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Cerebral small vessel disease (CSVD) is considered as one of the main causes of cognitive decline and dementia. However, despite extensive research, the pathogenesis of CSVD and the mechanisms through which CSVD leads to its clinical manifestations remain largely unclear. The challenging in vivo quantification of CSVD hampers progress in further unraveling the pathogenesis and pathophysiology of CSVD. Currently, markers of CSVD are mainly brain abnormalities attributed to CSVD, but these are limited in reflecting morphological and functional changes of the microvasculature. We describe aspects of CSVD that are reflected by currently used techniques and those that are still insufficiently captured.

BACKGROUND: Low serum sodium may be associated with cognitive impairment and dementia in the general population, but the data remain inconclusive. Therefore, we aimed to determine the association of low serum sodium with cognitive function and incident dementia in the general population. METHODS: Participants from a prospective population-based cohort were eligible if data on serum sodium (collected between 1997 and 2008), dementia prevalence and dementia incidence were available (follow-up until 2018). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE) and the general cognitive factor (G-factor, derived from principal component analysis of individual tests). Linear regression and Cox proportional-hazards models were used to assess associations of standardised continuous and categorised low serum sodium (mean - 1.96*SD: cut-off of 137 mmol/L) with overall cognitive function and incident dementia, respectively. RESULTS: In all, 8,028 participants free of dementia at baseline (mean age 63.6 years, 57% female, serum sodium 142 ± 2 mmol/L), including 217 participants with low serum sodium, were included. Cross-sectionally, continuous serum sodium and/or low serum sodium were not associated with the MMSE or G-factor. However, participants with low serum sodium performed worse on the Stroop and Purdue Pegboard tests. During a median follow-up of 10.7 years, 758 subjects developed dementia. Continuous serum sodium (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.92;1.05) and low serum sodium (HR 1.27, 95% CI 0.90;1.79) were not associated with a higher risk of incident dementia. CONCLUSION: We identified no significant associations of low serum sodium with overall cognitive functioning and risk of dementia. However, low serum sodium-including levels above the clinical cut-off for hyponatremia-was associated with impairments in selected cognitive domains including attention and psychomotor function.

BACKGROUND AND OBJECTIVES: Low bone mineral density (BMD) and dementia commonly co-occur in older individuals, with bone loss accelerating in patients with dementia due to physical inactivity and poor nutrition. However, uncertainty persists over the extent to which bone loss already exists before onset of dementia. Therefore, we investigated how dementia risk was affected by BMD at various skeletal regions in community-dwelling older adults. METHODS: In a prospective population-based cohort study, BMD at the femoral neck, lumbar spine, and total body and the trabecular bone score (TBS) were obtained using dual-energy X-ray absorptiometry in 3,651 participants free from dementia between 2002 and 2005. Persons at risk of dementia were followed up until January 1, 2020. For analyses of the association between BMD at baseline and the risk of incident dementia, we used Cox proportional hazards regression analyses, adjusting for age, sex, educational attainment, physical activity, smoking status, body mass index, systolic and diastolic blood pressure, cholesterol level, high-density lipoprotein cholesterol, history of comorbidities (stroke and diabetes mellitus), and APOE genotype. RESULTS: Among the 3,651 participants (median age 72.3 ± 10.0 years, 57.9% women), 688 (18.8%) developed incident dementia during a median of 11.1 years, of whom 528 (76.7%) developed Alzheimer disease (AD). During the whole follow-up period, participants with lower BMD at the femoral neck (per SD decrease) were more likely to develop all-cause dementia (hazard ratio [HR] total follow-up 1.12, 95% CI 1.02-1.23) and AD (HRtotal follow-up 1.14, 95% CI 1.02-1.28). Within the first 10 years after baseline, the risk of dementia was greatest for groups with the lowest tertile of BMD (femoral neck BMD, HR0-10 years 2.03; 95% CI 1.39-2.96; total body BMD, HR0-10 years 1.42; 95% CI 1.01-2.02; and TBS, HR0-10 years 1.59; 95% CI 1.11-2.28). DISCUSSION: In conclusion, participants with low femoral neck

