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Background and objectives The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes—and their microstructural underpinnings—remain unclear. Eighteen healthy males received 1 hour of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

Background White matter hyperintensities (WMH) are the result of cerebral small vessel disease and may increase the risk of cognitive impairment (CI), recurrent stroke, and depression. We aimed to explore the association between selected cerebrovascular risk factors (CVRF) and WMH load as well as the effect of increased WMH burden on recurrent vascular events, CI, and depression in first-ever ischemic stroke patients. Methods 431 from the PROSpective Cohort with Incident Stroke (PROSCIS) were included; Age-Related White Matter Changes (ARWMC) score was used to assess WMH burden on FLAIR. The presence of CVRF (defined via blood pressure, body-mass-index, and serological markers of kidney dysfunction, diabetes mellitus, and hyperlipoproteinemia) was categorized into normal, borderline, and pathological profiles based on commonly used clinical definitions. The primary outcomes included recurrent vascular events (combined endpoint of recurrent stroke, myocardial infarction and/or death), CI 3 years post-stroke, and depression 1-year post-stroke. Results There was no clear association between CVRF profiles and WMH burden. High WMH lesion load (ARWMC score ≥ 10) was found to be associated with CI (adjusted OR 1.05 [95% CI 1.00–1.11]; p p = 0.18). WMH burden was not associated with depression 1-year post stroke (adjusted OR 0.72 [95% CI 0.31–1.64]; p = 0.44). Conclusion Higher WMH burden was associated with a significant decline in cognition 3 years post-stroke in this cohort of first-ever stroke patients.

Background White matter hyperintensities (WMH) in subjects across the Alzheimer’s disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology—not just arterial hypertension—impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition. Methods We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function—derived from multiple neuropsychological tests using confirmatory factor analysis—, baseline preclinical Alzheimer’s cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5). Results Subjects with hypertension or Aβ positivity presented the largest WMH volumes (pFDR pFDR direct effect—memory: − 0.33 ± 0.08, pFDR pFDR pFDR = 0.006; ΔPACC5: − 0.34 ± 0.04, pFDR indirect-only effect—memory: − 0.05 ± 0.02, pFDR = 0.029; executive: − 0.04 ± 0.02, pFDR = 0.067; PACC5: − 0.05 ± 0.02, pFDR = 0.030; ΔPACC5: − 0.09 ± 0.03, pFDR = 0.043) and WMH in the optic radiation partially mediated that between Aβ positivity and memory (indirect effect—memory: − 0.05 ± 0.02, pFDR = 0.029). Conclusions Posterior white matter is susceptible to hypertension and Aβ accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies. Trial registration German Clinical Trials Register (DRKS00007966, 04/05/2015).

ObjectivesIt has been suggested that diffusion tensor imaging (DTI) measures sensitive to white matter (WM) damage may predict future dementia risk not only in cerebral small vessel disease (SVD), but also in mild cognitive impairment. To determine whether DTI measures were associated with cognition cross-sectionally and predicted future dementia risk across the full range of SVD severity, we established the International OPtimising mulTImodal MRI markers for use as surrogate markers in trials of Vascular Cognitive Impairment due to cerebrAl small vesseL disease collaboration which included six cohorts.MethodsAmong the six cohorts, prospective data with dementia incidences were available for three cohorts. The associations between six different DTI measures and cognition or dementia conversion were tested. The additional contribution to prediction of other MRI markers of SVD was also determined.ResultsThe DTI measure mean diffusivity (MD) median correlated with cognition in all cohorts, demonstrating the contribution of WM damage to cognition. Adding MD median significantly improved the model fit compared to the clinical risk model alone and further increased in all single-centre SVD cohorts when adding conventional MRI measures. Baseline MD median predicted dementia conversion. In a study with severe SVD (SCANS) change in MD median also predicted dementia conversion. The area under the curve was best when employing a multimodal MRI model using both DTI measures and other MRI measures.ConclusionsOur results support a central role for WM alterations in dementia pathogenesis in all cohorts. DTI measures such as MD median may be a useful clinical risk predictor. The contribution of other MRI markers varied according to disease severity.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10−8), was associated with F2 expression in blood (P = 6.4 × 10−5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood–brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood–brain barrier possibly due to disrupted cell–cell and cell–extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood–brain barrier disruption.

Although endurance running (ER) seems to be a simple repetitive exercise, good ER performance also requires and relies on multiple cognitive and motor control processes. Most of previous neuroimaging studies on ER were conducted using a single MRI modality, yet no multimodal study to our knowledge has been performed in this regard. In this study, we used multimodal MRI data to investigate the brain structural and functional differences between endurance runners (n = 22; age = 26.27 ± 6.07 years; endurance training = 6.23 ± 2.41 years) and healthy controls (HCs; n = 20; age = 24.60 ± 4.14 years). Compared with the HCs, the endurance runners showed greater gray matter volume (GMV) and cortical surface area in the left precentral gyrus, which at the same time had higher functional connectivity (FC) with the right postcentral and precentral gyrus. Subcortically, the endurance runners showed greater GMV in the left hippocampus and regional inflation in the right hippocampus. Using the bilateral hippocampi as seeds, further seed-based FC analyses showed higher hippocampal FC with the supplementary motor area, middle cingulate cortex, and left posterior lobe of the cerebellum. Moreover, compared with the HCs, the endurance runners also showed higher fractional anisotropy in several white matter regions, involving the corpus callosum, left internal capsule, left corona radiata, left external capsule, left posterior lobe of cerebellum and bilateral precuneus. Taken together, our findings provide several lines of evidence for the brain structural and functional differences between endurance runners and HCs. The current data suggest that these brain characteristics may have arisen as a result of regular ER training; however, whether they represent the neural correlates underlying the good ER performances of the endurance runners requires further investigations.

