Arnaud Charil

Prenatal stress and brain development.

Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Animal studies have clearly demonstrated PS effects on the offsprings brain, however, while it has been speculated that PS most likely affects the brains of exposed human fetuses as well, no study has to date examined this possibility prospectively using an independent stressor (i.e., a stressful event that the pregnant woman has no control over, such as a natural disaster). The aim of this review is to summarize the existing animal literature by focusing on specific brain regions that have been shown to be affected by PS both macroscopically and microscopically. These regions include the hippocampus, amygdala, corpus callosum, anterior commissure, cerebral cortex, cerebellum and hypothalamus. We first discuss the mechanisms by which the effects of PS might occur. In particular, we show that maternal and fetal hypothalamic-pituitary-adrenal (HPA) axes, and the placenta, are the most likely candidates for these mechanisms. We see that, although animal studies have obvious advantages over human studies, the integration of findings in animals and the transfer of these findings to human populations remains a complex issue. Finally, we show how it is possible to circumvent these challenges by studying the effects of PS on brain development directly in humans, by taking advantage of natural or man-made disasters and assessing the impact and consequences of such stressful events on pregnant women and their offspring prospectively.

Focal cortical atrophy in multiple sclerosis: relation to lesion load and disability.

Multiple sclerosis (MS) is thought to predominantly affect white matter (WM). Recently, however, loss of cortical gray matter has also been described. Little is known about the cause of cortical atrophy in MS, whether it occurs early in the disease course, and whether it affects all cortical regions equally or if there is a preferential pattern of focal cortical atrophy. An automated method was used to compute the thickness at every vertex of the cortical surface of the brains of 425 early relapsing-remitting MS patients. We correlated cortical thickness with the WM lesion load and the Expanded Disability Status Scale score. Mean cortical thickness correlated with WM lesion load and disability. The correlations of cortical thickness with total lesion load and disability were most significant in cingulate gyrus, insula, and associative cortical regions. Conversely, primary sensory, visual, and motor areas showed a less significant relationship. The highest amount of atrophy per lesion volume or disability scale unit was in the anterior cingulate cortex. This study confirms the relation between cortical atrophy, WM lesion load, and disability in MS, and suggests that cortical atrophy occurs even in MS patients with only mild disability. Most interestingly, we show a specific regional pattern of focal atrophy in MS that is distinctively different from the one in normal aging. The predilection of the atrophic process for areas that are heavily inter-connected with other brain regions suggests that interruption of WM tracts by MS plaques contributes, at least in part, to the development of cortical atrophy.

Statistical mapping analysis of lesion location and neurological disability in multiple sclerosis: application to 452 patient data sets.

In multiple sclerosis (MS), the correlation between disability and the volume of white matter lesions on magnetic resonance imaging (MRI) is usually weak. This may be because lesion location also influences the extent and type of functional disability. We applied an automatic lesion-detection algorithm to 452 MRI scans of patients with relapsing-remitting MS to identify the regions preferentially responsible for different types of clinical deficits. Statistical parametric maps were generated by performing voxel-wise linear regressions between lesion probability and different clinical disability scores. There was a clear distinction between lesion locations causing physical and cognitive disability. Lesion likelihood correlated with the Expanded Disability Status Scale (EDSS) in the left internal capsule and in periventricular white matter mostly in the left hemisphere. Pyramidal deficits correlated with only one area in the left internal capsule that was also present in the EDSS correlation. Cognitive dysfunction correlated with lesion location at the grey-white junction of associative, limbic, and prefrontal cortex. Coordination impairment correlated with areas in interhemispheric and pyramidal periventricular white matter tracts, and in the inferior and superior longitudinal fascicles. Bowel and bladder scores correlated with lesions in the medial frontal lobes, cerebellum, insula, dorsal midbrain, and pons, areas known to be involved in the control of micturition. This study demonstrates for the first time a relationship between the site of lesions and the type of disability in large scale MRI data set in MS.

