Accurate dementia risk prediction is challenging, and may be facilitated by better use of imaging and genetic data, including their complex interactions. We explored using deep survival neural networks to integrate these multi-modal, high-dimensional data. We included 3521 Rotterdam Study participants, 6340 magnetic resonance imaging (MRI) scans, with follow-up clinical diagnosis for dementia, and used 504 samples from Alzheimer's Disease Neuroimaging Initiative (ADNI) as an external validation. Genetic data included APOE-ε4 status and 76 additional SNPs. We developed models combining Convolutional Neural Networks (CNN) and Cox Proportional Hazards (CPH) models and provided post-hoc explanations. Our models outperformed CPH models including age, sex, and genetic inputs in both Rotterdam Study and ADNI by C-index of 0.88/0.63 V.S. 0.85/0.58, p-value of 0.02/0.002. Although their performance did not surpass CPH models also included MRI markers (0.89/0.66), additional predictability was obtained in age-stratified prediction in ADNI. Incorporating CNN image features in CPH models further increased performance to highest C-index of 0.90/0.69. Age and image had the highest importance in prediction, with age, image and genetic features showing the strongest interactions. Our approach indicates that imaging and genetic data can be feasibly integrated for dementia risk prediction, with informative extraction, reliable explanations and potential predictive gains.

Higher Mediterranean- DASH for Neurodegenerative Delay (MIND) diet scores have previously been associated with larger total brain volume (TBV) in the Framingham Offspring Study (FOS) community-based cohort. We investigated cross-sectional relationships between the MIND diet and structural brain imaging volumes and white matter hyperintensity volume (WMHV) across six community-based cohorts. We analyzed data from 3130 dementia-, stroke- and other neurological disease free adults (aged 65 to 74) who participated in the Atherosclerosis Risk in Communities (ARIC) cohort, Cardiovascular Health Study (CHS), Three City (3C) cohort, FOS cohort, Rotterdam Study (RS) or the Study of Health in Pomerania (SHIP) cohort. Individuals completed a brain magnetic resonance imaging (MRI) scan, and a validated food frequency questionnaire (FFQ) (ARIC, CHS, FOS, RS), 24h dietary recall (3C), or an extensive food list (SHIP). The MIND diet consists of ten healthy (e.g. green leafy vegetables, berries and fish) and five unhealthy (e.g. cheese, red meat and products and fast fried foods) components. Outcomes from brain MRI included TBV, total grey matter volume (TGMV), hippocampal volume (HPV), and WMHV. We used multivariable linear regression to relate MIND diet adherence to the outcomes. Results were combined in meta-analysis using fixed effects and random effects models. Higher MIND diet scores (score range: 0-15) were associated with larger HPV (beta = 0.015, 95% confidence interval = 0.004 to 0.026, cm³ per one unit MIND diet score increase) after adjustment for age, age squared, sex, time from clinical exam to brain MRI exam, total intracranial volume and energy intake, but not with TBV, TGMV and WMHV. Heterogeneity between studies was low (I 2 = 0% TBV, TGMV, HPV) to moderate (I 2 = 44% WMHV). In cross-sectional analyses, higher MIND diet scores were associated with larger HPV, but not with other brain volume measures. It might be that HPV was a more sensitive marker of brain health in the populations under study. Future studies are encouraged to examine the associations between the MIND diet and amyloid and tau positron emission tomography (PET) imaging to elucidate whether a relationship between the MIND diet and dementia pathologies exists.

