Is Hippocampal Volume a Relevant Early Marker of Dementia?

OBJECTIVE: Hippocampal volume (HV) is a key imaging marker to improve Alzheimer's disease risk prediction. However, longitudinal studies are rare, and hippocampus may also be implicated in the subtle aging-related cognitive decline observed in dementia-free individuals. Our aim was to determine whether HV, measured by manual or automatic segmentation, is associated with dementia risk and cognitive decline in participants with and without incident dementia. METHODS: At baseline, 510 dementia-free participants from the French longitudinal ESPRIT cohort underwent magnetic resonance imaging. HV was measured by manual and by automatic segmentation (FreeSurfer 6.0). The presence of dementia and cognitive functions were investigated at each follow-up (2, 4, 7, 10, 12, and 15 years). Cox proportional hazards models and linear mixed models were used to assess the association of HV with dementia risk and with cognitive decline, respectively. RESULTS: During the 15-years follow-up, 42 participants developed dementia. Reduced HV (regardless of the measurement method) was significantly associated with higher dementia risk and cognitive decline in the whole sample. However, only the automatically measured HV was associated with cognitive decline in dementia-free participants. CONCLUSION: These results suggest that HV can be used to predict the long-term risk of dementia but also cognitive decline in a dementia-free population. This raises the question of the relevance of HV measurement as an early marker of dementia in the general population.

Late-life cynical hostility is associated with white matter alterations and the risk of Alzheimer's disease.

BACKGROUND: Cynical hostility (CH), a specific dimension of hostility that consists of a mistrust of others, has been suggested as a high-risk trait for dementia. However, the influence of CH on the incidence of Alzheimer's disease (AD) remains poorly understood. This study investigated whether late-life CH is associated with AD risk and structural neuroimaging markers of AD. METHODS: In community-dwelling older adults from the French ESPRIT cohort (n = 1388), incident dementia rate according to CH level was monitored during an 8-year follow-up and analyzed using Cox proportional hazards regression models. Brain magnetic resonance imaging volumes were measured at baseline (n = 508). Using automated segmentation procedures (Freesurfer 6.0), the authors assessed brain grey and white volumes on all magnetic resonance imaging scans. They also measured white matter hyperintensities volumes using semi-automated procedures. Mean volumes according to the level of CH were compared using ANOVA. RESULTS: Eighty-four participants developed dementia (32 with AD). After controlling for potential confounders, high CH was predictive of AD (HR 2.74; 95% CI 1.10-6.85; p = 0.030) and all dementia types are taken together (HR 2.30; 95% CI 1.10-4.80; p = 0.027). High CH was associated with white matter alterations, particularly smaller anterior corpus callosum volume (p < 0.01) after False Discovery Rate correction, but not with grey matter volumes. CONCLUSIONS: High CH in late life is associated with cerebral white matter alterations, designated as early markers of dementia, and higher AD risk. Identifying lifestyle and biological determinants related to CH could provide clues on AD physiopathology and avenues for prevention strategies.

Refined carbohydrate-rich diet is associated with long-term risk of dementia and Alzheimer's disease in apolipoprotein E ε4 allele carriers.

INTRODUCTION: In animal models, refined carbohydrates (RF) worsen Alzheimer's disease (AD). However, the long-term effects of high RF intake on the risk of dementia and AD are poorly described in epidemiological studies. Moreover, the interaction between RF and the apolipoprotein E ε4 allele (APOE-ε4) is unknown. Our study investigated whether RF-rich diets are associated with the risk of dementia and AD. METHODS: The glycemic load (GL) was quantified in 2777 elderly participants from the French Three-City Study to estimate RF intake. Then, the associations between GL and risk of dementia and AD, and the interaction with APOE-ε4 over a 12-year period were assessed using proportional hazards models. RESULTS: After adjustment for potential confounders, high afternoon-snack GL was associated with increased dementia and AD risk in APOE-ε4 carriers (hazard ratio = 1.27 [1.03-1.56]). DISCUSSION: This study highlights that RF-rich diets are a risk factor for dementia and AD in APOE-ε4 carriers.