Influence of aging on brain gray and white matter changes assessed by conventional, MT, and DT MRI

Background: Conventional MRI can reveal decreases in brain volumes with aging but fails to provide information about the underlying microstructural modifications. Magnetization transfer (MT) and diffusion tensor (DT) MRI can in part overcome these limitations. Objective: To investigate the influence of aging on conventional and MT and DT MRI–derived measurements in brain white (WM) and gray (GM) matter. Methods: Dual-echo, T1-weighted, MT and DT MR images of the brain were obtained in 89 healthy subjects (age range 11 to 76 years). Normalized GM and WM volumes were measured and MT ratio (MTR) and mean diffusivity (MD) histograms produced for both tissue compartments. Results: Normalized brain (r = −0.78), GM (r = −0.75), and WM (r = −0.34) volumes and the number of brain T2 hyperintensities (r = 0.49) were correlated with age. Additionally, all GM MT- and DT-derived parameters also correlated with age (r values ranging from 0.28 to 0.64), whereas only the peak height (ph) of the normal-appearing (NA) WM MD histogram did so (r = −0.34). After correcting for the number of T2 hyperintensities, gender, and the corresponding normalized tissue volumes, only the correlations between age and GM average MD (r = 0.24), GM-MD-ph (r = −0.37), and NAWM-MD-ph (r = −0.29) remained significant. A multivariate regression analysis including both brain tissues variables retained the GM volume (β = −0.18, SE = 0.02, p < 0.001) and the GM average MD (β = 45, SE = 19, p = 0.02) as independent predictors of subject’s age. Conclusions: Brain white matter and gray matter have different vulnerabilities to aging. Microstructural imaging is important to achieve a complete picture of the complex changes occurring in the aging brain.

Structural and metabolic changes in the brain of patients with upper motor neuron disorders: A multiparametric MRI study

Our objective was to assess and compare the diagnostic sensitivity of conventional MRI (cMRI), magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), and proton magnetic resonance spectroscopic imaging (1H-MRSI) in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Thirty-eight ALS patients, nine PLS patients, and 22 healthy controls were enrolled. cMRI, MTI, DWI and 1H-MRSI were obtained. ALS patients were classified as advanced phase (Ap)-ALS (definite+probable) and early phase (Ep)-ALS (possible+probable-laboratory supported). cMRI was highly sensitive in detecting corticospinal tract (CST) hyperintensities in Ap-ALS (63.4%) and PLS (71.9%), but it was poorly sensitive in Ep-ALS (17.1%). Hyperintensity on proton density-weighted images correlated with ALS severity (p=0.02). CST apparent diffusion coefficient was significantly increased in ALS (p<0.01) and PLS (p=0.02) versus controls. The N-acetylaspartate/creatine ratio was significantly reduced in the motor cortex of patients versus controls (p≤ 0.01 in PLS, p=0.02 in Ap-ALS). The study shows the utility of cMRI for diagnosing ALS. Nevertheless, MRI sensitivity is limited at the early stages of the disease. In these cases, DWI and 1H-MRSI seem to have the potential to ameliorate the patients’ work-up and estimate the nature and extent of the underlying pathological damage.

The relationship between normal cerebral perfusion patterns and white matter lesion distribution in 1,249 patients with multiple sclerosis.

The pathological differences underlying the clinical disease phases in multiple sclerosis (MS) are poorly characterized. We sought to explore the relationship between the distribution of white matter (WM) lesions in relapsing‐remitting (RR) and secondary progressive (SP) MS and the normal regional variability of cerebral perfusion.

Medulla Oblongata Volume: A Biomarker of Spinal Cord Damage and Disability in Multiple Sclerosis