Hearing loss is considered a potentially modifiable risk factor for dementia. The sensory deprivation theory postulates that hearing loss adversely affects cognition in older adults through structural brain changes, but longitudinal studies are scarce. To find evidence for a possible detrimental effect of hearing loss on white matter microstructure, we carried out a longitudinal study in the population-based Rotterdam Study. A total of 1877 participants with a median age at baseline of 56.4 years (IQR: [52.2-60.0]) underwent audiometry and had longitudinal diffusion imaging data available with a mean follow-up of 4.0 years. A lower level of hearing acuity was associated with worse white matter microstructure in the left uncinate fasciculus and superior longitudinal fasciculus at baseline. Poorer hearing acuity was also associated with faster microstructural deterioration over time in the left superior longitudinal fasciculus. The strongest effects were observed for low-frequency hearing thresholds, while the high-frequency thresholds showed the weakest associations. These results suggest that hearing loss may contribute to the age-related decline in brain structure, consistent with the sensory deprivation theory.

INTRODUCTION:Physical activity is linked to lower dementia risk, but its connection to Alzheimer's disease (AD) pathology remains uncertain. This study examined the relationship between objectively measured physical activity and early AD biomarkers in cognitively unimpaired adults. METHODS:Accelerometer-measured physical activity and plasma AD biomarkers (beta-amyloid [Aβ]42/Aβ40, p-tau217) were assessed in 242 participants (age = 63.37 [54-79] years) of the population-based Rotterdam Study. Cortical Aβ was assessed via 18F-florbetaben positron emission tomography (PET) 7 years later. Robust regression assessed the relationship between physical activity, plasma AD biomarkers, and Aβ PET burden, while compositional analysis examined how the time-use composition relates to AD outcomes. RESULTS:Physical activity was not associated with plasma Aβ42/Aβ40, p-tau217, or brain Aβ burden 7 years later. Reallocating awake sedentary time to physical activity showed no association with AD biomarkers. DISCUSSION:No relationship was identified between physical activity and AD biomarkers, suggesting physical activity might affect dementia risk through other pathways or in an earlier life phase. HIGHLIGHTS:Physical activity was not associated with plasma beta-amyloid (Aβ)42/Aβ40 nor p-tau217. No association was observed between physical activity and brain Aβ 7 years later. Age, sex, and apolipoprotein E ε4 carriership did not moderate these relationships. Reallocating 30 minutes of sedentary time to physical activity resulted in no change in Alzheimer's disease (AD) biomarkers.

INTRODUCTION:Numerous dementia risk prediction models have been developed, but uptake in clinical practice is poor. METHODS:We determined public attitude toward dementia risk prediction through the means of a focus group (n = 9) and subsequent online survey (n = 687). Thematic content analysis was used for focus group data and descriptive statistics for survey responses. RESULTS:Focus group participants expressed reluctance in knowing dementia risk due to fear, emotional burden, and belief that prevention was impossible. Conversely, practical benefits and maximizing present quality of life motivated others to know dementia risk. Of survey respondents, 66.1% would want to know their 10-year risk at present, increasing to 82.3% if preventive medication were available. People perceived their 10-year risk as rather high, yet lower still than their own personal threshold for considering preventive action. DISCUSSION:Development and implementation of dementia risk prediction tools require attention for personal actionability and emotional impact of risk communication. HIGHLIGHTS:Among citizens with a particular interest in dementia, a large group is keen to learn their personal dementia risk, particularly when effective preventive measures are available. In focus group participants, hesitancy to learn about dementia risk was common, driven by fear, emotional burden, and doubts about the effectiveness of preventive interventions. The majority of survey participants (72%) believed a healthy lifestyle could reduce dementia risk. People perceived their 10-year risk as rather high, yet lower still than their own personal threshold for considering preventive action.