Lifetime major depression and grey-matter volume

Background: There is evidence of structural brain alterations in major depressive disorder (MDD), but little is known about how these alterations might be affected by age at onset or genetic vulnerability. This study examines whether lifetime episodes of MDD are associated with specific alterations in grey-matter volume, and whether those alterations vary according to sex or serotonin transporter-linked promoter region (5-HTTLPR) genotype (LL, SL or SS). Methods: We used structural MRI to acquire anatomic scans from 610 community-dwelling participants. We derived quantitative regional estimates of grey-matter volume in 16 subregions using FreeSurfer software. We diagnosed MDD according to DSM-IV criteria. We adjusted analyses for age, sex, total brain volume, education level, head injury and comorbidities. Results: Lifetime MDD was associated with a smaller insula, thalamus, ventral diencephalon, pallidum and nucleus accumbens and with a larger pericalcarine region in both men and women. These associations remained after adjustment for false discovery rate. Lifetime MDD was also associated with a smaller caudate nucleus and amygdala in men and with a larger rostral anterior cingulate cortex in women. Late-onset first episodes of MDD (after age 50 years) were associated with a larger rostral anterior cingulate cortex and lingual and pericalcarine regions; early-onset MDD was associated with a smaller ventral diencephalon and nucleus accumbens. Some associations differed according to 5-HTTLPR genotype: the thalamus was smaller in participants with MDD and the LL genotype; pericalcarine and lingual volumes were higher in those with the SL genotype. Limitations: This study was limited by its cross-sectional design. Conclusion: Major depressive disorder was associated with persistent volume reductions in the deep nuclei and insula and with enlargements in visual cortex subregions; alterations varied according to age of onset and genotype.

Antihypertensive Drug Use, Blood Pressure Variability, and Incident Stroke Risk in Older Adults: Three-City Cohort Study.

BACKGROUND AND PURPOSE: The aim was to determine the association between antihypertensive drug class and incident stroke controlling for long-term blood pressure (BP) variability (BPV) in people aged ≥65 years. METHODS: The sample included 5951 participants (median age 74 years, 60% women) taking at least 1 drug for hypertension (3727/5951) or with systolic BP >140 mm Hg or diastolic BP >90 mm Hg. Participants were evaluated for incident fatal and nonfatal stroke to 12 years follow-up. BPV was calculated with the coefficient of variation method and regressed against 9 antihypertensive drug classes (BPVreg). Hazard models were used to determine hazard ratios for incident stroke risk attributable to drug class, adjusted for BP, BPVreg, covariates, and delayed entry bias. RESULTS: There were 273 incident strokes over a median of 9.1 years (interquartile range 6.4-10.4). Stroke risk was generally not reduced by BP-lowering drugs. Angiotensin receptor blockers (hazard ratio 1.56; 95% confidence interval 1.06-2.28; P=0.02) and ß-blockers (hazard ratio 1.41; 95% confidence interval 1.03-1.92; P=0.03) were associated with an increased total stroke risk. Angiotensin receptor blockers and ß-blockers were also associated with ischemic strokes after adjustment for systolic BPV. Diastolic BPV was associated with stroke risk in analyses stratified by systolic BP 140 to 160 mm Hg (per 0.10 increase in coefficient of variation, hazard ratio 1.59; 95% confidence interval 1.05-2.40; P=0.03). CONCLUSIONS: The angiotensin receptor blocker and ß-blocker drug classes were associated with incident stroke and ischemic stroke in older adults. BPV was generally not associated with incident stroke.

A meta-analysis of cytokines in suicidal behavior.

BACKGROUND: We conducted the first meta-analysis of studies comparing the plasma and CSF concentrations of cytokines in suicidal patients vs. non-suicidal patients or healthy controls. METHODS: We searched Medline, Web of Science, and PsycINFO from 1965 to November 2014 for relevant studies. Manual searches of references and unpublished data were also included. Suicidal patients included severe suicide ideators and suicide attempters. RESULTS: Eleven articles were available for the meta-analysis, for a total sample size of 494 suicidal patients, 497 non-suicidal patients and 398 healthy controls. Levels of 6 independent plasma cytokines (IL2, IL6, TNFalpha, IFNgamma, IL4, TGFbeta) were meta-analyzed for plasma studies comparing suicidal vs. both controls. IL8 level was meta-analyzed for cerebrospinal fluid studies comparing suicidal patients with healthy controls. We reported with medium effect size, that suicidal patients had: (1) lower IL2 plasma levels than both non-suicidal patients and healthy controls (medium effect size); (2) lower IL4 and higher TGFbeta plasma levels than healthy controls. CONCLUSION: Our results promote the hypothesis of altered inflammatory markers in suicidal patients, for both pro-inflammatory (IL2) and anti-inflammatory (IL4 and TGFbeta) cytokines.

