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 offspring's 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 hypothalamicpituitary-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

Memory concerns in the early Alzheimer’s disease prodrome: Regional association with tau deposition

Introduction: Relationship between self- and informant memory concerns and tau aggregation was assessed in adults at risk for Alzheimer's disease (AD). Methods: Regional mean standardized uptake value ratios were extracted from [18F]flortaucipir positron emission tomography (PET) scans of 82 at-risk adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Associations between self- and informant ECog memory scores and tau aggregation were analyzed on both regional and voxelwise bases. Analyses were completed both on the whole sample and restricted to amyloid-positive individuals only. Results: Memory concerns were associated with tau aggregation. Self-perception was more associated with frontal tau. In contrast, informant scores were more associated with parietal tau. This source-by-region interaction was more prominent in amyloid-positive participants and observed in both regional and voxelwise analyses. Discussion: Quantitative assessment of perceived memory functioning may be useful for screening older adults at risk for Alzheimer's disease. Individuals and their informants may provide complementary information relating to the anatomical distribution of tau

Topographic staging of tau positron emission tomography images

Introduction: It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology. Methods: Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2. Results: All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage. Discussion: Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust

Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline

Objective: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. Methods: Amyloid-positive participants with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n 5 229) and 2-year clinical follow-up (n 5 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. Results: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p , 0.05) and poorer baseline executive function (p , 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer’s Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p , 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p , 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p , 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. Conclusions: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation. Neurology® 2017;89:2176–218

Morphological and functional correlates of disability in multiple sclerosis

This doctoral dissertation presents a series of studies that were conducted to investigate the relationship between morphological, as well as functional, changes and clinical disability in multiple sclerosis (MS) using magnetic resonance imaging (MRI) and functional MRI (fMRI).The extent of macroscopic brain tissue damage, as seen on T2-weighted MRI scans, is poorly correlated with measures of functional impairment in MS. We hypothesized that this might be due to the failure to take lesion location into account. By combining sophisticated lesion segmentation tools with the statistical and stereotaxic techniques of functional neuroimaging, we have shown a relationship between lesion location and the extent and type of physical and cognitive disability.Brain atrophy is another manifestation of MS. We conducted the first large-scale study of focal cortical atrophy in MS that uses cortical thickness measurements across the entire cortex. We present evidence that cortical atrophy occurs relatively early in the course of the disease, despite the lack of severe disability in MS patients, as assessed by the Expanded Disability Status Scale (EDSS), and follows a pattern of focal thinning that is more pronounced in areas that are heavily inter-connected with other brain regions, such as anterior cingulate cortex and association areas, suggesting that interruption of white matter tracts by MS plaques might play a causative role in cortical atrophy.Finally, we conducted an fMRI study of working memory in controls, cognitively unimpaired and impaired MS patients that revealed significant differences in the regions that were activated between the groups. Most interestingly, while both cognitively unimpaired MS patients and control subjects significantly activated the left dorsolateral prefrontal cortex and the left thalamus, cognitively impaired MS patients failed to significantly activate these areas. Levels of deactivation within the medial prefrontal/anterior cingulate cortices and posterior cingulate cortex were inferior in MS patients than in controls. This study suggests that with an increased white matter lesion volume there is an increased damage to a number of afferents and efferents to and from the thalamus (cortico-basal ganglia-thalamo-cortical loops and other thalamo-cortical projections) that ultimately causes the observed cognitive deficits. These cognitive deficits seem also to be dependent on a reduced capacity of MS patients to show task-related deactivations

Simultaneous scanning of two mice in a small-animal PET scanner: a simulation-based assessment of the signal degradation

International audienceIn PET imaging, research groups have recently proposed different experimental set ups allowing multiple animals to be simultaneously imaged in a scanner in order to reduce the costs and increase the throughput. In those studies, the technical feasibility was demonstrated and the signal degradation caused by additional mice in the FOV characterized, however, the impact of the signal degradation on the outcome of a PET study has not yet been studied. Here we thoroughly investigated, using Monte Carlo simulated [F-18]FDG and [C-11]Raclopride PET studies, different experimental designs for whole-body and brain acquisitions of two mice and assessed the actual impact on the detection of biological variations as compared to a single-mouse setting. First, we extended the validation of the PET-SORTEO Monte Carlo simulation platform for the simultaneous simulation of two animals. Then, we designed [F-18]FDG and [C-11]Raclopride input mouse models for the simulation of realistic whole-body and brain PET studies. Simulated studies allowed us to accurately estimate the differences in detection between single- and dual-mode acquisition settings that are purely the result of having two animals in the FOV. Validation results showed that PET-SORTEO accurately reproduced the spatial resolution and noise degradations that were observed with actual dual phantom experiments. The simulated [F-18]FDG whole-body study showed that the resolution loss due to the off-center positioning of the mice was the biggest contributing factor in signal degradation at the pixel level and a minimal inter-animal distance as well as the use of reconstruction methods with resolution modeling should be preferred. Dual mode acquisition did not have a major impact on ROI-based analysis except in situations where uptake values in organs from the same subject were compared. The simulated [C-11]Raclopride study however showed that dual-mice imaging strongly reduced the sensitivity to variations when mice were positioned side-by-side while no sensitivity reduction was observed when they were facing each other. This is the first study showing the impact of different experimental designs for whole-body and brain acquisitions of two mice on the quality of the results using Monte Carlo simulated [F-18]FDG and [C-11]Raclopride PET studies