Prevalence, Severity, and Clinical Management of Brain Incidental Findings in Healthy Young Adults: MRi-Share Cross-Sectional Study.

Background and Objectives: Young adults represent an increasingly large proportion of healthy volunteers in brain imaging research, but descriptions of incidental findings (IFs) in this age group are scarce. We aimed to assess the prevalence and severity of IFs on brain MRIs of healthy young research participants aged 18-35 years, and to describe the protocol implemented to handle them. Methods: The study population comprised 1,867 participants aged 22.1 ± 2.3 years (72% women) from MRi-Share, the cross-sectional brain MRI substudy of the i-Share student cohort. IFs were flagged during the MRI quality control. We estimated the proportion of participants with IFs [any, requiring medical referral, potentially serious (PSIFs) as defined in the UK biobank]: overall, by type and severity of the final diagnosis, as well as the number of IFs. Results: 78/1,867 participants had at least one IF [4.2%, 95% Confidence Interval (CI) 3.4-5.2%]. IFs requiring medical referral (n = 38) were observed in 36/1,867 participants (1.9%, 1.4-2.7%), and represented 47.5% of the 80 IFs initially flagged. Referred IFs were retrospectively classified as PSIFs in 25/1,867 participants (1.3%, 0.9-2.0%), accounting for 68.4% of anomalies referred (26/38). The most common final diagnosis was cysts or ventricular abnormalities in all participants (9/1,867; 0.5%, 0.2-0.9%) and in those with referred IFs (9/36; 25.0%, 13.6-41.3%), while it was multiple sclerosis or radiologically isolated syndrome in participants with PSIFs (5/19; 26.3%, 11.5-49.1%) who represented 0.1% (0.0-0.4%) and 0.2% (0.03-0.5%) of all participants, respectively. Final diagnoses were considered serious in 11/1,867 participants (0.6%, 0.3-1.1%). Among participants with referred IFs, 13.9% (5/36) required active intervention, while 50.0% (18/36) were put on clinical surveillance. Conclusions: In a large brain imaging study of young healthy adults participating in research we observed a non-negligible frequency of IFs. The etiological pattern differed from what has been described in older adults.

Genetic effects on planum temporale asymmetry and their limited relevance to neurodevelopmental disorders, intelligence or educational attainment.

Previous studies have suggested that altered asymmetry of the planum temporale (PT) is associated with neurodevelopmental disorders, including dyslexia, schizophrenia, and autism. Shared genetic factors have been suggested to link PT asymmetry to these disorders. In a dataset of unrelated subjects from the general population (UK Biobank, N = 18,057), we found that PT volume asymmetry had a significant heritability of roughly 14%. In genome-wide association analysis, two loci were significantly associated with PT asymmetry, including a coding polymorphism within the gene ITIH5 that is predicted to affect the protein's function and to be deleterious (rs41298373, p = 2.01 × 10-15), and a locus that affects the expression of the genes BOK and DTYMK (rs7420166, p = 7.54 × 10-10). DTYMK showed left-right asymmetry of mRNA expression in post mortem PT tissue. Cortex-wide mapping of these SNP effects revealed influences on asymmetry that went somewhat beyond the PT. Using publicly available genome-wide association statistics from large-scale studies, we saw no significant genetic correlations of PT asymmetry with autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, educational attainment or intelligence. Of the top two individual loci associated with PT asymmetry, rs41298373 showed a tentative association with intelligence (unadjusted p = .025), while the locus at BOK/DTYMK showed tentative association with educational attainment (unadjusted Ps < .05). These findings provide novel insights into the genetic contributions to human brain asymmetry, but do not support a substantial polygenic association of PT asymmetry with cognitive variation and mental disorders, as far as can be discerned with current sample sizes.

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Multi-factorial modulation of hemispheric specialization and plasticity for language in healthy and pathological conditions: A review.