Objective: Women with anorexia nervosa (AN) have been shown to demonstrate differences in functional connectivity in brain regions associated with cognitive control, somatosensory processing, and emotion regulation. However, previous studies have been conducted on small samples and have inconsistent findings. Therefore, this study aimed to identify aberrant brain networks related to the core clinical symptoms of AN and to explore the longitudinal association with clinical outcome in a large population of adolescents experiencing their first episode of AN. Methods: Functional MRI (fMRI) of brain resting-state functional connectivity (RS-FC) of female adolescents with first-onset AN (n = 56) were compared to age- and education-matched typically developing (TD) adolescents (n = 64). To account for the severity of underweight, separate analyses were performed to investigate differences in RS-FC between underweight AN participants and TD adolescents, as well as between underweight (n = 30) and weight-restored AN (n = 26) participants. Clinical outcomes, i.e. body mass index and eating disorder (ED) symptoms, were assessed at baseline and one-year follow-up. Independent component analyses (ICA) were used to extract the brain networks of interest: the default mode (DMN), left and right frontoparietal (FPN), and the insular (IN) networks. Linear regression analyses were conducted to assess differences in RS-FC between AN and TD participants, as well as to assess whether RS-FC was associated with clinical symptoms at baseline and at one-year of follow-up. Two statistical models were used: model 1 adjusted for age and socioeconomic status (SES), and model 2 additionally adjusted for baseline anxiety and depressive symptoms. Results: Underweight AN participants had lower RS-FC between the DMN-IN, as well as between the FPN-IN compared to the TD adolescents. After correction for multiple testing, no significant differences in RS-FC were found between underweight AN participants and weight-restored AN participants, as well as between the whole AN group and the TD group. RS-FC was not associated with the severity of clinical symptoms at baseline nor at one-year of follow-up. Conclusion: AN is associated with changes in RS-FC between the FPN-IN and DMN-IN during the underweight state. These changes in RS-FC were no longer observed in weight-restored AN participants, emphasizing the impact of underweight on RS-FC in AN. Changes in these brain networks may partly explain the impaired cognitive control and difficulties with emotion and behavioral regulation in individuals with AN during the underweight state.

White matter hyperintensities (WMH) increase with age, with marked interindividual variation. There is a need for normative data by age and sex, to improve individualized WMH burden assessment. In this study, we pooled cross-sectional data from 15 population-based cohorts (14,876 nondemented individuals, age 18-97 years), through the Meta VCI Map consortium. Whole brain and tract-specific MRI-assessed WMH volumes were calculated in MNI-152 space. We used quantile regression to create centile curves of WMH volume versus age, stratified by sex. Total WMH volume and interindividual variance increased exponentially with age for both sexes, with females showing higher WMH volumes. WMH volume increase with aging was not uniform across the white matter, but instead followed one of three different patterns depending on location. Age- and sex-specific normative data for total and regional WMH volumes were created. Our study provides detailed information on the normal distribution of total and regional WMH volumes across adulthood. The normative data enable a quantitative approach to interpreting total and regional WMH volumes in clinical practice and research settings.

OBJECTIVES:Prevention of dementia is considered a healthcare priority. We aimed to identify potentially modifiable risk factors and mechanisms within the social health domain to find novel avenues to prevent cognitive decline and dementia. DESIGN:We integrated the results of eight sub-studies of the Social Health in Mice and Men (SHiMMy) project that were separately published in specialized journals, but not yet jointly considered. We followed the integrative methodology of Whittemore and Knafl, using the conceptual framework for social health to structure and integrate the results of human epidemiological and qualitative studies and experimental mice studies. This is a novel multi-method approach. PARTICIPANTS:Participants of the population-based longitudinal cohort Rotterdam study were included in the epidemiolocal studies (ranging from N = 1259 to N = 3.720) and in the qualitative study (n = 17). Mice intervention studies were performed using a transgenic mouse model for Alzheimer's pathology and matched controls, under group and single housed conditions. MEASUREMENTS:Epidemiological studies include social health markers (loneliness, perceived social support, marital status) and magnetic resonance imaging of the brain. The semi-structured qualitative study used an interview guide. The mice study assessed behavioral and histological markers. RESULTS:In human and mice studies, we identified several similar potentially modifiable risk (e.g. marital status, social group size) and protective (e.g. perceived social support, behavioral responses) factors. This alignment of findings showing that social health may impact brain health lend further support to our social health hypothesis. CONCLUSION:These results allow us to propose evidence-based social health targets for preventive interventions.

