Pauline Maillard

Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study

BACKGROUND Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure in the brain are evident as early as the fifth decade of life. METHODS In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders. FINDINGS 579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmanns area 48 on the medial surface of the temporal lobe and Brodmanns area 21 of the middle temporal gyrus. INTERPRETATION Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure. FUNDING National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.

Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study

Objective To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. Design Population based, cross sectional study. Setting Epidemiology of Vascular Ageing study, Nantes, France. Participants 780 participants (mean age 69, 58.5% women) with detailed headache assessment. Main outcome measures Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. Results 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. Conclusions In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking.

Genome-wide association studies of cerebral white matter lesion burden

White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

Antihypertensive Treatment and Change in Blood Pressure Are Associated With the Progression of White Matter Lesion Volumes The Three-City (3C)–Dijon Magnetic Resonance Imaging Study

Background— Blood pressure (BP) is recognized as a major risk factor for white matter lesions (WMLs), but longitudinal data are scarce, and there is insufficient evidence for the benefit of antihypertensive therapy on WML progression. We studied the relationship between BP change and WML volume progression over time in a sample of 1319 elderly individuals who had 2 cerebral magnetic resonance imaging examinations 4 years apart. We also examined the impact of antihypertensive treatment on WML progression. Methods and Results— Subjects were participants from the Three-City (3C)–Dijon Magnetic Resonance Imaging Study, a prospective population-based cohort of elderly ≥65 years of age. WML volumes and their progression were estimated with the use of a fully automatic procedure. We performed ANCOVA models first to assess the association between BP change and WML progression and second to estimate the relation between antihypertensive treatment and WML load progression. Baseline and change in BP were significant predictors of higher WML progression over time after controlling for potential confounders. Among subjects with high SBP (≥160 mm Hg) at baseline not treated by antihypertensive medication, antihypertensive treatment started within 2 years was related to a smaller increase in WML volume at a 4-year follow-up (0.24 cm3; SE=0.44 cm3) than no hypertensive treatment (1.60 cm3; SE=0.26 cm3; P=0.0008) on multivariable modeling. Conclusions— Our findings reinforce the hypothesis that hypertension is a strong predictor of WML and that adequate treatment may reduce the course of WML progression. Because WMLs are linked to both dementia and stroke risks, these results could have implications for future preventive trials.

White Matter Hyperintensity Penumbra

Background and Purpose— White matter hyperintensities (WMHs) are associated with progressive age-related cognitive decline and cardiovascular risk factors, but their biological relevance as indicators of generalized white matter injury is unclear. Diffusion tensor imaging provides more sensitive indications of subtle white matter disruption and can therefore clarify whether WMHs represent foci of generalized white matter damage that extends over a broader neighborhood. Methods— Two hundred eight participants from the University of California, Davis Alzheimers Disease Center received a comprehensive clinical evaluation and brain MRI including fluid-attenuated inversion recovery and diffusion tensor imaging sequences. Voxelwise maps of WMHs were produced from fluid-attenuated inversion recovery using a standardized WMH detection protocol. Fractional anisotropy maps were calculated from diffusion tensor imaging. All WMH and fractional anisotropy maps were coregistered to a standardized space. For each normal-appearing white matter voxel in each subject fluid-attenuated inversion recovery scan, a neighborhood white matter injury score was calculated that increased with increasing number and proximity of WMH in the vicinity of the normal-appearing white matter voxel. Fractional anisotropy was related to neighborhood white matter injury using a nonlinear mixed effect model controlling for relevant confounding factors. Results— Fractional anisotropy was found to decrease as neighborhood white matter injury increased (&bgr;=−0.0017/%, P<0.0001) with an accelerated rate (P<0.0001) for neighborhood white matter injury >0.4. An increase of 1% in neighborhood white matter injury score was associated with a decrease in mean fractional anisotropy of 0.012 (P<0.001). Conclusions— WMH may represent foci of more widespread and subtle white matter changes rather than distinct, sharply delineated anatomic abnormalities. We use the term white matter hyperintensities penumbra to explain this phenomenon.

Longitudinal neuroimaging correlates of subjective memory impairment: 4-year prospective community study

BACKGROUND Complaints about memory are common in older people but their relationship with underlying brain changes is controversial. AIMS To investigate the relationship between subjective memory impairment and previous or subsequent changes in white matter lesions and brain volumes. METHOD In a community cohort study of 1336 people without dementia, 4-year changes in brain magnetic resonance imaging measures were investigated as correlates of subjective memory impairment at baseline and follow-up. RESULTS Subjective memory impairment at baseline was associated with subsequent change in hippocampal volume and at follow-up impairment was associated with previous change in hippocampal, cerebrospinal fluid and grey matter volume and with subcortical white matter lesion increases. All associations with volume changes were U-shaped with significant quadratic terms - associations between least decline and subjective memory impairment were potentially explained by lower baseline hippocampal volumes in the groups with least volume change. Associations between hippocampal volume change and subjective memory impairment at follow-up were independent of cognitive decline and depressive symptoms, they were stronger in participants with the apolipoprotein E (APOE) ε4 allele and in those without baseline subjective memory impairment. CONCLUSIONS Complaints of poor memory by older people, particularly when new, may be a realistic subjective appraisal of recent brain changes independent of observed cognitive decline.