ObjectiveTo investigate serum neurofilament light protein (sNfL) levels in patients with spinocerebellar ataxia type 3 (SCA3) and to determine whether they are associated with disease severity.MethodsThis cross-sectional study enrolled 185 healthy controls and 235 ATXN3 mutation carriers (17 asymptomatic stage, 20 preclinical stage, and 198 ataxic stage). We measured sNfL levels with the single molecule array (Simoa) platform. Clinical disease severity was assessed using the Scale of Assessment and Rating of Ataxia (SARA) and the Inventory of Nonataxia Signs (INAS). In a subgroup of 50 ataxic stage patients, we further evaluated the gray matter volume and the integrity of white matter fibers by MRI.ResultssNfL concentrations were elevated in asymptomatic, preclinical, and ataxic ATXN3 mutation carriers compared to controls (12.18 [10.20–13.92], 21.84 [18.37–23.45], 36.06 [30.04–45.90], and 8.24 [5.92–10.84] pg/mL, median [interquartile range], respectively, p < 0.001). sNfL correlated with SARA (r = 0.406, 95% confidence interval [CI] 0.284–0.515, p < 0.0001) and INAS (r = 0.375, 95% CI 0.250–0.487, p < 0.0001), and remained significant after adjustment for age and CAG repeats. In addition, we observed negative correlations of the sNfL with gray matter volume in the left precentral gyrus and the left paracentral lobule as well as with the mean diffusivity in widespread white matter tracts.ConclusionOur results demonstrate that sNfL levels are increased in SCA3 and are associated with clinical disease severity, which supports sNfL as a biomarker for disease severity in SCA3.Classification of evidenceThis study provides Class II evidence that in patients with SCA3, sNfL elevations are associated with clinical disease severity.

ObjectiveTo examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS).MethodsFor the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool–based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes.ResultsPatients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all p < 0.001). Median WMHv in all patients with AIS was 5.86 cm3 (interquartile range 2.18–14.61 cm3) and differed significantly across CCS subtypes (p < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all p < 0.001), and diabetes mellitus (p = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes (p < 0.001).ConclusionIn this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke.

Objective To systematically investigate causal relationships between obesity and cerebrovascular disease and the extent to which hypertension and hyperglycemia mediate the effect of obesity on cerebrovascular disease. Methods We used summary statistics from genome-wide association studies for body mass index (BMI), waist-to-hip ratio (WHR), and multiple cerebrovascular disease phenotypes. We explored causal associations with 2-sample Mendelian randomization (MR) accounting for genetic covariation between BMI and WHR, and we assessed what proportion of the association between obesity and cerebrovascular disease was mediated by systolic blood pressure (SBP) and blood glucose levels, respectively. Results Genetic predisposition to higher BMI did not increase the risk of cerebrovascular disease. In contrast, for each 10% increase in WHR there was a 75% increase (95% confidence interval [CI] = 44-113%) in risk for large artery ischemic stroke, a 57% (95% CI = 29-91%) increase in risk for small vessel ischemic stroke, a 197% increase (95% CI = 59-457%) in risk of intracerebral hemorrhage, and an increase in white matter hyperintensity volume (β = 0.11, 95% CI = 0.01-0.21). These WHR associations persisted after adjusting for genetic determinants of BMI. Approximately one-tenth of the observed effect of WHR was mediated by SBP for ischemic stroke (proportion mediated: 12%, 95% CI = 4-20%), but no evidence of mediation was found for average blood glucose. Interpretation Abdominal adiposity may trigger causal pathological processes, partially independent from blood pressure and totally independent from glucose levels, that lead to cerebrovascular disease. Potential targets of these pathological processes could represent novel therapeutic opportunities for stroke. ANN NEUROL 2020;87:516-524.

