Enhancing fetal alcohol spectrum disorders diagnosis with a classifier based on the intracerebellar gradient of volumetric undersizing.

In fetal alcohol spectrum disorders (FASD), brain growth deficiency is a hallmark of subjects both with fetal alcohol syndrome (FAS) and with non-syndromic FASD (NS-FASD, i.e., those without specific diagnostic features). However, although the cerebellum was suggested to be more severely undersized than the rest of the brain, it has not yet been given a specific place in the FASD diagnostic criteria where neuroanatomical features still count for little if anything in diagnostic specificity. We applied a combination of cerebellar segmentation tools on a 1.5 T 3DT1 brain MRI dataset from a monocentric population of 89 FASD (52 FAS, 37 NS-FASD) and 126 typically developing controls (6-20 years old), providing 8 volumes: cerebellum, vermis and 3 lobes (anterior, posterior, inferior), plus total brain volume. After adjustment of confounders, the allometric scaling relationship between these cerebellar volumes (Vi ) and the total brain or cerebellum volume (Vt ) was fitted (Vi = bVt a ), and the effect of group (FAS, control) on allometric scaling was evaluated. We then estimated for each cerebellar volume in the FAS population the deviation from the typical scaling (v DTS) learned in the controls. Lastly, we trained and tested two classifiers to discriminate FAS from controls, one based on the total cerebellum v DTS only, the other based on all the cerebellar v DTS, comparing their performance both in the FAS and the NS-FASD group. Allometric scaling was significantly different between FAS and control group for all the cerebellar volumes (p < .001). We confirmed the excess of total cerebellum volume deficit (v DTS = -10.6%) and revealed an antero-inferior-posterior gradient of volumetric undersizing in the hemispheres (-12.4%, 1.1%, 2.0%, respectively) and the vermis (-16.7%, -9.2%, -8.6%, repectively). The classifier based on the intracerebellar gradient of v DTS performed more efficiently than the one based on total cerebellum v DTS only (AUC = 92% vs. 82%, p = .001). Setting a high probability threshold for >95% specificity of the classifiers, the gradient-based classifier identified 35% of the NS-FASD to have a FAS cerebellar phenotype, compared to 11% with the cerebellum-only classifier (pFISHER = 0.027). In a large series of FASD, this study details the volumetric undersizing within the cerebellum at the lobar and vermian level using allometric scaling, revealing an anterior-inferior-posterior gradient of vulnerability to prenatal alcohol exposure. It also strongly suggests that this intracerebellar gradient of volumetric undersizing may be a reliable neuroanatomical signature of FAS that could be used to improve the specificity of the diagnosis of NS-FASD.

Exploring the emergence of morphological asymmetries around the brain's Sylvian fissure: a longitudinal study of shape variability in preterm infants.

Brain folding patterns vary within the human species, but some folding properties are common across individuals, including the Sylvian fissure's inter-hemispheric asymmetry. Contrarily to the other brain folds (sulci), the Sylvian fissure develops through the process of opercularization, with the frontal, parietal, and temporal lobes growing over the insular lobe. Its asymmetry may be related to the leftward functional lateralization for language processing, but the time course of these asymmetries' development is still poorly understood. In this study, we investigated refined shape features of the Sylvian fissure and their longitudinal development in 71 infants born extremely preterm (mean gestational age at birth: 26.5 weeks) and imaged once before and once at term-equivalent age (TEA). We additionally assessed asymmetrical sulcal patterns at TEA in the perisylvian and inferior frontal regions, neighbor to the Sylvian fissure. While reproducing renowned strong asymmetries in the Sylvian fissure, we captured an early encoding of its main asymmetrical shape features, and we observed global asymmetrical shape features representative of a more pronounced opercularization in the left hemisphere, contrasting with the previously reported right hemisphere advance in sulcation around birth. This added novel insights about the processes governing early-life brain folding mechanisms, potentially linked to the development of language-related capacities.

Cross-sectional associations between cortical thickness and physical activity in older adults with spontaneous memory complaints: The MAPT Study.