Introduction: We determined associations of total and regional adiposity with incident dementia among older adults. Methods: Within the population-based Rotterdam Study, adiposity was measured as total, android, and gynoid fat mass using dual-energy X-ray absorptiometry in 3408 men and 4563 women, every 3 to 6 years between 2002 and 2016. Incident dementia was recorded until 2020. Results: Higher adiposity measures were associated with a decreased risk of dementia in both sexes. After excluding the first 5 years of follow-up, only the association of gynoid fat among women remained significant (hazard ratio 0.85 [95% confidence interval 0.75–0.97] per standard deviation increase). No major differences in trajectories of adiposity measures were observed between dementia cases and dementia-free controls. Discussion: Higher total and regional fat mass related to a decreased risk of dementia. These results may be explained by reverse causality, although a protective effect of adiposity cannot be excluded. Highlights: Total and regional adiposity were assessed using dual-energy X-ray absorptiometry scans in 7971 older adults. All adiposity measures were associated with a decreased risk of dementia. The results suggest a beneficial effect of gynoid fat on the risk of dementia in women. Reverse causation and competing risk may explain these inverse associations.

Introduction: We determined associations of total and regional adiposity with incident dementia among older adults. Methods: Within the population-based Rotterdam Study, adiposity was measured as total, android, and gynoid fat mass using dual-energy X-ray absorptiometry in 3408 men and 4563 women, every 3 to 6 years between 2002 and 2016. Incident dementia was recorded until 2020. Results: Higher adiposity measures were associated with a decreased risk of dementia in both sexes. After excluding the first 5 years of follow-up, only the association of gynoid fat among women remained significant (hazard ratio 0.85 [95% confidence interval 0.75–0.97] per standard deviation increase). No major differences in trajectories of adiposity measures were observed between dementia cases and dementia-free controls. Discussion: Higher total and regional fat mass related to a decreased risk of dementia. These results may be explained by reverse causality, although a protective effect of adiposity cannot be excluded. Highlights: Total and regional adiposity were assessed using dual-energy X-ray absorptiometry scans in 7971 older adults. All adiposity measures were associated with a decreased risk of dementia. The results suggest a beneficial effect of gynoid fat on the risk of dementia in women. Reverse causation and competing risk may explain these inverse associations.

Background: Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been linked to a decreased risk of dementia, but reverse causality and residual confounding by lifestyle may partly account for this link. We aimed to address these issues by studying the associations over cumulative time periods, which may provide insight into possible reverse causality, and by using both historical and more contemporary dietary data as this could give insight into confounding since historical data may be less affected by lifestyle factors. Methods: In the population-based Rotterdam Study, dietary intake was assessed using validated food frequency questionnaires in 5375 participants between 1989 and 1993 (baseline I) and in a largely non-overlapping sample in 2861 participants between 2009 and 2013 (baseline II). We calculated the MIND diet score and studied its association with the risk of all-cause dementia, using Cox models. Incident all-cause dementia was recorded until 2018. Results: During a mean follow-up of 15.6 years from baseline I, 1188 participants developed dementia. A higher MIND diet score at baseline I was associated with a lower risk of dementia over the first 7 years of follow-up (hazard ratio (HR) [95% confidence interval (CI)] per standard deviation (SD) increase, 0.85 [0.74, 0.98]), but associations disappeared over longer follow-up intervals. The mean follow-up from baseline II was 5.9 years during which 248 participants developed dementia. A higher MIND diet score at baseline II was associated with a lower risk of dementia over every follow-up interval, but associations slightly attenuated over time (HR [95% CI] for 7 years follow-up per SD increase, 0.76 [0.66, 0.87]). The MIND diet score at baseline II was more strongly associated with the risk of dementia than the MIND diet score at baseline I. Conclusion: Better adherence to the MIND diet is associated with a decreased risk of dementia within the first years of follow

Background: Various clinical studies have provided estimates of life expectancy of patients with mild cognitive impairment (MCI) from outpatient clinics, but whether these apply to community-dwelling individuals at home or in primary care is uncertain. Methods: Within the population-based Rotterdam Study, we studied life expectancy with and without dementia in 648 community-dwelling persons with MCI and 6410 without MCI. Participants aged 60 years and older were assessed for MCI at baseline (2002–2014) and subsequently followed for the onset of dementia and death. We used multistate life tables to determine age-specific life expectancy with and without dementia by sex, educational attainment, and MCI subtype. Results: Total life expectancy for MCI ranged from 21.4 years (95% CI: 19.0–23.6) at age 60 to 2.6 years (1.6–3.6) at age 95. With advancing age, an increasing proportion of these years was lived with dementia (2.9 years [1.8–4.0] at age 60; 1.2 [0.2–2.2] at age 95). Women and higher educated individuals lived longer and lived more years with dementia. No differences in total life expectancy were observed by MCI subtype, although individuals with amnestic MCI lived a larger proportion of those years with dementia. Conclusions: Prognosis of MCI, in terms of life years lived with and without dementia, is more favorable in the general population than described in prior clinical observations, due likely to a substantial proportion of individuals with MCI in the clinic not seeking medical attention in an earlier stage.

