL) is an early clinical feature of Alzheimer's disease (AD). The neurobiology underlying IADL disruptions is still unclear. We aimed to investigate the relationship between IADL functioning and cortical atrophy across the AD spectrum. We selected 162 memory-clinic subjects with subjective cognitive decline (n = 49), mild cognitive impairment (n = 26) or AD dementia (n = 87), and an available structural MRI acquired at 3.0 Tesla and Amsterdam IADL Questionnaire (A-IADL-Q) assessment. We used linear regression correcting for age, sex, education, vascular injuries, and total intracranial volume to investigate the association between gray matter volume and A-IADL-Q score, and voxel-based morphometry to investigate whether any associations were specific for distinct regions. Less gray matter volume was associated with lower A-IADL-Q scores (β = 0.346, 95% CI = [0.185-0.507], p < 0.001), specifically in cortical regions covering the medial temporal lobes, cingulate cortex, and precuneus (all p(familywise error–corrected) < 0.05). Results were similar when repeating the analyses in amyloid-positive subjects (n = 78). Our findings illustrate that the A-IADL-Q detects functional impairment related to AD-specific neurodegeneration.

Self-perceived word-finding difficulties are common in aging individuals as well as in Alzheimer's Disease (AD). Language and speech deficits are difficult to objectify with neuropsychological assessments. We therefore aimed to investigate whether amyloid, an early AD pathological hallmark, is associated with speech-derived semantic complexity. We included 63 individuals with subjective cognitive decline (age 64 ± 8, MMSE 29 ± 1), with amyloid status (positron emission tomography [PET] scans n = 59, or Aβ1-42 cerebrospinal fluid [CSF] n = 4). Spontaneous speech was recorded using three open-ended tasks (description of cookie theft picture, abstract painting and a regular Sunday), transcribed verbatim and subsequently, linguistic parameters were extracted using T-scan computational software, including specific words (content words, frequent, concrete and abstract nouns, and fillers), lexical complexity (lemma frequency, Type-Token-Ratio) and syntactic complexity (Developmental Level scale). Nineteen individuals (30%) had high levels of amyloid burden, and there were no differences between groups on conventional neuropsychological tests. Using multinomial regression with linguistic parameters (in tertiles), we found that high amyloid burden is associated with fewer concrete nouns (ORmiddle (95%CI): 7.6 (1.4–41.2), ORlowest: 6.7 (1.2–37.1)) and content words (ORlowest: 6.3 (1.0–38.1). In addition, we found an interaction for education between high amyloid burden and more abstract nouns. In conclusion, high amyloid burden was modestly associated with fewer specific words, but not with syntactic complexity, lexical complexity or conventional neuropsychological tests, suggesting that subtle spontaneous speech deficits might occur in preclinical AD.

Objectives The fraction of the population that reaches the age of 100 years is growing. At this age, dementia incidence is high and cognitive functioning is highly variable across individuals. Normative data for neuropsychological tests are lacking in centenarians, which hampers the ability to evaluate their cognitive functioning for both research and clinical practice. Here, we generated norms for neuropsychological tests in a sample of cognitively healthy centenarians while taking sensory impairments into account. Design Cross-sectional cohort study. Setting Centenarians who participate in the prospective 100-plus Study. Participants A total of 235 centenarians (71.5% female), who self-reported to be cognitively healthy, which was confirmed by an informant and a trained researcher. Measurements We generated normative data for 15 cognitive tests, measuring global cognition (Mini-Mental State Examination [MMSE]), premorbid intelligence, attention, language, memory, executive function, and visuospatial function by multiple linear regressions and/or by reporting percentiles. Results Normative data for global cognition resulted in a mean MMSE score of 25.6 ± 3.1 (range = 17-30; interquartile range = 24-28). Vision problems and fatigue often complicated the ability to complete tests, and these problems explained 41% and 22% of the missing test scores, respectively. In contrast, hearing problems (4%) and task incomprehension (6%) rarely complicated test performance. While educational level was associated with performance on the majority of the tests, sex and age were only weakly associated with test performance. Conclusions We generated normative data for 15 common neuropsychological tests in a large sample of cognitively healthy centenarians, while taking age-related sensory impairments into consideration. These normative data allow the detection of deficits across a wide range of cognitive domains. Our results suggest that, next to education level, vision ability and the level of fatigue should be taken into account when evaluating cognitive functioning in centenarians. J Am Geriatr Soc 67:759-767, 2019.

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.

© 2020 The Author(s)Frontotemporal dementia (FTD) is a neurodegenerative disease that presents with profound changes in social cognition. Music might be a sensitive probe for social cognition abilities, but underlying neurobiological substrates are unclear. We performed a meta-analysis of voxel-based morphometry studies in FTD patients and functional MRI studies for music perception and social cognition tasks in cognitively normal controls to identify robust patterns of atrophy (FTD) or activation (music perception or social cognition). Conjunction analyses were performed to identify overlapping brain regions. In total 303 articles were included: 53 for FTD (n = 1153 patients, 42.5% female; 1337 controls, 53.8% female), 28 for music perception (n = 540, 51.8% female) and 222 for social cognition in controls (n = 5664, 50.2% female). We observed considerable overlap in atrophy patterns associated with FTD, and functional activation associated with music perception and social cognition, mostly encompassing the ventral language network. We further observed overlap across all three modalities in mesolimbic, basal forebrain and striatal regions. The results of our meta-analysis suggest that music perception and social cognition share neurobiological circuits that are affected in FTD. This supports the idea that music might be a sensitive probe for social cognition abilities with implications for diagnosis and monitoring.