BackgroundArteriosclerosis in the heart-brain axis has emerged as an important area of study in Alzheimer's disease (AD) dementia research. While previous research primarily focused on structural brain changes, the relationship between arteriosclerosis and blood-based markers for AD dementia remains understudied.ObjectiveTo comprehensively assess arteriosclerosis in the heart-brain axis and investigate its link to AD dementia plasma markers.MethodsAnalyses are based on 2238 community-dwelling elderly from the population-based Rotterdam Study (52% female, mean age 69.5 ± 6.8 years) who underwent a non-contrast CT scan to quantify arteriosclerosis in the heart-brain axis. Coronary artery calcification, aortic arch calcification, extracranial carotid artery calcification, intracranial carotid artery calcification, and vertebrobasilar artery calcification were measured as proxies for arteriosclerosis. Participants had available total tau, neurofilament light chain (NfL), and amyloid-β (Aβ40, Aβ42, and Aβ42/40 ratio) plasma measures (median time difference between CT scan and plasma measurement 3.2 months). Using linear regression, we studied the relationship of calcification presence and burden in the abovementioned arteries with plasma markers.ResultsA higher arteriosclerosis burden correlated with higher plasma marker concentrations, especially for NfL (e.g., βintracranial carotid: 0.15, [95% Confidence interval (CI): 0.04, 0.26]) and Aβ40 (e.g., βintracranial carotid: 0.18, [95% CI: 0.05, 0.30]). Additionally, vertebrobasilar artery calcification was most consistently associated with elevated levels of AD dementia plasma markers (e.g., total tau; β: 0.06. [95% CI: 0.01, 0.10]).ConclusionsOur findings emphasize the critical role of vascular health in neurodegenerative processes and underscore the importance of monitoring and managing arteriosclerosis.

BACKGROUND AND OBJECTIVES:Insight into APOE-related pathways is important to unravel pathophysiology and identify therapeutic targets against late-life cognitive decline. We aimed to estimate mediators of APOE ε4 on cognition and dementia through different disease markers on structural in vivo brain imaging. METHODS:All participants from the population-based Rotterdam Study who underwent brain MRI between 2005 and 2009 were included. Cognition was assessed cross-sectionally during center visits, and participants were followed up for incident dementia until January 1, 2020. Imaging markers included hippocampal volume (HV), volume of white matter hyperintensities (WMHs), Alzheimer disease-specific regional cortical thickness, and presence of ≥2 cerebral microbleeds. We performed causal mediation analyses to decompose the total effect of APOE ε4 carriership on cognition and dementia into natural direct and indirect effects and corresponding percentage mediated. We adjusted models for potential confounders. RESULTS:Among 5,510 participants (mean age at time of MRI scan: 65.0 [±10.9] years, 55.0% women), 349 developed dementia, of whom 148 were ε4 carriers. Carriers of ε4 had slightly lower Z-scores for global cognition (β = -0.02 [-0.07 to 0.02], age-related cognitive decline = 4.4 months), with 7% (β = -0.00 [0.00-0.00]) of this association mediated by HV and 4% (β = -0.00 [-0.01 to 0.00]) by cortical thickness. In total, an estimated 25% of the effect of ε4 on cognition was mediated by microbleeds (p value = 0.24, [β = -0.00 {-0.01 to 0.00}]) and 12% by WMHs (p value = 0.44, [β = -0.00 {-0.01 to 0.00}]). In multiple mediator analyses, WMHs and microbleeds together accounted for 27% of the mediated effect of APOE ε4 on cognition (p value = 0.48). Carriers of ε4 had higher risk of incident dementia (HR 2.35 [95% CI 2.06-2.65]). For dementia, there was little to no evidence of mediation by either HV (3%, p value = 0.09, OR = 1.01 [1.00-1.03]) or regional cortical thickness (0%, p value = 0.79, OR = 1.00 [0.99-1.02]). In total, 1% of the effect of ε4 on dementia was mediated by WMHs (p value 0.29, OR = 1.00 [1.00-1.02]) and 5% by microbleeds (p value = 0.06), OR = 1.03 (1.00-1.07). In multiple mediator analyses, all 4 imaging markers together explained 6% of the mediated effect on incident dementia (p value = 0.04). DISCUSSION:In this population-based cohort study, we found that an estimated one-fourth of the effect of APOE ε4 on cognition is mediated by structural brain imaging markers, driven mainly by cerebral microbleeds. For dementia, mediation by these markers was limited.

