Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results.

INTRODUCTION: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. DISCUSSION: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. HIGHLIGHTS: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Effects of white matter hyperintensities, neuropsychiatric symptoms, and cognition on activities of daily living: Differences between Alzheimer's disease and dementia with Lewy bodies.

Introduction: Disability is common across Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). White matter hyperintensities (WMHs) are prevalent in both diagnoses and associated with disability; both diagnoses show neuropsychiatric symptoms (NPS) and impaired cognition. Methods: In AD and DLB, we examined if WMHs, NPS, and cognition associate with basic and/or instrumental activities of daily living (BADLs and/or IADLs) cross-sectionally, and longitudinally over ≈1.4 years. Results: Across both diagnoses, NPS were not only associated with greater disability in performing both BADLs and IADLs, but were also associated with a decline in the ability to perform BADLs in the AD group. In the DLB group only, higher WMH volume was associated with greater disability in performing both BADLs and IADLs, and was associated with a decline in the ability to perform BADL over time. Discussion: Management of NPS and WMHs, particularly in DLB, might help maintain functionality in dementia patients for longer.

Association of low-frequency and rare coding variants with information processing speed.

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10-6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

APOE ε4, white matter hyperintensities, and cognition in Alzheimer and Lewy body dementia.

OBJECTIVE: To determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB). METHODS: A total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed. RESULTS: A significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only. CONCLUSION: APOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study.

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

APOE-ε4 associates with hippocampal volume, learning, and memory across the spectrum of Alzheimer's disease and dementia with Lewy bodies.

INTRODUCTION: Although the apolipoprotein E ε4-allele (APOE-ε4) is a susceptibility factor for Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), its relationship with imaging and cognitive measures across the AD/DLB spectrum remains unexplored. METHODS: We studied 298 patients (AD = 250, DLB = 48; 38 autopsy-confirmed; NCT01800214) using neuropsychological testing, volumetric magnetic resonance imaging, and APOE genotyping to investigate the association of APOE-ε4 with hippocampal volume and learning/memory phenotypes, irrespective of diagnosis. RESULTS: Across the AD/DLB spectrum: (1) hippocampal volumes were smaller with increasing APOE-ε4 dosage (no genotype × diagnosis interaction observed), (2) learning performance as assessed by total recall scores was associated with hippocampal volumes only among APOE-ε4 carriers, and (3) APOE-ε4 carriers performed worse on long-delay free word recall. DISCUSSION: These findings provide evidence that APOE-ε4 is linked to hippocampal atrophy and learning/memory phenotypes across the AD/DLB spectrum, which could be useful as biomarkers of disease progression in therapeutic trials of mixed disease.

12 Year Trajectories of Depressive Symptoms in Community-Dwelling Older Adults and the Subsequent Risk of Death Over 13 Years.

Background: Populations of depressed persons are typically comprised of individuals with different courses of depression and thus might carry different risks of death. This study aimed to identify different trajectories of depressive symptoms in community-dwelling older adults and study the risk of death across these trajectories. Methods: In the population-based Rotterdam Study, depressive symptoms (Center for Epidemiological Studies-Depression scale) at three examination rounds (1993-2004) from 3,325 dementia-free participants (mean age 64.6 ± 6.1 years) were used to identify depression trajectories by latent-class trajectory modeling. Mortality rates by trajectory were calculated over a subsequent 13 year period (2002-2015), that is using 23 years of follow-up data. Results: Five trajectories of depressive symptoms characterized by low (73.4%), decreasing (11.1%), remitting (5.1%), increasing (7.7%), and high (2.7%) depressive symptoms were identified. Compared with persons in the low symptoms trajectory, persons with a trajectory of increasing depressive symptoms (hazard ratio [HR]: 1.21 [95% CI = 1.02, 1.44]) had a higher risk of death, but not those with remitting depressive symptoms, HR: 1.06 (95% CI = 0.85, 1.32). The estimates for the high symptoms trajectory were also suggestive of a higher risk of mortality, HR: 1.20 (95% CI = 0.91, 1.58). Conclusions: Repeated measures of depression can help predict long-term health outcomes in persons with depressive symptoms. Participants with increasing symptoms over time had a higher risk of death than those with low or no depressive symptoms. Transient high depressive symptoms that remitted were not associated with a higher risk compared with those with no symptoms. Our results open avenues for etiological and prognostic research to focus upon risk factors' key to a particular trajectory.

