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Background: Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in older people without dementia is mixed. Embedded in the World-Wide FINGERS initiative, FINGER-NL aims to investigate the effectiveness of a 2-year multidomain lifestyle intervention on cognitive functioning in older Dutch at risk individuals. Methods: Multi-center, randomized, controlled, multidomain lifestyle intervention trial with a duration of 24 months. 1210 adults between 60–79 years old with presence of ≥ 2 modifiable risk factors and ≥ 1 non-modifiable risk factor for cognitive decline were recruited between January 2022 and May 2023 via the Dutch Brain Research Registry and across five study sites in the Netherlands. Participants were randomized to either a high-intensity or a low-intensity intervention group. The multidomain intervention comprises a combination of 7 lifestyle components (physical activity, cognitive training, cardiovascular risk factor management, nutritional counseling, sleep counseling, stress management, and social activities) and 1 nutritional product (Souvenaid®) that could help maintain cognitive functioning. The high-intensity intervention group receives a personalized, supervised and hybrid intervention consisting of group meetings (on-site and online) and individual sessions guided by a trained lifestyle coach, and access to a digital intervention platform that provides custom-made training materials and selected lifestyle apps. The low-intensity intervention group receives bi-monthly online lifestyle-related health advice via the digital intervention platform. Primary outcome is 2-year change on a cognitive composite score covering processing speed, executive function, and memory. Results: Within 17 months, participant recruitment has been successfully completed (N = 1210; mean age: 67.7 years (SD: 4.6); 64% female). Modifiable risk factors commonly present at baseline were physical inactivity (89%), low mental/cognitive activity (50%), low social engagement (39%), hypertension (39%) and high alcohol consumption (39%). The mean body mass index of participants was 28.3 (SD: 4.2) and the total serum cholesterol was 5.4 mmol/L (SD: 1.2). Conclusions: Baseline lifestyle and clinical measurements showed successful recruitment of participants with sufficient potential for prevention. Results of FINGER-NL will provide further insight into the efficacy of a multidomain lifestyle intervention to prevent cognitive decline in older adults. Trial registration: ClinicalTrials.gov (ID: NCT05256199)/2022–01-11. [ABSTRACT FROM AUTHOR]

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. Diagnostic group differences were investigated using chi-square tests or one-way ANOVAs. Next, a subsample (N = 12; 8 = CN, 4 = MCI) participated in focus groups to gain in-depth insight into their opinions on optimizing trial design from a participants' point of view. Audio recordings from focus group interviews were transcribed verbatim and analyzed by thematic content analysis by two independent researchers. Results: Most reported motives for enrolment included "to benefit future generations" (89%), followed by "for science" (66%) and "better monitoring" (42%). Frequent suggestions for increasing willingness to participate included a smaller chance to receive placebo (n = 38, 54%), shorter travel times (n = 27, 38%), and sharing individual results of different assessments (n = 57, 80%), as well as receiving trial results (n = 52, 73). Highest visual analogue burden scores (0–100) were found for the lumbar puncture (M = 47.2, SD = 38.2) and cognitive assessments (M = 27.2, SD = 25.7). Results did not differ between diagnostic groups, nor between patient and caregiver participants (all p-values>.05). Two additional themes emerged from the focus groups: "trial 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. [ABSTRACT FROM AUTHOR]

Background: Everyday functioning is a clinically relevant concept in dementia, yet little is known about the clinical meaningfulness of scores on functional outcome measures. We aimed to establish clinically meaningful scoring categories for the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), representing no, mild, moderate and severe problems in daily functioning.Methods: Informal caregivers (n = 6) of memory-clinic patients and clinicians (n = 13), including neurologists and nurse specialists, working at various memory clinics in The Netherlands. In focus groups, participants individually ranked nine summaries of fictional patients from least to most impairment in daily functioning. Then, they placed bookmarks to demarcate the thresholds for mild, moderate and severe problems. Individual bookmark placements were then discussed to reach consensus. Clinicians completed a survey in which they placed bookmarks, individually.Results: While individual categorizations varied somewhat, caregivers and clinicians generally agreed on the thresholds, particularly about the distinction between 'no' and 'mild' problems. Score categories were no problems (T-score ≥ 60), mild problems (T-score 50-59), moderate problems (T-score 40-49), and severe problems in daily functioning (T-score < 40), on a scale ranging 20-80.Conclusions: Our findings provide categories for determining the level of functional impairment, which can facilitate interpretation of A-IADL-Q scores. These categories can subsequently be used by clinicians to improve communication with patients and caregivers. [ABSTRACT FROM AUTHOR]