Sporadic degenerative ataxia patients fall into 2 major groups: multiple system atrophy with predominant cerebellar ataxia (MSA-C) and sporadic adult-onset ataxia (SAOA). Both groups have cerebellar volume loss, but little is known about the differential involvement of gray and white matter in MSA-C when compared with SAOA.The objective of this study was to identify structural differences of brain gray and white matter between both patient groups.We used magnetic resonance imaging to acquire T1-weighted images and diffusion tensor images from 12 MSA-C patients, 31 SAOA patients, and 55 healthy controls. Magnetic resonance imaging data were analyzed with voxel-based-morphometry, tract-based spatial statistics, and tractography-based regional diffusion tensor images analysis.Whole-brain and cerebellar-focused voxel-based-morphometry analysis showed gray matter volume loss in both patient groups when compared with healthy controls, specifically in the cerebellar areas subserving sensorimotor functions. When compared with controls, the SAOA and MSA-C patients showed white matter loss in the cerebellum, whereas brainstem white matter was reduced only in the MSA-C patients. The tract-based spatial statistics revealed reduced fractional anisotropy within the pons and cerebellum in the MSA-C patients both in comparison with the SAOA patients and healthy controls. In addition, tractography-based regional analysis showed reduced fractional anisotropy along the corticospinal tracts in MSA-C, but not SAOA.Although in our cohort extent and distribution of gray and white matter loss were similar between the MSA-C and SAOA patients, magnetic resonance imaging data showed prominent microstructural white matter involvement in the MSA-C patients that was not present in the SAOA patients. Our findings highlight the significance of microstructural white matter changes in the differentiation between both conditions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Alzheimer’s disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer’s and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer’s disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer’s disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer’s disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fibre density captures the effect of cerebral small vessel disease, while fibre-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine.

Background and ObjectivesMounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in older people. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim was to investigate these sex differences and age dependencies in WMH load across the adult life span and to examine the effect of menopause.MethodsThis cross-sectional analysis was based on participants of the population-based Rhineland Study (30–95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardized) using linear regression models while adjusting for age, age-squared, and vascular risk factors. We checked for an age × sex and (un)controlled hypertension × sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged 59 years or younger), men with postmenopausal women (persons aged 45 years or older), and premenopausal with postmenopausal women (age range 45–59 years).ResultsOf 3,410 participants with a mean age of 54.3 years (SD = 13.7), 1,973 (57.9%) were women, of which 1,167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared with men of similar age. In addition, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age. Women with uncontrolled hypertension had a higher WMH burden compared with men, which was unrelated to menopausal status.DiscussionAfter menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiologic changes that may inform on causal mechanisms involved in cerebral small vessel disease progression.

Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood. The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (n = 125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias (HSP; n = 40), a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups. After sDTI measurement at C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established. In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTFA (p < 0.001), elevated PTRD (p = 0.002) and reduced PTMD (p = 0.003) compared to healthy controls. Furthermore, FA was significantly reduced in DCFA (p < 0.001) with no differences in AH. In a genetically homogeneous subgroup of SPG4 patients (n = 12) with affection of the dorsal columns, DCRD significantly correlated with the overall disease severity as measured by the Spastic Paraplegia Rating Scale (SPRS) (r = - 0.713, p = 0.009). With the most extensive sDTI study in vivo to date, we showed that axial sDTI combined with motion correction and advanced data post-processing strategies enables robust measurements and is ready to use, allowing recognition and quantification of disease- and age-related changes of the PT, DC, and AH. These results may also encourage the usage of sDTI in other neurodegenerative diseases with spinal cord involvement to explore its capability as selective biomarkers.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-β, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

The human claustrum is a gray matter structure in the white matter between insula and striatum. Previous analysis found altered claustrum microstructure in very preterm-born adults associated with lower cognitive performance. As the claustrum development is related to hypoxia-ischemia sensitive transient cell populations being at-risk in premature birth, we hypothesized that claustrum structure is already altered in preterm-born neonates. We studied anatomical and diffusion-weighted MRIs of 83 preterm- and 83 term-born neonates at term-equivalent age. Additionally, claustrum development was analyzed both in a spectrum of 377 term-born neonates and longitudinally in 53 preterm-born subjects. Data was provided by the developing Human Connectome Project. Claustrum development showed increasing volume, increasing fractional anisotropy (FA), and decreasing mean diffusivity (MD) around term both across term- and preterm-born neonates. Relative to term-born ones, preterm-born neonates had (i) increased absolute and relative claustrum volumes, both indicating increased cellular and/or extracellular matter and being in contrast to other subcortical gray matter regions of decreased volumes such as thalamus; (ii) lower claustrum FA and higher claustrum MD, pointing at increased extracellular matrix and impaired axonal integrity; and (iii) aberrant covariance between claustrum FA and MD, respectively, and that of distributed gray matter regions, hinting at relatively altered claustrum microstructure. Results together demonstrate specifically aberrant claustrum structure in preterm-born neonates, suggesting altered claustrum development in prematurity, potentially relevant for later cognitive performance.

Introduction White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear. Methods Regional WMH were estimated in 54 cognitively impaired amyloid beta-positive AD (Aβpos-AD), compared to 40 cognitively unimpaired amyloid beta-negative older controls (Aβneg-controls) matched for vascular risk factors. The cross-sectional association between regional WMH volume and cognition was assessed within each group, controlling for cerebral amyloid burden, global cortical atrophy, and hippocampal atrophy. Results WMH volume was larger in Aβpos-AD compared to Aβneg-controls in all regions, with the greatest changes in the splenium of the corpus callosum (S-CC). In Aβpos-AD patients, larger total and regional WMH volume, especially in the S-CC, was strongly associated with decreased cognition. Discussion WMH specifically contribute to lower cognition in AD, independently from amyloid deposition and atrophy. This study emphasizes the clinical relevance of WMH in AD, especially posterior WMH, and most notably S-CC WMH.