Seasonal variation in cognitive function and underlying cerebral hemodynamics in humans has been suggested, but not consistently shown in previous studies. We assessed cognitive function in 10,276 participants from the population-based Rotterdam Study, aged 45 years and older without dementia, at baseline and at subsequent visits between 1999 and 2016. Seasonality of five cognitive test scores and of a summary measure of global cognition were determined, as well as of brain perfusion. Using linkage with medical records, we also examined whether a seasonal variation was present in clinical diagnoses of dementia. We found a seasonal variation of global cognition (0.05 standard deviations [95% confidence interval: 0.02–0.08]), the Stroop reading task, the Purdue Pegboard test, and of the delayed world learning test, with the best performance in summer months. In line with these findings, there were fewer dementia diagnoses of dementia in spring and summer than in winter and fall. We found no seasonal variation in brain perfusion. These findings support seasonality of cognition, albeit not explained by brain perfusion.

Background: Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet has been linked to a decreased risk of dementia, but reverse causality and residual confounding by lifestyle may partly account for this link. We aimed to address these issues by studying the associations over cumulative time periods, which may provide insight into possible reverse causality, and by using both historical and more contemporary dietary data as this could give insight into confounding since historical data may be less affected by lifestyle factors. Methods: In the population-based Rotterdam Study, dietary intake was assessed using validated food frequency questionnaires in 5375 participants between 1989 and 1993 (baseline I) and in a largely non-overlapping sample in 2861 participants between 2009 and 2013 (baseline II). We calculated the MIND diet score and studied its association with the risk of all-cause dementia, using Cox models. Incident all-cause dementia was recorded until 2018. Results: During a mean follow-up of 15.6 years from baseline I, 1188 participants developed dementia. A higher MIND diet score at baseline I was associated with a lower risk of dementia over the first 7 years of follow-up (hazard ratio (HR) [95% confidence interval (CI)] per standard deviation (SD) increase, 0.85 [0.74, 0.98]), but associations disappeared over longer follow-up intervals. The mean follow-up from baseline II was 5.9 years during which 248 participants developed dementia. A higher MIND diet score at baseline II was associated with a lower risk of dementia over every follow-up interval, but associations slightly attenuated over time (HR [95% CI] for 7 years follow-up per SD increase, 0.76 [0.66, 0.87]). The MIND diet score at baseline II was more strongly associated with the risk of dementia than the MIND diet score at baseline I. Conclusion: Better adherence to the MIND diet is associated with a decreased risk of dementia within the first years of foll

Importance: For informed decision making on diagnosis and treatment of dementia, physicians and their patients rely on the generalizability of evidence from published studies to clinical practice. However, it is uncertain whether everyday care of elderly patients with dementia is sufficiently captured in contemporary research. Objective: To systematically review contemporary dementia research in terms of study and patient characteristics in order to assess generalizability of research findings. Evidence Review: PubMed was searched for dementia studies published in the top 100 journals in the fields of neurology and neuroscience, geriatrics, psychiatry, and general medicine between September 1, 2018, and August 31, 2019. Two reviewers extracted study characteristics, including setting, number of participants, age at diagnosis, and use of biomarkers. Findings: Among 513 identified studies, 211 (41%) included fewer than 50 individuals with dementia and were excluded. The remaining 302 studies included a median (interquartile range) of 214 patients (98-628) with a mean (SD) age at diagnosis of 74.1 years (8.0). Age at diagnosis differed with study setting. Patients in the 180 clinic-based studies had a mean (SD) age of 71.8 (6.4) years at time of diagnosis compared with 80.6 (4.7) years among patients in the 79 population-based studies (mean difference, 8.8 years; 95% CI, 7.3-10.2). Use of magnetic resonance imaging, positron emission tomography imaging, and cerebrospinal fluid imaging was mostly done in clinic-based studies (80% to 96%) and consequently in relatively young patients (mean [SD] age, 71.6 [5.1] years). A longitudinal design was more common in population-based studies than in clinic-based studies (82 % vs 40%). Most studies originated from North America and Europe (89%), including almost exclusively White participants (among 74 studies [22%] reporting on ethnicity: median [interquartile range], 89% [78-97]). The 3