Aims: A clinical frontal lobe syndrome (FLS) is generally attributed to functional or structural disturbances within frontal-subcortical circuits. We studied the distribution of pathological brain changes in FLS. Additionally, the prevalence of FLS among various disorders was studied. Methods: We systematically screened clinical files of donors to the Netherlands Brain Bank (n = 2,814) for FLS. A total of 262 FLS cases were identified, and the distribution of postmortem pathological changes within the frontal-subcortical circuits was extracted from their neuropathological reports. Results: In 244 out of 262 patients (93%), pathological changes within the frontal-subcortical circuits were found: 90 subjects (34%) with frontal cortical pathology and 18 (7%) with pathology restricted to subcortical grey matter nuclei, whereas 136 subjects (52%) showed both cortical and subcortical pathology. In 18 subjects (7%), no pathology was found in the examined areas. The prevalence of FLS was highest in frontal-temporal lobar degeneration, followed by progressive supranuclear palsy and vascular dementia [χ2(6, n = 1,561) = 222.64, p < 0.01]. Conclusion: In this large brain bank study, the distribution of pathological changes in subjects with FLS was shown to be frontal-subcortical for the first time. A minority of FLS cases had pathology in the subcortical regions only or no frontal pathology at all. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is well validated and commonly used to assess difficulties in everyday functioning regarding dementia. To facilitate interpretation and clinical implementation across different European countries, we aim to provide normative data and a diagnostic cutoff for dementia., Methods: Cross-sectional data from Dutch Brain Research Registry ( N = 1,064; mean ( M ) age = 62 ± 11 year; 69.5% female), European Medial Information Framework-Alzheimer's Disease 90 + ( N = 63; Mage = 92 ± 2 year; 52.4% female), and European Prevention of Alzheimer's Dementia Longitudinal Cohort Study ( N = 247; Mage = 63 ± 7 year; 72.1% female) were used. The generalized additive models for location, scale, and shape framework were used to obtain normative values ( Z -scores). The beta distribution was applied, and combinations of age, sex, and educational attainment were modeled. The optimal cutoff for dementia was calculated using area under receiver operating curves (AUC-ROC) and Youden Index, using data from Amsterdam Dementia Cohort ( N = 2,511, Mage = 64 ± 8 year, 44.4% female)., Results: The best normative model accounted for a cubic-like decrease of IADL performance with age that was more pronounced in low compared to medium/high educational attainment. The cutoff for dementia was 1.85 standard deviation below the population mean (AUC = 0.97; 95% CI [0.97-0.98])., Conclusion: We provide regression-based norms for A-IADL-Q and a diagnostic cutoff for dementia, which help improve clinical assessment of IADL performance across European countries.

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 < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: β, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: β, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline., Conclusions and Relevance: While we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.

As nutrition is one of the modifiable risk factors for cognitive decline, we studied the relationship between dietary quality and clinical characteristics in cognitively normal individuals with subjective cognitive decline (SCD). We included 165 SCD subjects (age: 64 ± 8 years; 45% female) from the SCIENCe project, a prospective memory clinic based cohort study on SCD. The Dutch Healthy Diet Food Frequency Questionnaire (DHD-FFQ) was used to assess adherence to Dutch guidelines on vegetable, fruit, fibers, fish, saturated fat, trans fatty acids, salt and alcohol intake (item score 0-10, higher score indicating better adherence). We measured global cognition (Mini Mental State Examination), cognitive complaints (Cognitive Change Index self-report; CCI) and depressive symptoms (Center for Epidemiologic Studies Depression Scale; CES-D). Using principal component analysis, we identified dietary components and investigated their relation to clinical characteristics using linear regression models adjusted for age, sex and education. We identified three dietary patterns: (i) "low-Fat-low-Salt", (ii) "high-Veggy", and (iii) "low-Alcohol-low-Fish". Individuals with lower adherence on "low-Fat-low-Salt" had more depressive symptoms (β -0.18 (-2.27--0.16)). Higher adherence to "high-Veggy" was associated with higher MMSE scores (β 0.30 (0.21-0.64)). No associations were found with the low-Alcohol-low-Fish component. We showed that in SCD subjects, dietary quality was related to clinically relevant outcomes. These findings could be useful to identify individuals that might benefit most from nutritional prevention strategies to optimize brain health.