Brain Volumes and Longitudinal Cognitive Change: A Population-based Study.

OBJECTIVE: To investigate the association of brain volumes, white matter lesion (WML) volumes, and lacunes, with cognitive decline in a population-based cohort of nondemented persons. METHODS: Within the Rotterdam Study, 3624 participants underwent brain magnetic resonance imaging. Cognition was evaluated at baseline (2005 to 2009) and at the follow-up visit (2011 to 2013). We used a test battery that tapped into domains of executive function, information processing speed, motor speed, and memory. The volumetric measures assessed were total brain volume, lobar (gray matter and white matter) volumes, and hippocampal volumes. We also studied the association of WML volumes and lacunes with cognitive decline using linear regression models. RESULTS: Total brain volume was associated with decline in global cognition, information processing, and motor speed (P<0.001) in analyses controlled for demographic and vascular factors. Specifically, smaller frontal and parietal lobes were associated with decline in information processing and motor speed, and smaller temporal and parietal lobes were associated with decline in general cognition and motor speed (P<0.001 for all tests). Total WML volume was associated with decline in executive function. Lobar WML volume, hippocampal volume, and lacunes were not associated with cognitive decline. CONCLUSIONS: Lower brain volume is associated with subsequent cognitive decline. Although lower total brain volume was significantly associated with decline in global cognition, specific lobar volumes were associated with decline in certain cognitive domains.

The low single nucleotide polymorphism heritability of plasma and saliva cortisol levels.

Cortisol is an important stress hormone affected by a variety of biological and environmental factors, such as the circadian rhythm, exercise and psychological stress. Cortisol is mostly measured using blood or saliva samples. A number of genetic variants have been found to contribute to cortisol levels with these methods. While the effects of several specific single genetic variants is known, the joint genome-wide contribution to cortisol levels is unclear. Our aim was to estimate the amount of cortisol variance explained by common single nucleotide polymorphisms, i.e. the SNP heritability, using a variety of cortisol measures, cohorts and analysis approaches. We analyzed morning plasma (n=5705) and saliva levels (n=1717), as well as diurnal saliva levels (n=1541), in the Rotterdam Study using genomic restricted maximum likelihood estimation. Additionally, linkage disequilibrium score regression was fitted on the results of genome-wide association studies (GWAS) performed by the CORNET consortium on morning plasma cortisol (n=12,597) and saliva cortisol (n=7703). No significant SNP heritability was detected for any cortisol measure, sample or analysis approach. Point estimates ranged from 0% to 9%. Morning plasma cortisol in the CORNET cohorts, the sample with the most power, had a 6% [95%CI: 0-13%] SNP heritability. The results consistently suggest a low SNP heritability of these acute and short-term measures of cortisol. The low SNP heritability may reflect the substantial environmental and, in particular, situational component of these cortisol measures. Future GWAS will require very large sample sizes. Alternatively, more long-term cortisol measures such as hair cortisol samples are needed to discover further genetic pathways regulating cortisol concentrations.

Mild cognitive impairment and risk of depression and anxiety: A population-based study.

INTRODUCTION: Many people with mild cognitive impairment (MCI) suffer from concomitant depression or anxiety. Whether MCI increases the risk of future depression or anxiety is unknown. METHODS: In the Rotterdam Study, cross-sectional (n = 4168) and longitudinal associations (n = 2967) of MCI with Diagnostic and Statistical Manual of Mental Disorders-depressive and anxiety disorders-were assessed (2002-2005 to 2009-2011). RESULTS: At baseline, 413 persons had MCI; 125 (22 MCI and 103 non-MCI) had a depressive disorder and 330 had an anxiety disorder (46 MCI and 284 non-MCI). In longitudinal depression analysis, of the 212 persons with prevalent MCI, 6 (2.8%) developed depression compared with 29 (1%) in the nonexposed group. In longitudinal anxiety analysis, 11 (7.3%) of the 151 with prevalent MCI developed anxiety, compared with 75 (3.4%) in nonexposed group. Persons with MCI had more depressive and anxiety disorders and also a higher risk of developing depressive disorder, odds ratio (OR) 3.13 (95% confidence interval [CI]: 1.26, 7.77), and anxiety disorder, OR 2.59 (95% CI: 1.31, 5.12). DISCUSSION: MCI is a risk factor for dementia and for depressive and anxiety disorders, suggesting common pathological pathways for cognitive and psychiatric outcomes.

