Effects of Eligibility Criteria on Patient Selection and Treatment Implications from 10 Multidomain Dementia Prevention Trials: A Population-Based Study.

INTRODUCTION: Dementia prevention trials have so far shown little benefit of multidomain interventions against cognitive decline. Recruitment strategies in these trials often centre around dementia risk or cardiovascular risk profile, but it is uncertain whether this leads to inclusion of individuals who may benefit most from the intervention. We determined the effects of eligibility criteria on the recruitment of potential trial participants in the general population. METHODS: In a systematic search until January 1, 2022, we identified all published and ongoing large (≥500 participants), phase-3 multidomain trials for the prevention of cognitive decline or dementia. We applied trial eligibility criteria to 5,381 participants of the population-based Rotterdam Study (mean age: 72 years, 58% women), to compare participant characteristics, predicted risk of cardiovascular disease, and dementia risk, between trial eligible and ineligible persons. RESULTS: We identified 10 trials, of which 5 had been published (DR's EXTRA, FINGER, preDIVA, MAPT, and HATICE) and 5 are ongoing (US-POINTER, MIND-CHINA, MYB, AgeWell.de, and J-Mint). Among all Rotterdam Study participants, eligibility across published trials ranged from 48% for MAPT to 87% for preDIVA, in line with original trial reports. Variability in eligibility was wider for ongoing trials, from 1% for US-POINTER to over 94% for MYB trial. Over 70% of trial eligible individuals are recommended preventive intervention in routine care based on their cardiovascular risk, similar for lipid-lowering (71%) and blood pressure-lowering treatment (73%). Ten-year risks of dementia were similar for eligible compared to ineligible individuals (12 vs. 11%). CONCLUSION: Multidomain dementia prevention trials fail to preferentially include those at the highest risk of dementia and mostly include individuals who qualify for interventions already on the basis of cardiovascular prevention guidelines. These findings call for better targeted enrolment of individuals for whom trial results can improve clinical decision-making.

Patient perspectives on telemedicine during the COVID-19 pandemic: a mixed-methods community-based study.

BACKGROUND: Detailed community-based perspectives on patient experiences with telemedicine are currently lacking, yet essential to assess clinical applicability of telemedicine during and beyond pandemics, alike COVID-19. The aim of this study was to expose patient perspectives on virtual compared to in-person consultations, including determinants of these preferences. METHODS: We invited 5864 participants of the population-based Rotterdam Study to fill in a validated questionnaire using both close-ended and free-text questions. The questionnaire was sent on 30 July 2020, following a period of lockdowns and closures of non-essential workplaces. It assessed preferences for physician contact, healthcare utilisation, socioeconomic factors, and overall health. Those who experienced at least one virtual consultation (telephone or video call) between March 2020 and the beginning of July 2020 were asked whether those consultations were more, equally or less pleasant than in-person consultations, and to detail their experiences through free-text comments. These narrative data were examined using thematic analysis. RESULTS: 4514 participants completed the questionnaire (response rate 77.0%, 58.7% women, mean age 70.8 ± 10.5 years). 1103 participants (24.4%) reported having had experience with virtual consultations. Half of these participants considered virtual consultations less pleasant than in-person consultations (N = 556; 50.4%), while 11.5% found it more pleasant. In total, we coded free-text comments of 752 participants. Prominent themes behind patient preferences for virtual or in-person consultations were lack of nonverbal communication, lack of physical examination, consultation scheduling, personal circumstances, and the presence of somatic and/or language barriers. CONCLUSIONS: Based on the experiences of a large elderly patient population, we showed that preference for virtual or in-person consultations is dependent on personal and situational variety, and their interplay. Healthcare providers should consider patients' complex care needs and evaluate the potential added value of nonverbal communication and physical examination before scheduling a virtual consultation.

Sex-specific patterns and lifetime risk of multimorbidity in the general population: a 23-year prospective cohort study.