5-HTTLPR genotype, asthma, diabetes and late-life depression in an older French population.

OBJECTIVE: Associations between environmental risk factors and depression have been reported to be stronger in people with the S allele of the S/L polymorphism in the serotonin transporter gene-linked promoter region (5-HTTLPR); however, most studies have focused on adverse life events as a general exposure, and interactions with physical disorders have been less investigated. We therefore investigated associations of asthma and diabetes with depression in an older community population and compared these by 5-HTTLPR genotype. METHODS: A sample of 1617 people aged 65 years and over, from Montpellier, France, were examined for depression, using the Center for Epidemiologic Studies Depression Scale and Mini International Neuropsychiatric Interview assessments, and a standardised interview was conducted to establish physical health status. Blood samples were also taken for 5-HTTLPR genotype. RESULTS: Depression was significantly associated with asthma and diabetes but not with 5-HTTLPR genotype. After adjustment for age, sex, education and co-residency, the association between asthma and depression did increase in strength and significance across genotype groups (odds ratios in LL, SL and SS genotypes: 1.59 (0.66-3.82), 1.88 (1.05-3.36) and 3.00 (1.26-7.13), respectively) although the interaction term fell below statistical significance (p = 0.29). No modification was observed for diabetes as an exposure. CONCLUSIONS: The findings provided some support for effect modification by 5-HTTLPR genotype for asthma but for not diabetes as risk factors for depression.

Education modulates the impact of white matter lesions on the risk of mild cognitive impairment and dementia.

OBJECTIVES: Conflicting results have been reported regarding the association between white matter lesions (WML) and cognitive impairment. We hypothesized that education, a marker of cognitive reserve (CR), could modulate the effects of WML on the risk of mild cognitive impairment (MCI) or dementia. METHODS: We followed 500 healthy subjects from a cohort of community-dwelling persons aged 65 years and over (ESPRIT Project). At baseline, WML volume was measured using a semi-automatic method on T2-weighted MRI. Standardized cognitive and neurological evaluations were repeated after 2, 4, and 7 years. The sample was dichotomized according to education level into low (≤8 years) and high (>8 years) education groups. Cox proportional hazard models were constructed to study the association between WML and risk of MCI/dementia. RESULTS: The interaction between education level and WML volume reached significance (p = 0.017). After adjustment for potential confounders, the association between severe WML and increased MCI/dementia risk was significant in the low education group (≤8 years) (p = 0.02, hazard ratio [HR]: 3.77 [1.29-10.99]), but not in the high education group (>8 years) (p = 0.82, HR: 1.07 [0.61-1.87]). CONCLUSIONS: Severe WML significantly increases the risk of developing MCI/dementia over a 7-year period in low educated participants. Subjects with higher education levels were seen to be more likely to be resilient to the deleterious effects of severe WML. The CR hypothesis suggests several avenues for dementia prevention.

APOE ε4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role?

BACKGROUND: We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE ε4) have increased parietal WMH volume. METHODS: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE ε4 was examined separately in each group and then in a combined analysis. RESULTS: In WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE ε4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH. CONCLUSIONS: APOE ε4 is associated with increased parietal lobe WMH.

Cerebral white matter hyperintensities in the prediction of cognitive decline and incident dementia.

Cerebral white matter hyperintensities (WMH), detected in vivo with magnetic resonance imaging (MRI), are commonly used to assess cerebrovascular burden in cognitive impairment. However, the association between WMH and cognition is not consistent across the literature. The present review examines evidence from published longitudinal studies. We reviewed the PubMed data base from January 1990 to March 2013 and included studies investigating the association of WMH with (1) the risk of dementia in the general population, (2) the risk of conversion to dementia in the mild cognitive impairment (MCI) population, and (3) cognitive decline in the general population. WMH were associated with all types of dementia in the general population, but not in MCI patients. Results are discrepant for global decline. WMH appear to be early predictors of the risk of dementia, but this association appears to be modulated by cognitive reserve, age and the spatial distribution of lesions. There are, however, some limits in the use of WMH as a marker of vascular burden. In addition to their ischaemic origin, WMH may be the result of co-occurring morbidity. Further research is needed to elucidate to what extent WMH actually reflect vascular risk to evaluate the likely efficacy of interventions specifically targeting WMH reduction.