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., (© 2018 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.)

Although the incidence of dementia increases exponentially with age, some individuals reach more than 100 years with fully retained cognitive abilities. To identify the characteristics associated with the escape or delay of cognitive decline, we initiated the 100-plus Study ( www.100plus.nl ). The 100-plus Study is an on-going prospective cohort study of Dutch centenarians who self-reported to be cognitively healthy, their first-degree family members and their respective partners. We collect demographics, life history, medical history, genealogy, neuropsychological data and blood samples. Centenarians are followed annually until death. PET-MRI scans and feces donation are optional. Almost 30% of the centenarians agreed to post-mortem brain donation. To date (September 2018), 332 centenarians were included in the study. We analyzed demographic statistics of the first 300 centenarians (25% males) included in the cohort. Centenarians came from higher socio-economic classes and had higher levels of education compared to their birth cohort; alcohol consumption of centenarians was similar, and most males smoked during their lifetime. At baseline, the centenarians had a median MMSE score of 25 points (IQR 22.0-27.5); most centenarians lived independently, retained hearing and vision abilities and were independently mobile. Mortality was associated with cognitive functioning: centenarians with a baseline MMSE score ≥ 26 points had a mortality percentage of 17% per annual year  in the second year after baseline, while centenarians with a baseline MMSE score < 26 points had a mortality of  42% per annual year (p = 0.003). The cohort was 2.1-fold enriched with the neuroprotective APOE-ε2 allele relative to 60-80 year-old population controls (p = 4.8 × 10 -7 ), APOE-ε3 was unchanged and the APOE-ε4 allele was 2.3-fold depleted (p = 6.3 × 10 -7 ). Comprehensive characterization of the 100-plus cohort of cognitively healthy centenarians might reveal protective factors that explain the physiology of long-term preserved cognitive health.

Objective: Early differentiation between psychiatric disorders and behavioral variant frontotemporal dementia (bvFTD) is of paramount importance in patients with the late-onset frontal lobe syndrome. As bvFTD in patients will deteriorate, psychiatric disorders are treatable. To date, misdiagnosis often occurs due to an overlap of symptoms and lack of specific biomarkers. The aim of our study was to investigate whether specific symptoms could separate bvFTD from psychiatric disorders., Methods: In a naturalistic, prospective, multicenter study, 137 patients (aged 45-75 years, 72% male) with a late-onset frontal lobe syndrome were included based on their scores on the Frontal Behavioral Inventory (FBI) and the Stereotypy Rating Inventory (SRI) from April 2011 to June 2013. In a multidisciplinary consensus meeting, diagnoses were established based on elaborate neuropsychological testing, magnetic resonance imaging, fludeoxyglucose F 18 positron emission tomography, cerebrospinal fluid biomarkers, and clinical examination by a neurologist and a psychiatrist based on the International bvFTD Criteria Consortium for bvFTD and DSM-IV-TR criteria for psychiatric disorders., Results: Forty-four subjects (32.8%) were diagnosed with a psychiatric disorder, 10 (7.3%) with possible bvFTD, and 45 (32.8%) with probable bvFTD. A logistic regression analysis was performed with "psychiatry or bvFTD" as dependent variable and clinical variables (Montgomery-Asberg Depression Rating Scale [MADRS], SRI, FBI) and demographics as independent variables. A positive history of psychiatric illness, male gender, lower SRI scores and higher MADRS scores were predictive of psychiatric disorders, explaining 65.2% of the variance in diagnosis of psychiatry versus bvFTD (χ²₅ = 60.04, P < .001). On the FBI, symptom level verbal apraxia/aphasia and impulsivity were predictive of bvFTD, whereas irritability was predictive of psychiatric disorders., Conclusions: In daily clinical practice, specific subtyping of clinical symptoms in patients with late-onset frontal lobe syndrome may aid in differentiating bvFTD patients from psychiatric patients and may provide guidance in patient management., (© Copyright 2016 Physicians Postgraduate Press, Inc.)