Validating the predictive value of plasma markers for Alzheimer’s disease, cerebrovascular disease and cognitive dysfunction in older adults representative of primary care settings, is needed to guide prevention and treatment decisions. At baseline, single molecule array plasma measures of Aβ42/40, pTau217, pTau181, GFAP and NfL were collected from 625 dementia-free participants from the population-based Rotterdam Study (mean age 63 years [range 54-84], 51% women). After a mean follow-up time of seven years [range 5-9], participants underwent amyloid 18 F-florbetaben PET, brain MRI, and cognitive assessment. We investigated cross-sectional associations between basic sample characteristics and plasma markers using linear/logistic regression. We estimated how accurately single plasma markers at baseline predicted amyloid-PET positivity, high white matter hyperintensity burden (i.e. volume in 4 th quartile) and low cognitive performance at follow-up (i.e. composite score in 1 st quartile) using receiver operating characteristic curve analysis. Predictive performance between different models was compared with DeLong test. We further identified the most parsimonious multi-plasma marker model based on the lowest Akaike information criterion. Older participants had more abnormal plasma markers. Women showed higher GFAP, but lower pTau217 and 181 levels than men. APOE4 carriership was associated with more abnormal Ab42/40 and pTau217 levels. Education was not related to plasma markers. At follow-up, 102 participants (16%) were amyloid-PET positive. The area under the curve (AUC) for amyloid-PET positivity using a base model containing age, sex, APOE4, and follow-up time was 0.83 (Figure 1). Predictive accuracy significantly improved upon adding to the base model either GFAP (AUC=0.85), Aβ42/40 (AUC=0.87), or pTau217 (AUC=0.89; all p[DeLong]<0.05; Figure 1). AUC improved further to 0.92 for the most parsimonious model including all plasma markers (p[DeLong]<0.001). Using cutoffs based on Youden’s index, we estimated that 6.2 PET scans were needed to obtain one amyloid-PET positive individual after screening with the base model. This number decreased to 4.7 or 2.8 when pTau217 or all plasma markers were considered. No plasma marker model seemed to outperform the base model for predicting high white matter hyperintensities or low cognitive performance. Plasma pTau217, Aβ42/40 and GFAP levels markedly improved the prediction of amyloid-PET positivity in the general population

Treatment with anti-amyloid-β monoclonal antibodies slowed cognitive decline in recent RCTs in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer’s disease (AD). However, stringent trial eligibility criteria may affect generalisability to clinical practice. We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab, and applied these to participants with MCI and early clinical AD dementia from the population-based Rotterdam Study. Participants underwent questionnaires, genotyping, brain-MRI, cognitive testing, and cardiovascular assessment. We determined amyloid status using a validated prediction model based on age and APOE-g enotype. Of 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 dementia. Across trials, around 40% of participants would be ineligible because of predicted amyloid negativity. At least one clinical exclusion criterion was present in 76.3% of participants for aducanumab, 75.8% for lecanemab, and 59.8% for donanemab. Common criteria were cardiovascular disease (35.2%), anticoagulant (31.2%), psychotropic or immunological medication use (20.4%), anxiety or depression (15.9%), or lack of social support (15.6%). One-third were ineligible based on brain-MRI findings alone, similar across trials and predominantly due to cerebral small-vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 9% (95% CI:7.0-11.1) for aducanumab, 8% (6.2–9.9) lecanemab to 15% (12.4–17.5) for donanemab. Findings from recent RCTs reporting protective effects of monoclonal antibodies against amyloid-β are applicable to less than 15% of community-dwelling individuals with MCI or early AD. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with MCI/AD in routine clinical practice.