Several observations suggest an impact of prematurity on the claustrum. First, the claustrum’s development appears to depend on transient subplate neurons of intra-uterine brain development, which are affected by prematurity. Second, the claustrum is the most densely connected region of the mammalian forebrain relative to its volume; due to its effect on pre-oligodendrocytes, prematurity impacts white matter connections and thereby the development of sources and targets of such connections, potentially including the claustrum. Third, due to its high connection degree, the claustrum contributes to general cognitive functioning (e.g., selective attention and task switching/maintaining); general cognitive functioning, however, is at risk in prematurity. Thus, we hypothesized altered claustrum structure after premature birth, with these alterations being associated with impaired general cognitive performance in premature born persons. Using T1-weighted and diffusion-weighted magnetic resonance imaging in 70 very preterm/very low-birth-weight (VP/VLBW) born adults and 87 term-born adults, we found specifically increased mean diffusivity in the claustrum of VP/VLBW adults, associated both with low birth weight and at-trend with reduced IQ. This result demonstrates altered claustrum microstructure after premature birth. Data suggest aberrant claustrum development, which is potentially related with aberrant subplate neuron and forebrain connection development of prematurity., This work was supported by the Deutsche Forschungsgemeinschaft (SO 1336/1-1 to C.S.; BA 6370/2-1), German Federal Ministry of Education and Science (BMBF 01ER0801 to P.B. and D.W., BMBF 01ER0803 to C.S.), and the Kommission für Klinische Forschung, Technische Universität München (KKF 8765162 to C.S. and KKF8700000474 to D.M.H.). Michel J. Grothe is supported by the “Miguel Servet” program [CP19/00031] and a research grant [PI20/00613] of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER).

Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.

Retinal assessments have been discussed as biomarkers for brain atrophy. However, available studies did not investigate all retinal layers due to older technology, reported inconsistent results, or were based on small sample sizes. We included 2872 eligible participants of the Rhineland Study with data on spectral domain–optical coherence tomography (SD–OCT) and brain magnetic resonance imaging (MRI). We used multiple linear regression to examine relationships between retinal measurements and volumetric brain measures as well as fractional anisotropy (FA) as measure of microstructural integrity of white matter (WM) for different brain regions. Mean (SD) age was 53.8 ± 13.2 years (range 30–94) and 57% were women. Volumes of the inner retina were associated with total brain and grey matter (GM) volume, and even stronger with WM volume and FA. In contrast, the outer retina was mainly associated with GM volume, while both, inner and outer retina, were associated with hippocampus volume. While we extend previously reported associations between the inner retina and brain measures, we found additional associations of the outer retina with parts of the brain. This indicates that easily accessible retinal SD-OCT assessments may serve as biomarkers for clinical monitoring of neurodegenerative diseases and merit further research.

Several studies report neurological complications such as brain injury induced by ischemia or edema following exhaustive endurance sport. We aimed to detect the frequency of acute brain lesions after a marathon race. In the prospective observational Berlin Beat of Running study, 110 experienced endurance athletes underwent 3-Tesla brain MRI exams 2–3 days prior and within 2 days after a marathon run. MRI results were compared to an age- and sex-matched control group of 68 non-athletes, including the “Age-Related White Matter Changes” (ARWMC) scale to assess white matter lesions (WML) in the brain. 108 athletes (median age 48 years, 24% female, 8% with hypertension; 0% with diabetes) completed the race. No athlete reported neurological deficits, but a single acute ischemic lesion was detected in diffusion-weighted MRI after the race in one athlete. No other acute brain lesions compared to prior MRI were found. An ARWMC score ≥4 was found in 15% of athletes and 12% of non-athletic controls (p=0.7). Chronic ischemic lesions were not found in athletes but in four controls (6%) (p=0.02). In conclusion, acute ischemic brain lesions may be found in endurance runners. Every seventh endurance athlete and every ninth control showed evidence for substantial white matter lesions.

Subjective cognitive decline (SCD) can represent a preclinical stage of Alzheimer’s disease. Diffusion tensor imaging (DTI) could aid an early diagnosis, yet only few monocentric DTI studies in SCD have been conducted, reporting heterogeneous results. We investigated microstructural changes in SCD in a larger, multicentric cohort. 271 participants with SCD, mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) and healthy controls (CON) were included, recruited prospectively at nine centers of the observational DELCODE study. DTI was acquired using identical protocols. Using voxel-based analyses, we investigated fractional anisotropy (FA), mean diffusivity (MD) and mode (MO) in the white matter (WM). Discrimination accuracy was determined by cross-validated elastic-net penalized regression. Center effects were explored using variance analyses. MO and FA were lower in SCD compared to CON in several anterior and posterior WM regions, including the anterior corona radiata, superior and inferior longitudinal fasciculus, cingulum and splenium of the corpus callosum (p