BACKGROUND AND PURPOSE: While brain MR imaging is routinely performed, the MR imaging assessment of spinal cord pathology in multiple sclerosis (MS) is less frequent in clinical practice. The purpose of this study was to determine whether measurements of medulla oblongata volume (MOV) on routine brain MR imaging could serve as a biomarker of spinal cord damage and disability in MS. MATERIALS AND METHODS: We identified 45 patients with MS with both head and cervical spinal cord MR imaging and 29 age-matched and sex-matched healthy control subjects with head MR imaging. Disability was assessed by the expanded disability status scale (EDSS) and ambulation index (AI). MOV and upper cervical cord volume (UCCV) were manually segmented; semiautomated segmentation was used for brain parenchymal fraction (BPF). These measures were compared between groups, and linear regression models were built to predict disability. RESULTS: In the patients, MOV correlated significantly with UCCV (r = 0.67), BPF (r = 0.45), disease duration (r = −0.64), age (r = −0.47), EDSS score (r = −0.49) and AI (r = −0.52). Volume loss of the medulla oblongata was −0.008 cm3/year of age in patients with MS, but no significant linear relationship with age was found for healthy control subjects. The patients had a smaller MOV (mean ± SD, 1.02 ± 0.17 cm3) than healthy control subjects (1.15 ± 0.15 cm3), though BPF was unable to distinguish between these 2 groups. MOV was smaller in patients with progressive MS (secondary- progressive MS, 0.88 ± 0.19 cm3 and primary-progressive MS, 0.95 ± 0.30 cm3) than in patients with relapsing-remitting MS (1.08 ± 0.15 cm3). A model including both MOV and BPF better predicted AI than BPF alone (P = .04). Good reproducibility in MOV measurements was demonstrated for intrarater (intraclass correlation coefficient, 0.97), interrater (0.79), and scan rescan data (0.81). CONCLUSION: MOV is associated with disability in MS and can serve as a biomarker of spinal cord damage.

Clinical and conventional MRI predictors of disability and brain atrophy accumulation in RRMS. A large scale, short-term follow-up study.

To assess the value of clinical and MRI variables in predicting short-term brain atrophy accumulation and clinical evolution in a large cohort of patients with RRMS, we studied a cohort of 548 patients, previously enrolled as a placebo arm of a 14-month, double-blind trial of oral glatiramer acetate (GA). A logistic regression model with EDSS progression as the dependent variable was built to assess baseline clinical and MRI variables associated with clinical worsening during follow-up. In 466 patients with complete central brain atrophy assessment, another linear regression model with percentage central brain volume change (PCBVC) as the dependent variable was built to assess baseline clinical and MRI variables associated with atrophy development.A total of 80 patients (15 %) had EDSS progression over the follow-up period. Factors independently predicting the probability to have a clinical progression were lower EDSS (OR = 0.78, 95 % CI = 0.62–0.97 p = 0.02) and higher T2 LL (OR = 1.022, 95 % CI = 1.006–1.038, p = 0.007) at baseline. In the 466 patients with atrophy assessment, PCBVC declined, on average, by –2.0 % (SD = 2.8) (p < 0.001) over the follow-up. The multivariate PCBVC analysis revealed that the PCBVC decrease was independently correlated with higher EDSS (p = 0.03) and T2 LL (p = 0.005) at baseline. The squared correlation coefficients of the composite scores made up of EDSS and T2 LL considered together were able to explain only 3 % of the variance in disability progression and only 4 % of the variance of PCBVC.In RRMS patients, clinical and conventional MRI findings at baseline only modestly predict shortterm accumulation of brain atrophy and disability. These data confirm the need to develop clinical and MRI measures more sensitive towards the more disabling aspects of the disease.

Cervical cord magnetization transfer ratio and clinical changes over 18 months in patients with relapsing-remitting multiple sclerosis: a preliminary study.

Background Magnetization transfer ratio (MTR) permits the quantitative estimation of cervical cord tissue damage in patients with multiple sclerosis (MS). Objective To determine whether a single time-point MTR scan of the cervical cord is associated with short-term disease evolution in patients with relapsing-remitting (RR) MS. Methods Using a 1.5-T magnetic resonance imaging (MRI) system with a tailored cervical cord phased array coil, fast short-tau inversion recovery (fast-STIR) and MTR scans were obtained from 14 untreated patients with RRMS at baseline. Cervical cord MTR histograms were derived. Over the 18- month follow-up period, relapse rate was measured and disability assessed by the Expanded Disability Status Scale (EDSS) score. Results Average cervical cord MTR was correlated with relapse rate (r= -0.56, P = 0.037). A moderate correlation (r values ranging from -0.33 to -0.36) between baseline cervical cord MTR metrics and EDSS changes over 18 months was also noted, albeit statistical significance was not reached (P = 0.26 and 0.21, respectively) perhaps because of the relatively small sample size. Conclusions This study suggests that a ‘snapshot’ MT MRI assessment of the cervical cord may detect cervical cord tissue changes associated with short-term disease evolution in RRMS.

β-Amyloid is associated with aberrant metabolic connectivity in subjects with mild cognitive impairment.

Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimers disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein ε4 (APOE ε4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimers Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ε4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ε4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.