BACKGROUND: Age-related changes in brain structure may constitute the starting point for cerebral function alteration. Physical activity (PA) demonstrated favorable associations with total brain volume, but its relationship with cortical thickness (CT) remains unclear. We investigated the cross-sectional associations between PA level and CT in community-dwelling people aged 70 years and older. METHODS: A total of 403 older adults aged 74.8 ± 4.0 years (mean ± SD) who underwent a baseline magnetic resonance imaging examination and who had data on PA and confounders were included. PA was assessed with a questionnaire. Participants were categorized according to PA levels. Multiple linear regressions were used to compare the brain CT (mm) of the inactive group (no PA at all) with 6 active groups (growing PA levels) in 34 regions of interest. RESULTS: Compared with inactive persons, people who achieved PA at a level of 1500-1999 metabolic equivalent task-min/week (i.e., about 6-7 h of brisk walking for exercise and those who achieved it at 2000-2999 metabolic equivalent task-min/week (i.e., 8-11 h of brisk walking for exercise) had higher CT in the fusiform gyrus and the temporal pole. Additionally, dose-response associations between PA and CT were found in the fusiform gyrus (B = 0.011, SE = 0.004, adj. p = 0.035), the temporal pole (B = 0.026, SE = 0.009, adj. p = 0.048), and the caudal middle frontal gyrus, the entorhinal, medial orbitofrontal, lateral occipital, and insular cortices. CONCLUSION: This study demonstrates a positive association between PA level and CT in temporal areas such as the fusiform gyrus, a brain region often associated to Alzheimer's disease in people aged 70 years and older. Future investigations focusing on PA type may help to fulfil remaining knowledge gaps in this field.

Digital ergonomics and digital work planning in university education: experiences from Germany and Austria.

The publication presents an overview of the use of digital human models (DHM) in academic education at five exemplary universities in Germany and Austria. In addition to the presentation of different human models, the integration of them into the respective lectures is discussed. The teaching concepts of the individual courses of the universities, exercise examples and scenarios are presented. Experience shows that the active and independent use of digital ergonomics tools gives students pleasure and motivates them to deal intensively with complex tasks in terms of time and content. Feedback is consistently positive over all the involved lectures and universities. As a consequence of the recent Covid-19 pandemic, universities significantly increased online and blended learning. Based on the experience with the use of digital human models, the paper derives recommendations for future developments. Practical Relevance To sustain global value chains, companies are increasingly planning trans-regionally adapted products and production processes. Tools for digital ergonomics contribute to increasing competitiveness by using prospective working methods. Companies increasingly need experts with the corresponding know-how. Firmly anchoring the topic of digital ergonomics in relevant subjects of university teaching is therefore a prerequisite for this transfer of trained graduates.

Prodromal characteristics of dementia with Lewy bodies: baseline results of the MEMENTO memory clinics nationwide cohort.

BACKGROUND: Isolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. METHODS: Participants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done. RESULTS: The pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years. CONCLUSIONS: Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01926249.

Association of APOE ε4 with cerebral gray matter volumes in non-demented older adults: The MEMENTO cohort study.

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2. METHODS: We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed. FINDINGS: Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36-57) in the riluzole group and 49 years (40-56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5-16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of -10·3% (95% CI -37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR -1·5 to 1·5) in the riluzole group versus 0·3 points (-1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49). INTERPRETATION: We were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials. FUNDING: French Ministry of Health.

Shape variability of the central sulcus in the developing brain: A longitudinal descriptive and predictive study in preterm infants.

Despite growing evidence of links between sulcation and function in the adult brain, the folding dynamics, occurring mostly before normal-term-birth, is vastly unknown. Looking into the development of cortical sulci in infants can give us keys to address fundamental questions: what is the sulcal shape variability in the developing brain? When are the shape features encoded? How are these morphological parameters related to further functional development? In this study, we aimed to investigate the shape variability of the developing central sulcus, which is the frontier between the primary somatosensory and motor cortices. We studied a cohort of 71 extremely preterm infants scanned twice using MRI - once around 30 weeks post-menstrual age (w PMA) and once at term-equivalent age, around 40w PMA -, in order to quantify the sulcus's shape variability using manifold learning, regardless of age-group or hemisphere. We then used these shape descriptors to evaluate the sulcus's variability at both ages and to assess hemispheric and age-group specificities. This led us to propose a description of ten shape features capturing the variability in the central sulcus of preterm infants. Our results suggested that most of these features (8/10) are encoded as early as 30w PMA. We unprecedentedly observed hemispheric asymmetries at both ages, and the one captured at term-equivalent age seems to correspond with the asymmetry pattern previously reported in adults. We further trained classifiers in order to explore the predictive value of these shape features on manual performance at 5 years of age (handedness and fine motor outcome). The central sulcus's shape alone showed a limited but relevant predictive capacity in both cases. The study of sulcal shape features during early neurodevelopment may participate to a better comprehension of the complex links between morphological and functional organization of the developing brain.