Background:Carotid artery stenosis could contribute to gradual loss of brain function through chronic hypoxia and ischemia. Methods:We included consecutive participants of the population-based Rotterdam Study with unilateral ≥50 % stenosis at the carotid artery bifurcation on time-of-flight carotid MR angiography, and compared between hemispheres the presence of ischemic lesions, tissue volumes, and white matter integrity on structural brain MRI. Results:Among 50 participants (mean age 76 years, 50 % women), flow was lower in the affected carotid artery than on the unaffected side (160mL/min versus 202mL/min; flow reduction [95 %CI] per 1 % increase in stenosis: 1.7 mL/min [1.0-2.5]). Twelve individuals had radiographic evidence of cortical infarction, of whom 8 had cortical microinfarcts, all on the side of the stenosis (P = 0.001). Downstream of the stenotic artery, parenchymal volume was lower than in the contralateral hemisphere (mean difference: -2.7 mL [-4.9;-0.4]), similar for grey and white matter. Differences were most profound in the frontoparietal lobes, and increased with severity of stenosis to roughly 5 mL in individuals with ≥70 % stenosis. White matter hyperintensity volume and microstructural integrity did not differ between hemispheres. Conclusions:Carotid artery stenosis is associated with downstream presence of cortical microinfarcts as well as lower parenchymal tissue volume.

OBJECTIVE:To determine gender differences in career progression of physicians. DESIGN:Retrospective cohort study. METHOD:We examined career progression until 2023 of 715 physicians who received their PhD in the Netherlands in 2007/2008. We also pooled data from 7 national grant programs from 2005 up until Jan 1, 2023. RESULTS:Fifteen years after their PhD defence, 43% of physicians worked in academia, similar for men and women. Men published more than women (9[3-27] vs. 6[2-15] publications; p=0.001), especially in academia. Women were less likely than men to be appointed full professor (10/330 vs. 27/385; odds ratio[95% CI]: 0.41[0.20-0.87]), which was mediated for 55% by their number of scientific publications. Women increasingly applied for research grants over time, with an equal number of women and men receiving 'early career' grants since 2015. More men applied for 'established investigator' grants, without any gender differences in award rates. CONCLUSION:Career perspectives in the early phase after obtaining a PhD, including grant allocation, are similar for male and female physicians. Differences in their later career phase were partly related to a higher number of scientific publications by men, compared to women.

BACKGROUND AND OBJECTIVES:Cardiac dysfunction and heart failure are linked to cognitive impairment, but the underlying brain pathology remains undetermined. We investigated associations between cardiac function (measured by echocardiography or cardiac MRI), clinical heart failure, and structural markers on brain MRI, including volumes of gray and white matter (WM), the hippocampus, and white matter hyperintensities (WMHs). METHODS:We leverage data from 7 prospective, community-based cohorts across Europe and the United States, all part of the Cross-Cohort Collaboration. The included cohorts were the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in Communities study, Austrian Stroke Prevention Study, Cardiovascular Health Study, Framingham Heart Study, Rotterdam Study, and Study of Health in Pomerania (SHIP-START and SHIP-TREND). Each cohort performed cross-sectional multivariable linear regression analyses, after which estimates were pooled through random-effects meta-analysis. Heterogeneity was assessed by the I2 index (%). RESULTS:Among 10,889 participants (mean age: 66.8 years, range 52.0-76.0; 56.7% women), markers of systolic dysfunction were consistently associated with smaller total brain volume (TBV) (e.g., adjusted standardized mean difference for moderate to severe dysfunction -0.19, 95% CI -0.31 to -0.07, I2 = 20%). Impaired relaxation and restrictive diastolic dysfunction were also associated with smaller TBV (e.g., for impaired relaxation -0.08, 95% CI -0.15 to -0.01, I2 = 32%) and hippocampal volume (-0.18, 95% CI -0.33 to -0.03, I2 = 0%), with similar results for the E/A-ratio. Systolic and diastolic dysfunction was not consistently associated with volume of WMHs. Among 5 cohorts with available data, 302 (3.4%) participants had clinical heart failure, which was associated with smaller brain volumes, particularly in the hippocampus (-0.13, 95% CI -0.23 to -0.02, I2 = 1%). DISCUSSION:In this large study among community-dwelling adults, subclinical cardiac dysfunction was associated with brain imaging markers of neurodegeneration. These findings encourage longitudinal investigations on the effect of maintaining cardiac function on brain health.