BACKGROUND: Multimorbidity poses a major challenge for care coordination. However, data on what non-communicable diseases lead to multimorbidity, and whether the lifetime risk differs between men and women are lacking. We determined sex-specific differences in multimorbidity patterns and estimated sex-specific lifetime risk of multimorbidity in the general population. METHODS: We followed 6,094 participants from the Rotterdam Study aged 45 years and older for the occurrence of ten diseases (cancer, coronary heart disease, stroke, chronic obstructive pulmonary disease, depression, diabetes, dementia, asthma, heart failure, parkinsonism). We visualised participants' trajectories from a single disease to multimorbidity and the most frequent combinations of diseases. We calculated sex-specific lifetime risk of multimorbidity, considering multimorbidity involving only somatic diseases (1) affecting the same organ system, (2) affecting different organ systems, and (3) multimorbidity involving depression. RESULTS: Over the follow-up period (1993-2016, median years of follow-up 9.2), we observed 6334 disease events. Of the study population, 10.3% had three or more diseases, and 27.9% had two or more diseases. The most frequent pair of co-occurring diseases among men was COPD and cancer (12.5% of participants with multimorbidity), the most frequent pair of diseases among women was depression and dementia (14.9%). The lifetime risk of multimorbidity was similar among men (66.0%, 95% CI: 63.2-68.8%) and women (65.1%, 95% CI: 62.5-67.7%), yet the risk of multimorbidity with depression was higher for women (30.9%, 95% CI: 28.4-33.5%, vs. 17.5%, 95% CI: 15.2-20.1%). The risk of multimorbidity with two diseases affecting the same organ is relatively low for both sexes (4.2% (95% CI: 3.2-5.5%) for men and 4.5% (95% CI: 3.5-5.7%) for women). CONCLUSIONS: Two thirds of people over 45 will develop multimorbidity in their remaining lifetime, with women at nearly double the risk of multimorbidity involving depression than men. These findings call for programmes of integrated care to consider sex-specific differences to ensure men and women are served equally.

Prevalence and determinants of healthcare avoidance during the COVID-19 pandemic: A population-based cross-sectional study.

BACKGROUND: During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance. METHODS AND FINDINGS: On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19-specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population. CONCLUSIONS: In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.

Plasma tau, neurofilament light chain and amyloid-ß levels and risk of dementia; a population-based cohort study.

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-ß, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-ß40 and amyloid-ß42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-ß42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-ß42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-ß42 and lowest of NfL. Total-tau and amyloid-ß40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-ß42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-ß42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-ß42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.

Season of birth and the risk of dementia in the population-based Rotterdam Study.

Early-life environmental factors have been suggested in the pathophysiology of dementia. Season of birth has previously been used as a proxy for these external exposures. We investigated the link between season of birth and the risk of dementia and further explored underlying pathways by studying structural brain changes on MRI. From the Dutch, population-based Rotterdam Study, 12,964 participants born between 1887 and 1960 were followed between 1990 and 2018 for dementia. Cox regression was conducted to assess the association between season of birth and dementia. In addition, we distinguished between mild and cold winters. The association of season of birth with structural brain markers on MRI was examined in 5237 participants. The risk of dementia in participants born in winter and fall was higher than of those born in summer (hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.01-1.31] for winter and HR 1.17 [95% CI 1.01-1.33] for fall), especially for Alzheimer's disease (HR 1.23 [1.06-1.43] for winter and HR 1.15 [95% CI 0.99-1.35] for fall). The risk was particularly increased for participants born in a cold winter. Except for slightly lower hippocampus in fall born participants (ß - 0.03; 95% CI - 0.06 to 0.00), we did not find associations with brain imaging markers. In conclusion, winter and fall births were associated with a higher incidence of dementia, especially of AD. We did not find evidence for structural brain changes as an underlying mechanism.

Design, implementation and initial findings of COVID-19 research in the Rotterdam Study: leveraging existing infrastructure for population-based investigations on an emerging disease.

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown.

Variation in blood pressure and long-term risk of dementia: A population-based cohort study.

BACKGROUND: Variation in blood pressure may relate to dementia risk via autonomic disturbance or hemodynamic mechanisms, but the long-term associations are unclear. We aimed to determine whether blood pressure variation over a period of years, considering both magnitude and direction, is associated with the risk of dementia. METHODS AND FINDINGS: In a prospective cohort study ongoing since 1989 in the Netherlands, 5,273 dementia-free participants (58.1% women; mean [SD] age, 67.6 [8.0] years) were included. As of 2016, 1,059 dementia cases occurred during a median follow-up of 14.6 years. Absolute variation in systolic blood pressure (SBP) was assessed as the absolute difference in SBP divided by the mean over two sequential visits every 4.2 (median) years, with the first quantile set as the reference level. The direction was the rise or fall in SBP, with the third quantile set as the reference level. We estimated the risk of dementia in relation to SBP variation measured at different time windows (i.e., at least 0, 5, 10, and 15 years) prior to dementia diagnosis, with adjustments for age, sex, education, apolipoprotein E (APOE) genotype, vascular risk factors, and history of cardiovascular disease. We repeated the above analysis for variation in diastolic blood pressure (DBP). A large SBP variation was associated with an increased dementia risk, which became more pronounced with longer intervals between the assessment of SBP variation and the diagnosis of dementia. The hazard ratio (HR) associated with large variation (the highest quintile) increased from 1.08 (95% confidence interval [CI] 0.88-1.34, P = 0.337) for risk within 5 years of SBP variation measurement to 3.13 (95% CI 2.05-4.77; P < 0.001) for risk after at least 15 years since the measurement of SBP variation. The increased long-term risk was associated with both large rises (HR for the highest quintile, 3.31 [95% CI 2.11-5.18], P < 0.001) and large falls in SBP (HR for the lowest quintile, 2.20 [95% CI 1.33-3.63], P = 0.002), whereas the higher short-term risk was only associated with large falls in SBP (HR, 1.21 [95% CI 1.00-1.48], P = 0.017). Similar findings were observed for variation in DBP. Despite our assessment of major confounders, potential residual confounding is possible, and the findings on blood pressure variability over periods of years may not be generalizable to variability over periods of days and other shorter periods. CONCLUSIONS: Results of this study showed that a large blood pressure variation over a period of years was associated with an increased long-term risk of dementia. The association between blood pressure variation and dementia appears most pronounced when this variation occurred long before the diagnosis. An elevated long-term risk of dementia was observed with both a large rise and fall in blood pressure.

Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population: A population-based cohort study.

BACKGROUND: Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk. METHODS AND FINDINGS: Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (>90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent. CONCLUSIONS: Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs.

Balance between innate versus adaptive immune system and the risk of dementia: a population-based cohort study.

BACKGROUND: Immunity has been suggested to be important in the pathogenesis of dementia. However, the contribution of innate versus adaptive immunity in the development of dementia is not clear. In this study, we aimed to investigate (1) the association between components of innate immunity (granulocytes and platelets) and adaptive immunity (lymphocytes) with risk of dementia and (2) the association between their derived ratios (granulocyte-to-lymphocyte ratio [GLR], platelet-to-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII]), reflecting the balance between innate and adaptive immunity, with risk of dementia. METHODS: Blood cell counts were measured repeatedly between 2002 and 2015 in dementia-free participants of the prospective population-based Rotterdam Study. Participants were followed-up for dementia until 1 January 2016. Joint models were used to determine the association between granulocyte, platelets, and lymphocyte counts, and their derived ratios with risk of dementia. RESULTS: Of the 8313 participants (mean [standard deviation] age 61.1 [7.4] years, 56.9% women), 664 (8.0%) developed dementia during a median follow-up of 8.6 years. Doubling of granulocyte and platelet counts tended to be associated with an increased risk of dementia (HR [95%CI] 1.22 [0.89-1.67] and 1.45 [1.07-1.95], respectively). Doubling of the derived ratios GLR, PLR, and SII were all associated with an increased dementia risk (HR [95%CI] 1.26 [1.03-1.53], 1.27 [1.05-1.53], and 1.15 [0.98-1.34], respectively). CONCLUSIONS: GLR, PLR, and SII are associated with an increased risk of dementia in the general population. This supports the role of an imbalance in the immune system towards innate immunity in the pathogenesis of dementia.

Lifetime risk of common neurological diseases in the elderly population.

OBJECTIVE: To quantify the burden of common neurological disease in older adults in terms of lifetime risks, including their co-occurrence and preventive potential, within a competing risk framework. METHODS: Within the prospective population-based Rotterdam Study, we studied lifetime risk of dementia, stroke and parkinsonism between 1990 and 2016. Among 12 102 individuals (57.7% women) aged ≥45 years free from these diseases at baseline, we studied co-occurrence, and quantified the combined, and disease-specific remaining lifetime risk of these diseases at various ages for men and women separately. We also projected effects on lifetime risk of hypothetical preventive strategies that delay disease onset by 1, 2 and 3 years, respectively. RESULTS: During follow-up of up to 26 years (156 088 person-years of follow-up), 1489 individuals were diagnosed with dementia, 1285 with stroke and 263 with parkinsonism. Of these individuals, 438 (14.6%) were diagnosed with multiple diseases. Women were almost twice as likely as men to be diagnosed with both stroke and dementia during their lifetime. The lifetime risk for any of these diseases at age 45 was 48.2% (95% CI 47.1% to 51.5%) in women and 36.2% (35.1% to 39.3%) in men. This difference was driven by a higher risk of dementia as the first manifesting disease in women than in men (25.9% vs 13.7%; p<0.001), while this was similar for stroke (19.0%vs18.9% in men) and parkinsonism (3.3% vs 3.6% in men). Preventive strategies that delay disease onset with 1 to 3 years could theoretically reduce lifetime risk for developing any of these diseases by 20%-50%. CONCLUSION: One in two women and one in three men will develop dementia, stroke or parkinsonism during their life. These findings strengthen the call for prioritising the focus on preventive interventions at population level which could substantially reduce the burden of common neurological diseases in the ageing population.