Neuroimaging correlates of persistent fatigue in older adults: A secondary analysis from the Multidomain Alzheimer Preventive Trial (MAPT) trial.

OBJECTIVES: Fatigue has been suggested as a marker of biological aging. It seems plausible that this symptom might be associated with changes in brain health. The objective of this study was to examine the associations between persistent fatigue and neuroimaging correlates in a non-disease-specific population of community-dwelling older adults. METHODS: We performed a cross-sectional analysis using data from The Multidomain Alzheimer Preventive Trial (MAPT). We included 458 subjects. Persistent fatigue was defined as meeting exhaustion criterion of Fried frailty phenotype in two consecutive clinical visits six months apart between study baseline and one year. Brain imaging correlates, assessed by magnetic resonance imaging (MRI), were the outcomes. The associations between persistent fatigue and brain correlates were explored using mixed model linear regressions with random effect at the center level. RESULTS: The mean age of the participants was 74.8 ± 4 years old, and 63% of the subjects were women. Forty-seven participants (10%) exhibited a persistent fatigue profile. People with persistent fatigue were older compared to subjects without persistent fatigue (76.2 years ± 4.3 vs.74.7 ± 3.9 p = 0.009). Persistent fatigue was associated with higher white matter hyperintensity volume in the fully adjusted analysis. We did not find any cross-sectional association between persistent fatigue and sub-cortical volumes and global and regional cortical thickness. CONCLUSION: Persistent fatigue was cross-sectionnally associated with higher white matter hyperintensity volume in older adults. Further longitudinal studies, using an assessment tool specifically designed and validated for measuring fatigue, are needed to confirm our findings.

Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint: Subset from the Montpellier center of the ancillary MAPT-MRI study.

Introduction: The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC). Methods: To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints. Results: No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden. Discussion: These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

As predicted by theory: choice and competition in a publicly funded and regulated regional health system yield improved access and cost control.

BACKGROUND: New Public Management (NPM) has been widely used to introduce competition into public healthcare. Results have been mixed, and there has been much controversy about the appropriateness of a private sector-mimicking governance model in a public service. One voice in the debate suggested that rather than discussing whether competition is "good" or "bad" the emphasis should be on exploring the conditions for a successful implementation. METHODS: We report a longitudinal case study of the introduction of patient choice and allowing private providers to enter a publicly funded market. Patients in need of hip or knee replacement surgery are allowed to choose provider, and those are paid a fixed reimbursement for the full care episode (bundled payment). Providers are financially accountable for complications. Data on number of patients, waiting lists and times, costs to the public purchaser, and complications were collected from public registries. Providers were interviewed at three points in time during a nine-year follow-up period. Time-series of the quantitative data were exhibited and the views of actors involved were explored in a thematic analysis of the interviews. RESULTS: The policy goals of improving access to care and care quality while controlling total costs were achieved in a sustained way. Six themes were identified among actors interviewed and those were consistent over time. The design of the patient choice model was accepted, although all providers were discontent with the level of reimbursement. Providers felt that quality, timeliness of service and staff satisfaction had improved. Public and private providers differed in terms of patient-mix and developed different strategies to adjust to the reimbursement system. Private providers were more active in marketing and improving operation room efficiency. All providers intensified cooperation with referring physicians. Close attention was paid to following the rules set by the purchaser. DISCUSSION AND CONCLUSIONS: The sustained cost control was an effect of bundled payment. What this study shows is that both public and private providers adhere long-term to regulations by a public purchaser that also controls entrance to the market. The compensation was fixed and led to competition on quality, as predicted by theory.

Clinical relevance of brain atrophy subtypes categorization in memory clinics.

INTRODUCTION: The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. METHODS: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. RESULTS: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups. DISCUSSION: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.

Biological and Neuroimaging Markers as Predictors of 5-Year Incident Frailty in Older Adults: A Secondary Analysis of the MAPT Study.