Background White matter hyperintensities (WMH) have been implicated in the pathogenesis of neuropsychiatric symptoms of dementia but the functional significance of WMH in specific white matter (WM) tracts is unclear. We investigate whether WMH burden within major WM fibre classes and individual WM tracts are differentially associated with different neuropsychiatric syndromes in a large multicentre study.Method Neuroimaging and neuropsychiatric data of seven memory clinic cohorts through the Meta VCI Map consortium were harmonised. Class-based analyses of major WM fibres (association, commissural and projection) and region-of-interest-based analyses on 11 individual WM tracts were used to evaluate associations of WMH volume with severity of hyperactivity, psychosis, affective and apathy syndromes.Results Among 2935 patients (50.4% women; mean age=72.2 years; 19.8% subjective cognitive impairment, 39.8% mild cognitive impairment, and 40.4% dementia), larger WMH volume within projection fibres (B=0.24, SE=0.10, p=0.013) was associated with greater apathy. Larger WMH volume within association (B=0.31, SE=0.12, p=0.009), commissural (B=0.47, SE=0.17, p=0.006) and projection (B=0.39, SE=0.16, p=0.016) fibres was associated with greater hyperactivity, driven by the inferior fronto-occipital fasciculus (B=0.50, SE=0.18, p=0.006), forceps major (B=0.48, SE=0.18, p=0.009) and anterior thalamic radiation (B=0.49, SE=0.19, p=0.011), respectively. Larger WMH volume in the uncinate fasciculus (B=1.82, SE=0.67, p=0.005) and forceps minor (B=0.61, SE=0.19, p=0.001) were additionally associated with greater apathy. No associations with affective and psychosis were observed.Conclusions Tract-syndrome specificity of WMH burden with apathy and hyperactivity suggests that disruption of strategic neuronal pathways may be a potential mechanism through which small vessel disease affects emotional and behavioural regulation in memory clinic patients.

BACKGROUND:Substantial evidence suggests an association between hypertensive disorders of pregnancy and long-term cerebrovascular health. We aimed to determine the associations between hypertensive disorders of pregnancy and markers of cerebral small vessel disease 15 years after pregnancy. METHODS:This was a nested cohort study embedded in a population-based prospective cohort followed from early pregnancy. We included 538 women, 445 (82.8%) with normotensive index pregnancies, and 93 (17.2%) with hypertensive disorders in the index pregnancy. Fifteen years after the index pregnancy (median, 14.6 years; 90% range, 14.0-15.7 years), women underwent magnetic resonance imaging to assess brain tissue and white matter hyperintensity volume, lacunar infarcts, and cerebral microhemorrhages as markers of cerebral small vessel disease. RESULTS:Women with prior hypertensive disorders of pregnancy had higher white matter hyperintensity volume compared with women with previous normotensive pregnancy (adjusted β, 0.32 [95% CI, 0.08-0.56]). This association was driven by women with gestational hypertension, who had higher white matter hyperintensity volume compared with women with previous normotensive pregnancy (adjusted β, 0.39 [95% CI, 0.10-0.67]). The effect was larger in those with gestational hypertension who developed chronic hypertension after the index pregnancy. No differences were found in infarcts or cerebral microhemorrhages. CONCLUSIONS:In a prospective cohort of midlife Dutch women, those with a history of hypertensive disorders of pregnancy, particularly gestational hypertension, showed some signs of cerebral small vessel disease, compared with those with normotensive pregnancies. These results support epidemiological data suggesting that not only preeclampsia but also gestational hypertension is associated with long-term cerebrovascular risk.