ObjectiveTo investigate the relationship between baseline white matter hyperintensities (WMH) in patients with ischemic stroke and long-term risk of dementia, functional impairment, recurrent stroke, and mortality.MethodsFollowing the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO protocol: CRD42018092857), we systematically searched Medline and Scopus for cohort studies of ischemic stroke patients examining whether MRI- or CT-assessed WMH at baseline are associated with dementia, functional impairment, recurrent stroke, and mortality at 3 months or later poststroke. We extracted data and evaluated study quality with the Newcastle–Ottawa scale. We pooled relative risks (RR) for the presence and severity of WMH using random-effects models.ResultsWe included 104 studies with 71,298 ischemic stroke patients. Moderate/severe WMH at baseline were associated with increased risk of dementia (RR 2.17, 95% confidence interval [CI] 1.72–2.73), cognitive impairment (RR 2.29, 95% CI 1.48–3.54), functional impairment (RR 2.21, 95% CI 1.83–2.67), any recurrent stroke (RR 1.65, 95% CI 1.36–2.01), recurrent ischemic stroke (RR 1.90, 95% CI 1.26–2.88), all-cause mortality (RR 1.72, 95% CI 1.47–2.01), and cardiovascular mortality (RR 2.02, 95% CI 1.44–2.83). The associations followed dose-response patterns for WMH severity and were consistent for both MRI- and CT-defined WMH. The results remained stable in sensitivity analyses adjusting for age, stroke severity, and cardiovascular risk factors, in analyses of studies scoring high in quality, and in analyses adjusted for publication bias.ConclusionsPresence and severity of WMH are associated with substantially increased risk of dementia, functional impairment, stroke recurrence, and mortality after ischemic stroke. WMH may aid clinical prognostication and the planning of future clinical trials.

ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive.We performed a genome-wide association study of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity and fractional anisotropy) in up to 31 128 individuals from UK Biobank (age 45–81 years) based on a two degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP × Age effects.We identified 18 loci that were associated at genome-wide significance with either mean diffusivity (n = 16) or fractional anisotropy (n = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both mean diffusivity [best SNP: 6:28866209_TTTTG_T, beta (standard error, SE) = −0.069 (0.009); 2df P = 6.5 × 10−15] and fractional anisotropy [best SNP: rs3129787, beta (SE) = −0.056 (0.008); 2df P = 3.5 × 10−12]. Of the imputed human leukocyte antigen (HLA) alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant [for mean diffusivity: beta (SE) = −0.070 (0.010); P = 2.7 × 10−11; for fractional anisotropy: beta (SE) = −0.054 (0.011); P = 1.6 × 10−7]. After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older participants [age ≥ 65; interaction P = 0.0019 (mean diffusivity), P = 0.015 (fractional anisotropy)] and in participants without a history of smoking [interaction P = 0.00093 (mean diffusivity), P = 0.021 (fractional anisotropy)].Taken together, our findings demonstrate a role of the complement system and of gene–environment interactions in age-related loss of white matter microstructural integrity.

RationaleType 2 diabetes mellitus (T2D) is an established risk factor for cerebrovascular disease but the mechanisms underlying this association remain elusive. Disentangling the causal effects of T2D, hyperglycemia, and pre-diabetic phenotypes (insulin resistance, β-cell dysfunction) on major etiological stroke subtypes (ischemic stroke, intracerebral hemorrhage, ischemic stroke subtypes) could inform the development of preventive strategies.ObjectiveWe employed Mendelian randomization (MR) to explore the effects of genetic predisposition to T2D, hyperglycemia, insulin resistance, and β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.Methods and ResultsWe selected instruments for genetic predisposition to T2D, HbA1c levels, fasting glucose levels, insulin resistance, and β-cell dysfunction (proxied by pro-insulin levels) based on published genome-wide association studies (up to 898,130 individuals). Applying two-sample MR, we examined associations with ischemic stroke, intracerebral hemorrhage, and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke; up to 60,341 cases and 454,450 controls). We further explored associations with the related phenotypes of carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy. Genetic predisposition to T2D and elevated HbA1c levels in the pre-diabetic range were associated with higher risk of any ischemic stroke, large artery stroke, carotid plaque and small vessel stroke. Independently of HbA1c levels, we further found genetic predisposition to insulin resistance to be associated with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke. Predisposition to β-cell dysfunction was further associated with intracerebral hemorrhage, lower grey matter volume, and total brain volume.ConclusionsThis study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show differential effects of genetically determined insulin resistance and β-cell dysfunction on large artery and small vessel stroke that might have implications for anti-diabetic treatments targeting these mechanisms.

Background: White matter hyperintensities (WMH) are frequently found in Alzheimer's disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (A beta) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with A beta burden, glucose hypometabolism, and gray matter volume reduction. Methods: In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical A beta deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results: There were no significant associations between global A beta burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater A beta deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions: This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Ass deposition and neurodegeneration.

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = −0.74, standard error (SE) = 0.13, P = 9.7 × 10−9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10−6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204–364; β = 0.79, SE = 0.14, P = 9.4 × 10−8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10−59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10−4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54–35.25; P = 8.3 × 10−5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.