Mid- to Late-Life Trajectories of Blood Pressure and the Risk of Stroke: The Rotterdam Study.

Hypertension is a major modifiable risk factor for stroke. Associations of blood pressure with incident stroke are mostly based on single or average blood pressure levels. However, this approach does not take into account long-term trajectories of blood pressure, which can vary considerably in the elderly. Within the population-based Rotterdam Study, we examined trajectories of systolic blood pressure in 6745 participants (60.0% women) over an age-range from 55 to 106 years and jointly modeled their risk of stroke and competing causes of death using joint latent class mixed modeling. Four trajectories were identified. Class 1 was characterized by blood pressure increasing gradually from on average 120 to 160 mm Hg over 5 decades (n=4938). Compared with this class, class 2, characterized by a similar midlife blood pressure, but a steep increase (n=822, increasing from 120 to 200 mm Hg), and class 4, characterized by a high midlife blood pressure (n=115; average 160 mm Hg) and had a higher risk of stroke and death. Class 3, characterized by a moderate midlife blood pressure (n=870; average 140 mm Hg), had a similar risk of death as class 1, but the highest risk of stroke. Assessing trajectories of blood pressure provides a more nuanced understanding of the associations between blood pressure, stroke, and mortality. In particular, high blood pressure and rapidly increasing blood pressure patterns are associated with a high risk of stroke and death, whereas moderately high blood pressure is only related to an increased risk of stroke. Future studies should explore the potential pathogenic significance of these patterns.

10-year trajectories of depressive symptoms and risk of dementia: a population-based study.

BACKGROUND: Late-life depressive symptoms have been extensively studied for their relationship with incident dementia, but have been typically assessed at a single timepoint. Such an approach neglects the course of depression, which, given its remitting and relapsing nature, might provide further insights into the complex association of depression with dementia. We therefore repeatedly measured depressive symptoms in a population of adults over a decade to study the subsequent risk of dementia. METHODS: Our study was embedded in the Rotterdam Study, a population-based study of adults aged 55 years or older in Rotterdam (Netherlands), ongoing since 1990. The cohort is monitored continuously for major events by data linkage between the study database and general practitioners. We examined a cohort of participants who were free from dementia, but had data for depressive symptoms from at least one examination round in 1993-95, 1997-99, or 2002-04. We assessed depressive symptoms with the validated Dutch version of the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale-Depression. We used these data to identify 11-year trajectories of depressive symptoms by latent class trajectory modelling. We screened participants for dementia at each examination round and followed up participants for 10 years for incident dementia by latent trajectory from the third examination round to 2014. We calculated hazard ratios (HR) for dementia by assigned trajectory using two Cox proportional hazards models (model 1 adjusted for age and sex only, and model 2 adjusted additionally for APOEɛ4 carrier status, educational level, body-mass index, smoking, alcohol consumption, cognitive score, use of antidepressants, and prevalent disease status at baseline). We repeated the analyses censoring for incident stroke, restricting to Alzheimer's disease as an outcome, and accounting for mortality as a competing risk for dementia. FINDINGS: From 1993-2004, we obtained data for depressive symptoms from at least one examination round for 3325 participants (median age: 74·88 years [IQR 70·62-80·06], 1995 [60%] women). We identified five trajectories of depressive symptoms in these 3325 individuals, characterised by maintained low CES-D scores (low; 2441 [73%]); moderately high starting scores but then remitting (decreasing; 369 [11%]); low starting scores, increasing, then remitting (remitting; 170 [5%]); low starting scores that steadily increased (increasing; 255 [8%]); and maintained high scores (high; 90 [3%]). During 26 330 person-years, 434 participants developed incident dementia. Only the trajectory with increasing depressive symptoms was associated with a higher risk of dementia compared with the low depressive symptom trajectory, using model 2 (HR 1·42, 95% CI 1·05-1·94; p=0·024). Additionally, only the increasing trajectory was associated with a higher risk of dementia compared with the low trajectory after censoring for incident stroke (1·58, 1·15-2·16; p=0·0041), restricting to Alzheimer's disease as an outcome (1·44, 1·03-2·02; p=0·034), and accounting for mortality as a competing risk (1·45, 1·06-1·97; p=0·019). INTERPRETATION: Risk of dementia differed with different courses of depression, which could not be captured by a single assessment of depressive symptoms. The higher risk of dementia only in the increasing trajectory suggests depression might be a prodrome of dementia. FUNDING: Erasmus Medical Center; ZonMw; the Netherlands Ministry of Education Culture and Science; and the Netherlands Ministry for Health, Welfare and Sports.

Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study.

BACKGROUND: Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia. OBJECTIVE: To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance. METHODS: In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0-1, >1-3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders. RESULTS: We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95% CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95% CI:0.39;1.88)], Word Fluency test [0.74(95% CI:0.04,1.45)], Stroop interference task [1.82(95% CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95% CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally. CONCLUSION: We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.

GENOME-WIDE ASSOCIATION STUDY (GWAS) AND GENOME-WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN.

BACKGROUND: Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. METHODS: Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. RESULTS: No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10(-8) ) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10(-7) ). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10(-7) ) and rs4542757 (intronic to DCC, P = 7.31 × 10(-7) ). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10(-10) ; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. CONCLUSIONS: Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

Higher Education Is Associated with a Lower Risk of Dementia after a Stroke or TIA. The Rotterdam Study.

BACKGROUND: Higher education is associated with a lower risk of dementia, possibly because of a higher tolerance to subclinical neurodegenerative pathology. Whether higher education also protects against dementia after clinical stroke or transient ischemic attack (TIA) remains unknown. METHODS: Within the population-based Rotterdam Study, 12,561 participants free of stroke, TIA and dementia were followed for occurrence of stroke, TIA and dementia. Across the levels of education, associations of incident stroke or TIA with subsequent development of dementia and differences in cognitive decline following stroke or TIA were investigated. RESULTS: During 124,862 person-years, 1,463 persons suffered a stroke or TIA, 1,158 persons developed dementia, of whom 186 developed dementia after stroke or TIA. Risk of dementia after a stroke or TIA, compared to no stroke or TIA, was highest in the low education category (hazards ratio [HR] 1.46, 95% CI 1.18-1.81) followed by intermediate education category (HR 1.36, 95% CI 1.03-1.81). No significant association was observed in the high education category (HR 0.62, 95% CI 0.25-1.54). In gender stratified analyses, decrease in risk of dementia with increasing education was significant only in men. CONCLUSION: Higher education is associated with a lower risk of dementia after stroke or TIA, particularly in men, which might be explained by a higher cognitive reserve.

The N-terminal pro B-type natriuretic peptide, and risk of dementia and cognitive decline: a 10-year follow-up study in the general population.

BACKGROUND: The N-terminal pro B-type natriuretic peptide (NT-proBNP) has a well-documented prognostic value for cardiovascular disease (CVD) and higher levels are associated with cognitive-dysfunction in patients with CVD. However, how NT-proBNP relates to incident dementia and cognitive-decline in community-dwelling persons is unknown. METHODS: Between 1997 and 2001, serum NT-proBNP was measured in 6040 participants (mean age 69 years, 57% women) free of heart-failure and dementia from the Rotterdam Study. Participants were continuously followed-up for incident dementia until 2012, for 56,616 person-years. Cognition was assessed at baseline and reassessed between 2002 and 2006 by Letter-Digit-Substitution-task, Stroop test and Word-Fluency test. Associations of NT-proBNP with dementia (555 cases), Alzheimer's disease (357 cases) and vascular dementia (32 cases) were assessed linearly, and in quartiles using Cox regression. Associations of NT-proBNP with cognitive-decline were assessed using multiple linear regression. All analyses were repeated after excluding patients with CVD. RESULTS: Higher NT-proBNP was associated with a higher risk of dementia, even after excluding patients with CVD and adjusting for cardiovascular risk factors, HR per SD 1.27 (95% CI 1.13 to 1.44). Associations were particularly strong for vascular dementia, HR per SD 2.04 (95% CI 1.18 to 3.55), but also for Alzheimer's disease when comparing the second and third quartile with first. Higher NT-proBNP was cross-sectionally associated with poorer performance in multiple cognitive tests but longitudinally only in Letter-Digit-Substitution-task. CONCLUSIONS: NT-proBNP reflecting subclinical CVD is associated with dementia, particularly vascular dementia. NT-proBNP can be a useful marker of imminent cognitive-decline and dementia in absence of clinical CVD.