This review synthesizes anatomo-functional variability of language hemispheric representation and specialization (hemispheric specialization for language, HSL) as well as its modulation by several variables (demographic, anatomical, developmental, genetic, clinical, and psycholinguistic) in physiological and pathological conditions. The left hemisphere (LH) dominance for language, observed in approximately 90% of healthy individuals and in 70% of patients, is grounded by intra-hemispheric connections mediated by associative bundles such as the arcuate fasciculus and inter-hemispheric transcallosal connections mediated by the corpus callosum that connects homotopic regions of the left and right hemispheres (RH). In typical brains, inter-hemispheric inhibition, exerted from the LH to the RH, permits the LH to maintain language dominance. In pathological conditions, inter- and intra-hemispheric inhibition is decreased, inducing modifications on the degree of HSL and of language networks. HSL evaluation is classically performed in clinical practice with the Wada test and electro-cortical stimulation, gold standard methods. The advent of functional neuroimaging has allowed a more detailed assessment of the language networks and their lateralization, consistent with the results provided by the gold standard methods. In the first part, we describe anatomo-functional support for HSL in healthy conditions, its developmental course, its relationship with cognitive skills, and the various modulatory factors acting on HSL. The second section is devoted to the assessment of HSL in patients with focal and drug-resistant epilepsy (FDRE). FDRE is considered a neurological model associated with patterns of language plasticity, both before and after surgery: FDRE patients show significant modification of language networks induced by changes mediated by transcallosal connections (explaining inter-hemispheric patterns of language reorganization) or collateral connections (explaining intra-hemispheric patterns of language reorganization). Finally, we propose several predictive and explicative models of language organization and reorganization.

Sex-related and tissue-specific effects of tobacco smoking on brain atrophy: assessment in a large longitudinal cohort of healthy elderly.

We investigated the cross-sectional and longitudinal effects of tobacco smoking on brain atrophy in a large cohort of healthy elderly participants (65-80 years). MRI was used for measuring whole brain (WB), gray matter (GM), white matter (WM), and hippocampus (HIP) volumes at study entry time (baseline, N = 1451), and the annualized rates of variation of these volumes using a 4-year follow-up MRI in a subpart of the cohort (N = 1111). Effects of smoking status (never, former, or current smoker) at study entry and of lifetime tobacco consumption on these brain phenotypes were studied using sex-stratified AN(C)OVAs, including other health parameters as covariates. At baseline, male current smokers had lower GM, while female current smokers had lower WM. In addition, female former smokers exhibited reduced baseline HIP, the reduction being correlated with lifetime tobacco consumption. Longitudinal analyses demonstrated that current smokers, whether men or women, had larger annualized rates of HIP atrophy, as compared to either non or former smokers, independent of their lifetime consumption of tobacco. There was no effect of smoking on the annualized rate of WM loss. In all cases, measured sizes of these tobacco-smoking effects were of the same order of magnitude than those of age, and larger than effect sizes of any other covariate. These results demonstrate that tobacco smoking is a major factor of brain aging, with sex- and tissue specific effects, notably on the HIP annualized rate of atrophy after the age of 65.

White matter lesions as a predictor of depression in the elderly: the 3C-Dijon study.

BACKGROUND: There is increasing evidence for a link between cerebrovascular disease and depression in the elderly but the mechanisms are still unknown. This study examines the longitudinal relationship between depression and white matter lesions (WML) in a sample of elderly aged 65 years and older. METHODS: Three City (3C)-Dijon is a 4-year follow-up population-based prospective study of 1658 subjects. At baseline, lifetime major depressive episode diagnosis was established using the Mini International Neuropsychiatric Interview. At each study wave, severity of depressive symptoms was assessed using Center for Epidemiological Studies-Depression (CES-D), and antidepressants intake was recorded. At baseline, lifetime major depression (LMD) was defined as lifetime major depressive episode or antidepressant medication intake. At follow-up, subjects were classified "incident depression" if scoring high at CES-D or antidepressant users. At baseline, cerebral magnetic resonance imaging (MRI) was performed to quantify WML volumes using an automated method of detection. At 4-year follow-up, 1214 subjects had a second MRI. RESULTS: Cross-sectional analysis showed a significantly higher WML volume in subjects with LMD compared with other subjects. Adjusted longitudinal analysis showed that increase in WML load was significantly higher in subjects with baseline LMD (2.1 cm(3) vs. 1.5 cm(3), p = .004). Among subjects free of depression up to baseline (n = 956), the higher the baseline WML volume, the higher the risk of developing depression during follow-up (odds ratio one quartile increase: 1.3; 95% confidence interval: = 1.1-1.7). CONCLUSIONS: Our data show that depression and WML volumes are strongly related. These results are consistent with the hypothesis of a vascular depression in the elderly.