Quantitative gait, cognitive decline, and incident dementia: The Rotterdam Study.

INTRODUCTION: Poor gait has recently emerged as a potential prodromal feature of cognitive decline and dementia. We assessed to what extent various aspects of poor gait are independently associated with cognitive decline and incident dementia. METHODS: We leveraged detailed quantitative gait (GAITRite™) and cognitive assessments in 4258 dementia-free participants (median age 67 years, 55% women) of the population-based Rotterdam Study (baseline 2009-2013). We summarized 30 gait parameters into seven mutually independent gait domains and a Global Gait score. Participants underwent follow-up cognitive assessments between 2014 and 2016 and were followed up for incident dementia until 2016 (median 4 years). RESULTS: Three independent gait domains (Base of Support, Pace, and Rhythm) and Global Gait were associated with cognitive decline. Two independent gait domains (Pace and Variability) and Global Gait were associated with incident dementia. Associations of gait with cognitive decline and incident dementia were only present in individuals who had been cognitively unimpaired at baseline. DISCUSSION: Poor performance on several independent gait domains precedes cognitive decline and incident dementia.

Subregional volumes of the hippocampus in relation to cognitive function and risk of dementia.

BACKGROUND: Total hippocampal volume has been consistently linked to cognitive function and dementia. Yet, given its complex and parcellated internal structure, the role of subregions of the hippocampus in cognition and risk of dementia remains relatively underexplored. We studied subregions of the hippocampus in a large population-based cohort to further understand their role in cognitive impairment and dementia risk. METHODS: We studied 5035 dementia- and stroke-free persons from the Rotterdam Study, aged over 45 years. All participants underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Automatic segmentation of the hippocampus and 12 of its subregions was performed using the FreeSurfer software (version 6.0). A cognitive test battery was performed, and participants were followed up for the development of dementia until 2015. Associations of hippocampal subregion volumes with cognition and incident dementia were examined using linear and Cox regression models, respectively. All analyses were adjusted for age, sex, education, and total hippocampal volume. RESULTS: Mean age was 64.3 years (SD 10.6) with 56% women. Smaller volumes of the hippocampal fimbria, presubiculum and subiculum showed the strongest associations with poor performance on several cognitive domains, including executive function but not memory. During a mean follow-up of 5.5 years, 76 persons developed dementia. Smaller subiculum volume was associated with risk of dementia adjusted for total volume (hazard ratio per SD decrease in volume: 1.75, 95% confidence interval 1.35; 2.26). CONCLUSIONS: In a community-dwelling non-demented population, we describe patterns of association between hippocampal subregions with cognition and risk of dementia. Specifically, the subiculum was associated with both poorer cognition and higher risk of dementia.

External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study.

To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55 years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53-0.58) for CAIDE, 0.78 (0.76-0.81) for BDSI, 0.75 (0.74-0.77) for ANU-ADRI, and 0.81 (0.78-0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53-0.58) for CAIDE, 0.81 (0.78-0.83) for BDSI, 0.77 (0.75-0.79) for ANU-ADRI, and 0.81 (0.78-0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population.

Cognitive Impairment, Sexual Activity and Physical Tenderness in Community-Dwelling Older Adults: A Cross-Sectional Exploration.

BACKGROUND: The ability to engage in sexual activity and better cognitive functioning are both associated with better health. However, the association between cognitive functioning and sexual activity is understudied. OBJECTIVE: To examine the association between cognitive functioning with sexual activity and physical tenderness among community-dwelling older adults. METHODS: From the Rotterdam Study, cognitive impairment and sexual activity were assessed in 4,201 community-dwelling, 60+ year olds between 2008 and 2014 in the Netherlands. Mild cognitive impairment (MCI) was based upon subjective complaints related to age and education-adjusted test scores. Mini-Mental State Examination (MMSE) impairment was defined by a score of < 26. Sexual activity and physical tenderness (e.g., fondling or kissing) in the last 6 months were assessed at an interview. Analyses were stratified by gender and partner status, with prevalence rates for the "no impairment" categories weighted based on age from the cognitive impairment categories. Inter-rater reliability was examined utilising 74 cohabiting couples of opposite gender. RESULTS: It was found that 14% were categorised as having cognitive impairment, and < 1% as dementia (excluded from subsequent analyses). There was strong evidence that the odds of engaging in physical tenderness (observed through MMSE < 26, OR 2.14, 95% CI 1.32-3.48, p = 0.002) and sexual activity (MCI, OR 2.36, 95% CI 1.35-4.12, p = 0.003) among partnered females with no impairment was twice that observed among cognitively impaired partnered females. There was weak evidence that the odds of engaging in physical tenderness (MMSE < 26, OR 1.59, 95% CI 1.04-2.42, p = 0.03) and sexual activity (MMSE < 26, OR 1.51, 95% CI 1.02-2.24, p = 0.04) among partnered males with no impairment was 50% greater than observed among cognitively impaired partnered males. The associations between cognitive functioning and physical tenderness continued to remain after adjustment for physical function, diabetes, cardiovascular disease and cancer. There was no clear evidence of a difference between amnestic and non-amnestic MCI for sexual behaviour. There was moderate to substantial agreement among the coupled adults who had 1 partner categorised with MCI. CONCLUSION: Having no cognitive impairment was associated with more engagement in sexual activity and physical tenderness among community-dwelling older adults. Sexuality is an important aspect of active aging and our findings illustrate a potential barrier to maintaining or instigating intimate relationships as we age. Longitudinal analyses are required to explore the direction of effect.

Healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality: a longitudinal community-based study.

Background During the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health. Aim To determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality. Design and setting 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all non-institutionalised participants (response rate 73%). Method Cox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided healthcare because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records. Results Of 5656 respondents, one-fifth avoided healthcare due to the COVID-19 pandemic (N=1143). Compared to non-avoiders, those who avoided healthcare more often reported symptoms of depression (31.2% versus 12.3%) and anxiety (29.7% versus 12.2%), and more often valued their health as poor to fair (29.4% versus 10.1%). Healthcare avoiders had an increased adjusted risk of all-cause mortality (HR: 1.30; 95%CI 1.01-1.67), which remained nearly identical after adjustment for history of any non-communicable disease (1.20;0.93-1.54). However, this association attenuated after additional adjustment for mental and self-appreciated health factors (0.96;0.74-1.24). Conclusion We found an increased risk of all-cause mortality among individuals who avoided healthcare during COVID-19. These individuals were characterised by poor mental and physical self-appreciated health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care in order to limit health disparities, inside and beyond healthcare crises.

Seasonality of cognitive function in the general population: the Rotterdam Study.

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.

Life expectancy with and without dementia in persons with mild cognitive impairment in the community.

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.

Changes in the Diagnosis of Stroke and Cardiovascular Conditions in Primary Care During the First 2 COVID-19 Waves in the Netherlands.

BACKGROUND AND OBJECTIVES: Although there is evidence of disruption in acute cerebrovascular and cardiovascular care during the coronavirus disease 2019 (COVID-19) pandemic, its downstream effect in primary care is less clear. We investigated how the pandemic affected utilization of cerebrovascular and cardiovascular care in general practices (GPs) and determined changes in GP-recorded diagnoses of selected cerebrovascular and cardiovascular outcomes. METHODS: From electronic health records of 166,929 primary care patients aged 30 or over within the Rotterdam region, the Netherlands, we extracted the number of consultations related to cerebrovascular and cardiovascular care, and first diagnoses of selected cerebrovascular and cardiovascular risk factors (hypertension, diabetes, lipid disorders), conditions, and events (angina, atrial fibrillation, TIA, myocardial infarction, stroke). We quantified changes in those outcomes during the first COVID-19 wave (March-May 2020) and thereafter (June-December 2020) by comparing them to the same period in 2016-2019. We also estimated the number of potentially missed diagnoses for each outcome. RESULTS: The number of GP consultations related to cerebrovascular and cardiovascular care declined by 38% (0.62, 95% confidence interval 0.56-0.68) during the first wave, as compared to expected counts based on prepandemic levels. Substantial declines in the number of new diagnoses were observed for cerebrovascular events: 37% for TIA (0.63, 0.41-0.96) and 29% for stroke (0.71, 0.59-0.84), while no significant changes were observed for cardiovascular events (myocardial infarction [0.91, 0.74-1.14], angina [0.77, 0.48-1.25]). The counts across individual diagnoses recovered following June 2020, but the number of GP consultations related to cerebrovascular and cardiovascular care remained lower than expected throughout the June to December period (0.93, 0.88-0.98). DISCUSSION: While new diagnoses of acute cardiovascular events remained stable during the COVID-19 pandemic, diagnoses of cerebrovascular events declined substantially compared to prepandemic levels, possibly due to incorrect perception of risk by patients. These findings emphasize the need to improve symptom recognition of cerebrovascular events among the general public and to encourage urgent presentation despite any physical distancing measures.