BACKGROUND: This study aims to investigate the predictive value of biological and neuroimaging markers to determine incident frailty among older people for a period of 5 years. METHODS: We included 1394 adults aged 70 years and older from the Multidomain Alzheimer Preventive Trial, who were not frail at baseline (according to Fried's criteria) and who had at least 1 post-baseline measurement of frailty. Participants who progressed to frailty during the 5-year follow-up were categorized as "incident frailty" and those who remained non-frail were categorized as "without frailty." The differences of baseline biochemical factors (25-hydroxyvitamin D, homocysteine, omega-3 index, C-reactive protein), other biological markers (Apolipoprotein E genotypes, amyloid-ß deposits), and neuroimaging data (gray matter volume, hippocampal volume, white matter hyperintensities) were compared between groups. Cox proportional hazard model was used to evaluate the associations between biomarkers and incident frailty. RESULTS: A total of 195 participants (14.0%) became frail over 5 years. Although 25-hydroxyvitamin D deficiency, homocysteine levels, low-grade inflammation (persistently increased C-reactive protein 3-10 mg/L), gray matter, and hippocampal volume were significantly associated with incident frailty in unadjusted models, these associations disappeared after adjustment for age, sex, and other confounders. Omega-3 index was the sole marker that presented a trend of association with incident frailty (hazard ratio: 0.92; 95% confidence interval: 0.83-1.01; p = .082). CONCLUSIONS: This study failed to identify biomarkers able to predict frailty incidence in community-dwelling older adults for a period of 5 years. Further longitudinal research with multiple measurements of biomarkers and frailty is needed to evaluate the long-term relationships between changes in biomarkers levels and frailty evolution.

Subjective cognitive and non-cognitive complaints and brain MRI biomarkers in the MEMENTO cohort.

INTRODUCTION: Subjective cognitive complaints may be a signature of preclinical stage Alzheimer's disease. However, the link between subjective cognitive and non-cognitive complaints and brain alterations remains unclear. METHODS: The relationship between cognitive and non-cognitive complaints and brain biomarkers, measured by structural magnetic resonance imaging, was investigated in 2056 participants of the MEMENTO cohort of outpatients, who were dementia-free at baseline. We assessed whether the cognitive status at inclusion or the presence of the apolipoprotein E gene variant (APOE) ε4 could modulate the association between the intensity of complaints and brain lesions. RESULTS: Smaller hippocampal volume was associated with higher memory complaints and discomfort in daily life. In APOE ε4 carriers, smaller whole-brain white matter and gray matter volumes and gyrification indices in several regions of interest of the parietal and temporal lobes, in the entorhinal and the para-hippocampal gyrus, were associated with higher memory complaint score. CONCLUSIONS: The intensity of subjective complaints in not only memory but discomfort in daily life was associated with brain degeneration markers. The presence of APOE ε4 modulated the relationships between subjective memory complaints and brain alterations.

Cross-sectional and prospective associations between cerebral cortical thickness and frailty in older adults.

BACKGROUND: Several neurodegenerative markers measured by magnetic resonance imaging (MRI) have shown to be related with frailty. While most studies have focused on surrogates of cerebral vascular damage such as increased white matter lesions, the associations between cortical atrophy and frailty were less often investigated. OBJECTIVES: To investigate the cross-sectional and prospective associations between cortical thickness and frailty evolution in older adults. METHODS: We enrolled 484 community-dwelling adults aged ≥70 years, participants from the Multidomain Alzheimer Preventive Trial (MAPT), with data on cerebral cortical thickness and frailty. Cortical thickness was acquired by MRI for whole-brain and regional cortices. Two function-specific regions of interest, i.e., mobility-related regions and Alzheimer's disease (AD) signature, were selected on the basis of previous studies. Frailty status was assessed by the Fried frailty phenotype (i.e., weakness, slowness, involuntary weight loss, fatigue and low physical activity level) at baseline, after 6 months and every year until the end of the 5-year follow-up. RESULTS: Older adults with higher global cortical thickness were less likely to be pre-frail and frail at baseline (adjusted OR: 0.13, 95% CI: 0.03-0.65, p = 0.013). In addition, higher cortical thickness in mobility-related and AD-signature regions were associated with lower likelihood of being pre-frail and frail. Similar associations were observed for having weakness and slowness. However, neither global nor region-specific cortical thickness showed prospective associations with future frailty onset. CONCLUSIONS: The global and regional cortical thickness cross-sectionally associated with frailty in older adults, but no prospective associations with incident frailty were found. The longitudinal relationship between cortical thickness and frailty evolution requires further investigation.

"Plis de passage" Deserve a Role in Models of the Cortical Folding Process.

Cortical folding is a hallmark of brain topography whose variability across individuals remains a puzzle. In this paper, we call for an effort to improve our understanding of the pli de passage phenomenon, namely annectant gyri buried in the depth of the main sulci. We suggest that plis de passage could become an interesting benchmark for models of the cortical folding process. As an illustration, we speculate on the link between modern biological models of cortical folding and the development of the Pli de Passage Frontal Moyen (PPFM) in the middle of the central sulcus. For this purpose, we have detected nine interrupted central sulci in the Human Connectome Project dataset, which are used to explore the organization of the hand sensorimotor areas in this rare configuration of the PPFM.