Neuroimaging correlates of subjective memory deficits in a community population

Background: Subjective memory deficit (SMD) is one of few potential presenting symptoms for people with early cognitive impairment. However, associations with underlying brain changes are unclear. Methods: In a community sample of 1,779 people without dementia, and with neuroimaging (MRI) data, associations were investigated for SMD with white matter lesion volume and with the following volumetric measures: gray and white matter, CSF, hippocampal, parahippocampal, and amygdalar. Covariates included depressive symptoms (Center for Epidemiologic Studies Depression Scale), a battery of cognitive tests, physical health, and social activity. Results: SMD was present in 26.4% of the sample. Of the neuroimaging measures analyzed, SMD was most strongly associated with temporal WML (OR for highest quintile compared to the remainder 1.44, 95% CI 1.12–1.85), and lower hippocampal volume (OR per decreasing quintile 1.22, 1.11–1.35). These associations were independent of all other covariates, including cognitive function. Conclusions: Subjective memory deficit (SMD) was associated with neuroimaging characteristics in the temporal and hippocampal regions, suggesting that SMD may, at least in some cases, represent a realistic appraisal of underlying brain function independent of measured cognition. However, further research is required for volumetric measures and SMD to establish whether the association reflects lifelong structure or neurodegenerative changes. GLOSSARY: CES-D = Center for Epidemiologic Studies Depression Scale; GM = gray matter; MMSE = Mini-Mental State Examination; ROI = regions of interest; SMD = subjective memory deficit; TIV = total intracranial volume; VBM = voxel-based morphometry; WM = white matter; WML = white matter lesions.

White matter lesions volume and motor performances in the elderly

To investigate the cross‐sectional and longitudinal associations between performance‐based measures of motor function and volume of white matter lesions (WMLs), and to examine the influence of the localization of these lesions.

Coevolution of white matter hyperintensities and cognition in the elderly

Objective: To investigate the effects of baseline white matter hyperintensity (WMH) and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function). Methods: A total of 150 individuals including cognitively normal elderly individuals and those with Alzheimer disease and mild cognitive impairment completed serial episodic memory and executive function evaluations and serial MRI scans sufficient for longitudinal measurement of WMH (mean delay 4.0 years). Incident WMH voxels were categorized as extended (baseline WMH that grew larger) or emergent (newly formed WMH). We used a stepwise regression approach to investigate the effects of baseline WMH and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function). Results: WMH burden significantly increased over time, and approximately 80% of incident WMH voxels represented extensions of existing lesions. Each 1 mL/y increase in WMH extension was associated with an additional 0.70 SD/y of subsequent episodic memory decrease (p = 0.0053) and an additional 0.55 SD/y of subsequent executive function decrease (p = 0.022). Emergent WMHs were not found to be associated with a change in cognitive measures. Conclusions: Aging-associated WMHs evolve significantly over a 4-year period. Most of this evolution represents worsening injury to the already compromised surround of existing lesions. Increasing WMH was also significantly associated with declining episodic memory and executive function. This finding supports the view that white matter disease is an insidious and continuously evolving process whose progression has clinically relevant cognitive consequences.

FLAIR and Diffusion MRI Signals Are Independent Predictors of White Matter Hyperintensities

BACKGROUND AND PURPOSE: WMH, associated with cognitive decline and cardiovascular risk factors, may represent only the extreme end of a more widespread continuous WM injury process that progresses during aging and is poorly understood. We investigated the ability of FLAIR and DTI to characterize the longitudinal course of WMH development. MATERIALS AND METHODS: One hundred nineteen participants (mean age, 74.5 ± 7.4), including cognitively healthy elders and subjects diagnosed with Alzheimer disease and mild cognitive impairment, received a comprehensive clinical evaluation and brain MR imaging, including FLAIR and DTI on 2 dates. The risk for each baseline normal-appearing WM voxel to convert into WMH was modeled as a function of baseline FA (model M1) and both baseline FA and standardized FLAIR (M2). Sensitivity, specificity, accuracy, and AUC for predicting conversion to WMH were compared between models. RESULTS: Independent of clinical diagnosis, lower baseline FA (P < .001, both models) and higher baseline FLAIR intensity (P < .001, M2) were independently associated with increased risk for conversion from normal WM to WMH. M1 exhibited higher sensitivity but lower specificity, accuracy, and AUC compared with M2. CONCLUSIONS: These findings provide further evidence that WMH result from a continuous process of WM degeneration with time. Stepwise decreases in WM integrity as measured by both DTI and FLAIR were independently associated with stepwise increases in WMH risk, emphasizing that these modalities may provide complementary information for understanding the time course of aging-associated WM degeneration.