Diffusion-weighted magnetic resonance imaging (DWI) is undergoing constant evolution with the ambitious goal of developing in-vivo histology of the brain. A recent methodological advancement is Neurite Orientation Dispersion and Density Imaging (NODDI), a histologically validated multi-compartment model to yield microstructural features of brain tissue such as geometric complexity and neurite packing density, which are especially useful in imaging the white matter. Since NODDI is increasingly popular in clinical research and fields such as developmental neuroscience and neuroplasticity, it is of vast importance to characterize its reproducibility (or reliability). We acquired multi-shell DWI data in 29 healthy young subjects twice over a rescan interval of 4 weeks to assess the within-subject coefficient of variation (CVWS), between-subject coefficient of variation (CVBS) and the intraclass correlation coefficient (ICC), respectively. Using these metrics, we compared regional and voxel-by-voxel reproducibility of the most common image analysis approaches (tract-based spatial statistics [TBSS], voxel-based analysis with different extents of smoothing [“VBM-style”], ROI-based analysis). We observed high test–retest reproducibility for the orientation dispersion index (ODI) and slightly worse results for the neurite density index (NDI). Our findings also suggest that the choice of analysis approach might have significant consequences for the results of a study. Collectively, the voxel-based approach with Gaussian smoothing kernels of ≥4 mm FWHM and ROI-averaging yielded the highest reproducibility across NDI and ODI maps (CVWS mostly ≤3%, ICC mostly ≥0.8), respectively, whilst smaller kernels and TBSS performed consistently worse. Furthermore, we demonstrate that image quality (signal-to-noise ratio [SNR]) is an important determinant of NODDI metric reproducibility. We discuss the implications of these results for longitudinal and cross-sectional research designs commonly employed in the neuroimaging field.

ObjectiveTo test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics.MethodsWe included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners.ResultsMetrics from DKI showed the strongest associations with processing speed performance (R2 up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible.ConclusionMulti-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies.Classification of evidenceThis study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials., White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

International audience; Abstract Background White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. Methods One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). Results WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition. Conclusion WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

Inflammaging describes the complexity between low-grade chronic inflammation with the pathogenesis of brain aging and Alzheimer´s disease (AD). We aimed to find associations of inflammatory markers: i) white blood cell count (WBC), ii) high-sensitivity C-reactive protein (hs-CRP), and iii) fibrinogen with brain structures, sensitive neuroimaging markers of advanced brain aging and AD-like atrophy, and cognitive aging scores. We analyzed magnetic resonance imaging (MRI) scans of 2204 participants from the Study of Health in Pomerania-2 (SHIP-2) and SHIP-Trend (55.6% women, mean age 52.4±13.7 years). Associations of the inflammatory markers with specific brain signatures of brain aging (SPARE-BA), AD-like brain atrophy (SPARE-AD) and white matter disease (white matter hyperintensities volume (WMHV)) were investigated. Furthermore we explored their association with general brain structures including total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV), as well as cognitive scores (Nurnberger Age Inventory (NAI); Verbal Learning and Memory Test (VLMT). We adjusted for multiple vascular risk factors (VRF; e.g. smoking and blood pressure) and corresponding medication use to take their brain aging effects into account and corrected for false-discovery rate (FDR). Results:WBC was inversely associated with SPARE-BA (FDR-adjusted p=0.003), TBV (FDR-adjusted p=0.019) and GMV (FDR-adjusted p= 0.017). GMV was also inversely associated with hs-CRP (FDR-adjusted p=0.039) and fibrinogen (FDR-adjusted p=0.039). None of the inflammatory markers was associated with WMHV. Regression analysis also revealed a trend-level interaction between intake of antiinflammatory medication and hs-CRP with brain aging (SPARE-BA; FDR-adjusted p=0.062). Inflammatatory markers are associated with neuroimaging markers, with elevated WBC leading to significant acceleration in brain aging patterns but not with AD-like imaging structural changes. Given the overlap between accelerated brain aging and AD-like atrophy, increased WBC might be associated with global dementia symptoms due to this overlap in atrophy patterns. Elevated WBC may be not causal to preclinical AD dementia, but an accessory symptom of inflammaging. At population level, our results support the relevant roles of inflammatory markers on brain aging related atrophy.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases., Highlights • Serum NfL levels reflect white matter integrity in autosomal dominant Alzheimer disease. • Associations between NfL and white matter imaging are present throughout all brain regions. • Longitudinal white matter alterations are associated with changes in blood NfL. • Results improve interpretability of NfL as a marker of brain integrity.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo. Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2*) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo. Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2* maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively.