Alteration of the Cortex Shape as a Proxy of White Matter Swelling in Severe Cerebral Small Vessel Disease.

CADASIL is a monogenic small vessel disease characterized by the accumulation of brain tissue lesions of microvascular origin leading to strokes and cognitive deficits. Both cortical and parenchymal alterations have been described using various MRI markers. However, relationships between cortical and subcortical alterations remain largely unexplored. While brain atrophy is a preponderant feature in cerebral small vessel disease, recent results in CADASIL suggest slightly larger brain volumes and increased white matter water content at early stages of the disease by comparison to controls. We hypothesized in this study that increased water content in gyral white matter balances expected brain atrophy. Direct white matter volume computation is challenging in these patients given widespread subcortical alterations. Instead, our approach was that a gyral white matter swelling would translate into a modification of the shape of cortical gyri. Our goal was then to assess the relationship between subcortical lesions and possible alteration of the cortex shape. More specifically, aims of this work were to assess 1) morphometric differences of the cortex shape between CADASIL patients and controls 2) the relationship between the cortex shape and the volume of white matter hyperintensities (WMH), a reflect of white matter alterations. Twenty-one patients at the early stage of the disease and 28 age- and sex-matched controls were included. Cortical surfaces were reconstructed from 3D-T1-weighted images. Folding power assessed from spectral analysis of gyrification and cortical morphometry using curvedness and shape index were computed as proxies of the cortex shape. Influence of segmentation errors were evaluated through the simulation of WMH in controls. As a result, patients had larger folding power and curvedness compared to controls. They also presented lower shape indices both related to sulci and gyri. In patients, the volume of WMH was associated with decreased gyral shape index. These results suggest that the cortex shape of CADASIL patients is different compared to controls and that the enlargement of gyri is related to the extent of white matter alterations. The study of the cortex shape might be another way to evaluate subcortical swelling or atrophy in various neurological disorders.

The dynamics of cortical folding waves and prematurity-related deviations revealed by spatial and spectral analysis of gyrification.

In the human brain, the appearance of cortical sulci is a complex process that takes place mostly during the second half of pregnancy, with a relatively stable temporal sequence across individuals. Since deviant gyrification patterns have been observed in many neurodevelopmental disorders, mapping cortical development in vivo from the early stages on is an essential step to uncover new markers for diagnosis or prognosis. Recently this has been made possible by MRI combined with post-processing tools, but the reported results are still fragmented. Here we aimed to characterize the typical folding progression ex utero from the pre- to the post-term period, by considering 58 healthy preterm and full-term newborns and infants imaged between 27 and 62 weeks of post-menstrual age. Using a method of spectral analysis of gyrification (SPANGY), we detailed the spatial-frequency structure of cortical patterns in a quantitative way. The modeling of developmental trajectories revealed three successive waves that might correspond to primary, secondary and tertiary folding. Some deviations were further detected in 10 premature infants without apparent neurological impairment and imaged at term equivalent age, suggesting that our approach is sensitive enough to highlight the subtle impact of preterm birth and extra-uterine life on folding.

eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data.

The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (SE = 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer's disease in which brain shrinkage is a key biomarker.

Three-Dimensional Probabilistic Maps of Mesial Temporal Lobe Structures in Children and Adolescents' Brains.

The hippocampus and the adjacent perirhinal, entorhinal, temporopolar, and parahippocampal cortices are interconnected in a hierarchical MTL system crucial for memory processes. A probabilistic description of the anatomical location and spatial variability of MTL cortices in the child and adolescent brain would help to assess structure-function relationships. The rhinal sulcus (RS) and the collateral sulcus (CS) that border MTL cortices and influence their morphology have never been described in these populations. In this study, we identified the aforementioned structures on magnetic resonance images of 38 healthy subjects aged 7-17 years old. Relative to sulcal morphometry in the MTL, we showed RS-CS conformation is an additional factor of variability in the MTL that is not explained by other variables such as age, sex and brain volume; with an innovative method using permutation testing of the extrema of structures of interest, we showed that RS-SC conformation was not associated with differences of location of MTL sulci. Relative to probabilistic maps, we offered for the first time a systematic mapping of MTL structures in children and adolescent, mapping all the structures of the MTL system while taking sulcal morphology into account. Our results, with the probabilistic maps described here being freely available for download, will help to understand the anatomy of this region and help functional and clinical studies to accurately test structure-function hypotheses in the MTL during development. Free access to MTL pediatric atlas: http://neurovault.org/collections/2381/.