Ambient Air Pollution Exposure and Cerebral White Matter Hyperintensities in Older Adults: A Cross-Sectional Analysis in the Three-City Montpellier Study.

BACKGROUND: Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive health, and this could be related to the effect of air pollution on vascular health. OBJECTIVE: We aim to evaluate the association between air pollution exposure and a magnetic resonance imaging (MRI) marker of cerebral vascular burden, white matter hyperintensities (WMH). METHODS: This cross-sectional analysis used data from the French Three-City Montpellier study. Randomly selected participants 65-80 years of age underwent an MRI examination to estimate their total and regional cerebral WMH volumes. Exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) at the participants' residential address during the 5 years before the MRI examination was estimated with land use regression models. Multinomial and binomial logistic regression assessed the associations between exposure to each of the three pollutants and categories of total and lobar WMH volumes. RESULTS: Participants' (n=582) median age at MRI was 70.7 years [interquartile range (IQR): 6.1], and 52% (n=300) were women. Median exposure to air pollution over the 5 years before MRI acquisition was 24.3 (IQR: 1.7) µg/m3 for PM2.5, 48.9 (14.6) µg/m3 for NO2, and 2.66 (0.60) 10-5/m for BC. We found no significant association between exposure to the three air pollutants and total WMH volume. We found that PM2.5 exposure was significantly associated with higher risk of temporal lobe WMH burden [odds ratio (OR) for an IQR increase=1.82 (95% confidence interval: 1.41, 2.36) for the second volume tercile, 2.04 (1.59, 2.61) for the third volume tercile, reference: first volume tercile]. Associations for other regional WMH volumes were inconsistent. CONCLUSION: In this population-based study in older adults, PM2.5 exposure was associated with increased risk of high WMH volume in the temporal lobe, strengthening the evidence on PM2.5 adverse effect on the brain. Further studies looking at different markers of cerebrovascular damage are still needed to document the potential vascular effects of air pollution. https://doi.org/10.1289/EHP12231.

Metabolic syndrome and localization of white matter hyperintensities in the elderly population.

BACKGROUND: Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes. METHODS: Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique--Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions. RESULTS: After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25-6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region. CONCLUSION: Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.

Dietary Glycemic Load and Plasma Amyloid-ß Biomarkers of Alzheimer's Disease.

Previous studies have highlighted links between a high-glycemic-load (GL) diet and Alzheimer's disease in apolipoprotein E ε4 (APOE4) carriers. However, the impact of high-GL diet on plasma amyloid-ß (Aß), an Alzheimer's disease hallmark that can be detected decades before clinical symptomatology, is unknown. This study examined the association between plasma Aß peptides (Aß40, Aß42 concentration and Aß42/Aß40 ratio) and GL. The influence of the GL of four meal types (breakfast, lunch, afternoon snack, and dinner) was also determined. From the prospective Three-City study, 377 participants with plasma Aß measurements, and who completed the Food Frequency Questionnaire, were selected. The association between plasma Aß and GL was tested using an adjusted linear regression model. Lunch GL was associated with a lower plasma Aß42 concentration (ß = -2.2 [CI = -4.27, -0.12], p = 0.038) and lower Aß42/Aß40 ratio (ß = -0.009 [CI = -0.0172, -0.0007], p = 0.034) in the model adjusted for center, age, sex, education level, APOE4 status, energy intake, serum creatinine, total cholesterol, and Mediterranean-like diet. No significant association was found with the GL of the other meal types. These results suggest that dietary GL may independently modulate the plasma Aß of the APOE4 status. The mechanism underlying diet, metabolic response, and Aß peptide regulation must be elucidated.

Simple Carbohydrate Intake and Higher Risk for Physical Frailty Over 15 Years in Community-Dwelling Older Adults.