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.

© 2021 American Medical Association. All rights reserved.Importance: Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging. Objective: To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology. Design, Setting, and Participants: This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020. Exposures: Age, sex, APOE ϵ genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-β, neurofibrillary tangles, and neuritic plaques). Main Outcomes and Measures: In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology. Results: Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (β, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P

Purpose To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. Methods Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer’s disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. Results In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The ‘alcoholic beverages’ PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. Conclusion In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

Contains fulltext : 242557.pdf (Publisher’s version ) (Open Access) 2 p.

Objective:To propose a set of internationally harmonized procedures and methods for assessing neurocognitive functions, smell, taste, mental, and psychosocial health, and other factors in adults formally diagnosed with COVID-19 (confirmed as SARS-CoV-2 + WHO definition).Methods:We formed an international and cross-disciplinary NeuroCOVID Neuropsychology Taskforce in April 2020. Seven criteria were used to guide the selection of the recommendations’ methods and procedures: (i) Relevance to all COVID-19 illness stages and longitudinal study design; (ii) Standard, cross-culturally valid or widely available instruments; (iii) Coverage of both direct and indirect causes of COVID-19-associated neurological and psychiatric symptoms; (iv) Control of factors specifically pertinent to COVID-19 that may affect neuropsychological performance; (v) Flexibility of administration (telehealth, computerized, remote/online, face to face); (vi) Harmonization for facilitating international research; (vii) Ease of translation to clinical practice.Results:The three proposed levels of harmonization include a screening strategy with telehealth option, a medium-size computerized assessment with an online/remote option, and a comprehensive evaluation with flexible administration. The context in which each harmonization level might be used is described. Issues of assessment timelines, guidance for home/remote assessment to support data fidelity and telehealth considerations, cross-cultural adequacy, norms, and impairment definitions are also described.Conclusions:The proposed recommendations provide rationale and methodological guidance for neuropsychological research studies and clinical assessment in adults with COVID-19. We expect that the use of the recommendations will facilitate data harmonization and global research. Research implementing the recommendations will be crucial to determine their acceptability, usability, and validity.

Background: Heightened public awareness about Alzheimer's disease and dementia increases the need for at-home cognitive self-testing. We offered Cognitive Online Self-Test Amsterdam (COST-A) to independent groups of cognitively normal adults and investigated the robustness of a norm-score formula and cutoff. Methods: Three thousand eighty-eight participants (mean age ± standard deviation = 61 ± 12 years, 70% female) completed COST-A and evaluated it. Demographically adjusted norm scores were the difference between expected COST-A scores, based on age, gender, and education, and actual scores. We applied the resulting norm-score formula to two independent cohorts. Results: Participants evaluated COST-A to be of adequate difficulty and duration. Our norm-score formula was shown to be robust: ≈8% of participants in two cognitively normal cohorts had abnormal scores. A cutoff of -1.5 standard deviations proved optimal for distinguishing normal from impaired cognition. Conclusion: With robust norm scores, COST-A is a promising new tool for research and clinical practice, providing low cost and minimally invasive remote assessment of cognitive functioning.

Introduction The Dutch Brain Research Registry aims to facilitate online recruitment of participants for brain disease studies. Methods Registrants were primarily recruited through an online social media campaign. The registration process included a short questionnaire, which was subsequently used in the prescreening process to match participants to studies. Results In the first 18 months, 17,218 registrants signed up (58±11 years old, 78% female). Out of 34,696 study invitations that were sent, 36% were accepted by registrants, of which 50% to 84% were finally enrolled, resulting in 10,661 participants in 28 studies. Compared to non‐participants, study participants were more often older, male, more highly educated, retired or unemployed, non‐smoking, healthier, and more often had a family member with dementia. Discussion The Dutch Brain Research Registry facilitates effective matching of participants to brain disease studies. Participant factors related to study enrollment may reflect facilitators or barriers for participation, which is useful for improving recruitment strategies.

Key Points Question How does lack of awareness (anosognosia) of memory impairment evolve in the Alzheimer disease (AD) trajectory? Findings In this cohort study of 2379 members of the Alzheimer’s Prevention Initiative Registry with a presenilin (PSEN1 E280A) variant for autosomal dominant AD, awareness of memory function was increased in carriers and noncarriers approximately 14 years before their estimated median age of dementia onset (49 years). In variant carriers only, awareness of memory function was reduced in the predementia stages, reaching anosognosia 6 years before dementia onset. Meaning The findings suggest that alteration of awareness of memory function in predementia stages may inform practitioners about AD progression., Importance Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. Objective To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. Design, Setting, and Participants This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer’s Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Main Outcomes and Measures Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. Results This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P, This cohort study investigates the evolution of anosognosia of memory decline in individuals with the PSEN1 E280A variant for autosomal dominant Alzheimer disease compared with family members without the variant.