Arterial spin labeling (ASL) is increasingly applied for cerebral blood flow mapping, but \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 relaxation of the ASL signal magnetization is often ignored, although it may be clinically relevant. To investigate the extent, to which quantitative \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 values in gray matter (GM) obtained by pseudocontinuous ASL (pCASL) perfusion MRI can be reproduced, are reliable and a potential neuroscientific biomarker, a prospective study was performed with ten healthy volunteers (5F,28 ± 3y) at a 3 T scanner. A \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2-prepared pCASL sequence enabled the measurement of quantitative \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 and perfusion maps. \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 times were modeled per voxel and analyzed within four GM-regions-of-interest (ROI). The intraclass correlation coefficients (ICCs) of the quantified ASL-\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 varied across brain regions. When averaged across subjects and postlabeling delays (PLDs), the ICCs ranged from reasonable values in parietal regions (ICC = 0.56) to smaller values in frontal regions (ICC = 0.36). Corresponding subject-averaged within-subject coefficients of variation (WSCVs) showed good test–retest measurement precision (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{WSCV}}_{{{\text{PLD}}}} \le 0.14$$\end{document}WSCVPLD≤0.14 for all PLDs), but more pronounced inter-subject variance. Reliability and precision of quantified ASL-\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 were region-, PLD- and subject-specific, showing fair to robust results in occipital, parietal and temporal ROIs. The results give rise to consider the method for future cerebral studies, where variable perfusion or altered \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text{T}}_{{2}}$$\end{document}T2 times are suspected.

Contains fulltext : 282532.pdf (Publisher’s version ) (Open Access) BACKGROUND: DTI is sensitive to white matter (WM) microstructural damage and has been suggested as a surrogate marker for phase 2 clinical trials in cerebral small vessel disease (SVD). The study's objective is to establish the best way to analyse the diffusion-weighted imaging data in SVD for this purpose. The ideal method would be sensitive to change and predict dementia conversion, but also straightforward to implement and ideally automated. As part of the OPTIMAL collaboration, we evaluated five different DTI analysis strategies across six different cohorts with differing SVD severity. METHODS: Those 5 strategies were: (1) conventional mean diffusivity WM histogram measure (MD median), (2) a principal component-derived measure based on conventional WM histogram measures (PC1), (3) peak width skeletonized mean diffusivity (PSMD), (4) diffusion tensor image segmentation θ (DSEG θ) and (5) a WM measure of global network efficiency (Geff). The association between each measure and cognitive function was tested using a linear regression model adjusted by clinical markers. Changes in the imaging measures over time were determined. In three cohort studies, repeated imaging data together with data on incident dementia were available. The association between the baseline measure, change measure and incident dementia conversion was examined using Cox proportional-hazard regression or logistic regression models. Sample size estimates for a hypothetical clinical trial were furthermore computed for each DTI analysis strategy. RESULTS: There was a consistent cross-sectional association between the imaging measures and impaired cognitive function across all cohorts. All baseline measures predicted dementia conversion in severe SVD. In mild SVD, PC1, PSMD and Geff predicted dementia conversion. In MCI, all markers except Geff predicted dementia conversion. Baseline DTI was significantly different in patients converting to vascular dementia than to Alzheimer' s disease. Significant change in all measures was associated with dementia conversion in severe but not in mild SVD. The automatic and semi-automatic measures PSMD and DSEG θ required the lowest minimum sample sizes for a hypothetical clinical trial in single-centre sporadic SVD cohorts. CONCLUSION: DTI parameters obtained from all analysis methods predicted dementia, and there was no clear winner amongst the different analysis strategies. The fully automated analysis provided by PSMD offers advantages particularly for large datasets.

BACKGROUND: Falls are common among people with idiopathic Parkinson's disease (IPD) and are suggested to be associated with white matter hyperintensities (WMH) of the brain.OBJECTIVE: To investigate the contribution of brain area-specific WMH to the risk of falls in IPD.METHODS: In fifty participants with IPD, occurrence and severity of WMH in specific brain areas were determined using Scheltens (without lateralization) and Age-related white matter changes (ARWMC) (with lateralization) scores. Falls were evaluated with the fall item of the Unified PD Rating Scale (UPDRS). Correlations between area-specific WMH and falls were tested with stepwise backward regression and multivariate regression analyses.RESULTS: In this cohort of participants with IPD, left temporal WMH were associated with occurrence of falls. Frontal WMH of both hemispheres showed tendencies towards significance for the association with falls.CONCLUSION: According to our study, WMH in the left temporal area are significantly associated with falls in IPD. Potential reasons for this association could be deficits in memory, navigation, orientation, auditory processing, and fear conditioning, which are all associated with pathologies of the left temporal lobe.

Objective Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan–McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function. Methods and results Diffusion tensor imaging‐based and automatic volumetric brain mapping were performed in 12 SHANK3‐deficient participants (mean age 19 ± 15 years) versus 14 age‐ and gender‐matched controls (mean age 29 ± 5 years). Using whole brain–based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto‐occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back‐translational approach, we observed similar white matter alterations in heterozygous isoform–specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model. Interpretation In summary, these translational data provide strong evidence that the SHANK3‐deficiency–associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation.

The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimer's disease and vascular cognitive impairment. Most of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its sub-region the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39-77 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusion-based tracking of NBM white matter projections, and computed white matter hypointensities (WM-hypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous post-mortem and DTI tractography studies. We found that high WM-hypo load was associated with older age, male sex, and lower performance in attention and memory. A high WM-hypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WM-hypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to re-evaluate the cholinergic hypothesis of cognitive aging.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 753896 (M.D. Schirmer). This study was supported by NIH-NINDS (MRI-GENIE: R01NS086905 - PI N.Rost, K23NS064052, R01NS082285 - N. Rost, SiGN: U01 NS069208 - J. Rosand, S. Kittner, R01NS059775, R01NS063925, R01NS082285,P50NS051343, R01NS086905, U01 NS069208 - O. Wu), NIH NIBIBNAC (P41EB015902–P. Golland).