Insulin resistance is a major mechanism involved in the onset of physical frailty (PF). Although rich carbohydrate diets may promote insulin resistance, few studies have examined their association with PF risk. This study aimed to investigate the spectrum of carbohydrate exposure, including carbohydrate intake (simple, complex, and total), glycemic load (a measure of the diet-related insulin demand), and adherence to a low-carbohydrate diet with the incident risk of PF in community-dwelling older adults. Baseline carbohydrate exposure was assessed in nonfrail participants of the Three-City Bordeaux cohort using a 24-hour dietary recall. Over 15 years of follow-up, participants were screened for PF, defined by the FRAIL scale (≥3 criteria out of Fatigue, Resistance, Ambulation, Illnesses, and weight Loss). Associations were estimated using mixed-effects logistic models adjusted for sex, age, education, smoking status, alcohol consumption, depressive symptomatology, global cognitive performances, and protein and energy intakes. The sample included 1 210 participants (62% females, mean age 76 years). Over the follow-up, 295 (24%) incident cases of PF were documented (28% in females, 18% in males). Higher intake of simple carbohydrates was significantly associated with greater odds of incident PF (per 1-SD increased: OR = 1.29; 95% CI = 1.02-1.62), specifically among males (OR = 1.52; 95% CI = 1.04-2.22). No association was observed with complex or total carbohydrate intake, glycemic load, or low-carbohydrate diet. Among the whole carbohydrate exposure, only higher consumption of simple carbohydrates in older age was associated with a higher risk of developing PF. Further studies are required to explore underlying mechanisms.

Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia.

BACKGROUND: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer's disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated. OBJECTIVE: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia. METHODS: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm. RESULTS: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes. CONCLUSION: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.

War exposure, 5-HTTLPR genotype and lifetime risk of depression.

BACKGROUND: In 1962 approximately 1.5 million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These people constitute a cohort for the study of the long-term impact of gene-environment interaction on depression. AIMS: To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by a length polymorphism of the serotonin transporter gene (5-HTTLPR). METHOD: A community sample of people aged 65 years and over residing in the Montpellier region of the south of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressive disorders were assessed according to DSM-IV criteria. RESULTS: A significant relationship was observed between exposure to repatriation and subsequent depression (P<0.002), but there was no significant effect of gene alone (P = 0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (repatriation × 5-HTTLPR) was globally significant (P<0.002; OR = 3.21, 95% CI 2.48-5.12). Individuals carrying the two short (s) alleles of 5-HTTLPR were observed to be at higher risk (P<0.005; OR = 2.34, 95% CI 1.24-4.32), particularly when repatriation occurred before age 35 years (P<0.002; OR = 2.91, 95% CI 1.44-5.88), but this did not reach significance in those who were older at the time of the event (P = 0.067). CONCLUSIONS: The association between depression and war repatriation was significantly modulated by 5-HTTLPR genotype but this appeared to occur only in people who were younger at the time of exposure.

Structural brain alterations in older adults exposed to early-life adversity.

BACKGROUND: Adverse childhood events may have differential effects on the brain that persist into adulthood. Findings on structural brain alterations in older adults exposed to early-life adversity are inconsistent notably due to heterogeneity in imaging studies, population, psychiatric comorbidities, nature of adverse events, and genetic vulnerability. This study examines whether exposure related to physical or sexual maltreatment, emotional maltreatment, and global adverse environment during childhood are associated with specific alterations in grey matter volumes and if this varies according to sex and serotonin transporter-linked promoter region (5-HTTLPR) genotype. METHOD: Structural MRI was used to acquire anatomical scans from 398 community-dwelling older adults. Quantitative regional estimates of 23 subregional volumes were derived using FreeSurfer software. Retrospective reporting of childhood adversity was collected using structured self-reported questionnaire. Analyses adjusted for age, sex, brain volume, head injury, lifetime depression and anxiety disorder, psychiatric medication, and cardiovascular ischemic pathologies. RESULTS: Exposure to adverse family environment was associated with smaller volumes of several frontal, cingulate, and parietal subregions and larger amygdala in the 5-HTTLPR SS genotype participants specifically but larger volumes of caudate, putamen, pallidum, and nucleus accumbens in the SL genotype participants. Highly significant differences were found with excessive sharing of parent problems with children, associated with larger grey-matter volumes in the thalamus and several frontal and parietal regions in 5-HTTLPR SL male participants specifically. CONCLUSIONS: Early-life adversity is associated with grey-matter volume alterations in older adults and this varies according to the type of adversity experienced, sex, and serotonergic genetic vulnerability; 5-HTTLPR SS participants appearing most vulnerable and SL individuals most resilient.