BACKGROUND:Anxiety and depression are common in prodromal dementia, possibly due to changes in subcortical grey matter structures involved in emotion regulation. We aimed to determine the association between subcortical grey matter volumes and depression and anxiety symptoms. METHODS:We included dementia-free participants from the population-based Rotterdam Study, who underwent brain MRI between 2009 and 2015. Depression and anxiety symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale and the Hospital Anxiety and Depression scale- Anxiety subscale (HADS-A). We determined cross-sectional associations of standardized volumes with log-transformed CES-D and HADS scores using multivariable linear regression models. We repeated analyses among outpatients who attended the Alzheimer Center Erasmus Medical Center between 2016 and 2021. RESULTS:Among 3451 community-dwelling participants (mean age 69.3 years, 55.2 % women), median CES-D score was 3 (IQR:1-7) and HADS-A score 2 (IQR:0-4). Clinically relevant depressive symptoms (CES-D ≥ 16) were present in 284 (8.2 %) participants, and anxiety (HADS≥8) in 270 (8.2 %). Lower volumes of the caudate and pallidum were associated with fewer depressive symptoms (mean difference [95 %CI] for the caudate: -0.06[-0.10;-0.02], pallidum: -0.04[-0.08;0.00]), and less anxiety (caudate: -0.04[-0.07;-0.01], pallidum: -0.05[-0.09;-0.02]). Lower hippocampal volume was associated with higher odds of clinical depressive symptoms (OR: 1.27[1.05-1.52]), albeit not significant after multiple testing correction. We observed no associations for other structures. Among 315 memory clinic patients, (mean age 68.9 years, 43.5 % women), no associations were observed after multiple testing correction. CONCLUSION:Volumes of the caudate and pallidum are inversely associated with depression and anxiety symptoms in community-dwelling older adults, but not in a memory clinic population.

INTRODUCTION:The prognostic value of subcortical gray matter structures for dementia beyond the hippocampus remains unclear. METHODS:We included participants with subjective cognitive decline or mild cognitive impairment from two memory clinic-based cohorts (Amsterdam Dementia Cohort and National Alzheimer's Coordinating Center) and one population-based cohort (Rotterdam Study). We assessed volumes of subcortical structures on magnetic resonance imaging and determined 5-year dementia risk using Cox models. RESULTS:Of 7076 participants (mean age: 66-69 years, 58.8%-61.0% women; NSCC = 5425, NMCI = 1661), 622 developed dementia within 5 years. Smaller volumes of the hippocampus and amygdala were consistently associated with increased dementia risk, independent of other subcortical structures. Smaller hippocampal volume was predominantly associated with the clinical diagnosis of Alzheimer's disease, but the prognostic value did not differ by amyloid status. DISCUSSION:Hippocampal and amygdalar volume are consistently associated with dementia risk in individuals with subjective cognitive decline or mild cognitive impairment, which may hold potential for personalized prognosis. HIGHLIGHTS:Seven thousand seventy-six participants from three large longitudinal cohorts were followed for a maximum of 5 years. Hippocampal volume is associated with 5-year risk of dementia in subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Amygdalar volume is associated with a 5-year risk of dementia in SCD or MCI. Stratifying by SCD and MCI revealed no consistent major differences.