BACKGROUND AND PURPOSE Orthostatic hypotension is frequent with aging with a prevalence of 20%-30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years. METHODS In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score. RESULTS The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69, P ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%, P = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s, P ≤ 0.001; word list learning sum -0.53 vs. 0.38, P = 0.002) compared to participants without orthostatic hypotension. CONCLUSION Orthostatic hypotension seems to be associated with cognitive decline longitudinally.

Cerebrospinal fluid (CSF) YKL40 and sTREM2 are astroglial and microglial activity biomarkers, respectively. We assessed whether CSF YKL40 and sTREM2 baseline levels are associated with longitudinal brain volume and diffusivity changes in cognitively unimpaired adults. Two brain MRI scans of 36 participants (57 to 78-years old, 12 male) were acquired in a 2-year interval. Aβ42, p-tau, YKL40 and sTREM2 concentrations in CSF were determined at baseline. We calculated gray and white matter volume changes per year maps (ΔGM and ΔWM, respectively) by means of longitudinal pairwise registration, and mean diffusivity variation per year (ΔMD) by subtraction. We checked voxel-wise for associations between ΔGM, ΔWM and ΔMD and baseline CSF level of YKL40 and sTREM2 and verified to what extent these associations were modulated by age (YKL40xAGE and sTREM2xAGE interactions). We found a positive association between ΔGM and YKL40 in the left inferior parietal region and no association between sTREM2 and ΔGM. Negative associations were also observed between ΔGM and YKL40xAGE (bilateral frontal areas, left precuneus and left postcentral and supramarginal gyri) and sTREM2xAGE (bilateral temporal and frontal cortex, putamen and left middle cingulate gyrus). We found negative associations between ΔWM and YKL40xAGE (bilateral superior longitudinal fasciculus) and sTREM2xAGE (bilateral superior longitudinal fasciculus, left superior corona radiata, retrolenticular external capsule and forceps minor, among other regions) but none between ΔWM and neither YKL40 nor sTREM2. ΔMD was positively correlated with YKL40 in right orbital region and negatively with sTREM2 in left lingual gyrus and precuneus. In addition, significant associations were found between ΔMD and YKL40xAGE (tail of left hippocampus and surrounding areas and right anterior cingulate gyrus) and sTREM2xAGE (right superior temporal gyrus). Areas showing statistically significant differences were disjoint in analyses involving YKL40 and sTREM2. These results suggest that glial biomarkers exert a relevant and distinct influence in longitudinal brain macro- and microstructural changes in cognitively unimpaired adults, which appears to be modulated by age. In younger subjects increased glial markers (both YKL40 and sTREM2) predict a better outcome, as indicated by a decrease in ΔGM and ΔWM and an increase in ΔMD, whereas in older subjects this association is inverted and higher levels of glial markers are associated with a poorer neuroimaging outcome., Highlights • The CSF glial biomarkers predict brain longitudinal changes in cognitively healthy elderly. • The association of brain changes with glial biomarkers is modulated by age. • The presence of CSF glial biomarkers seems to be protective for younger subjects. • For elders, the increase in glial biomarkers is associated to a greater atrophy rate.

Cardiac troponin (hs-cTnT) is a sensitive marker of myocardial injury and has been linked to incident dementia. The underlying mechanism of that observation is still unknown. Given that severity of cerebral small vessel disease is a predictor of cognitive decline, we aimed to explore whether there is an association between hs-cTnT and severity of white matter lesions (WML) as a marker of cerebral small vessel disease in patients with ischemic stroke. We analyzed consecutive acute ischemic stroke patients admitted to Charite-University Hospital, Berlin from 2011 to 2013. Severity of WML was graded on 3T-MRI using the age-related white matter severity score (ARWMS). Patients with hs-cTnT elevation suggestive of acute coronary syndrome (ACS) were excluded (hs-cTnT > 52 ng/l or dynamic change of hs-cTnT > 50%, ESC guideline). We performed unadjusted and adjusted quantile regression models to assess the association between increased hs-cTnT (dichotomized at the 99th percentile, 14 ng/l) and severity of WML. A total of 860 patients was analyzed (median age 73 years, 44.8% female, median ARWMS 6). Patients with elevated hs-cTnT had more extensive WML than those without (median ARWMS 8 vs. 5, adjusted beta for 50th percentile 1.12, 95% CI 0.41–1.84). The association between WML and hs-cTnT elevation was strongest in patients with severe WML (adjusted beta 1.77, 95% CI 0.26–3.27 for 80th WML percentile). Elevated hs-cTnT levels were associated with extent of WML in acute stroke patients. Further studies are needed to assess whether hs-cTnT can be used to identify stroke patients at risk for cognitive decline.

Objective To identify novel genetic associations with white matter hyperintensities (WMH). Methods We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. Results We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, β [SE] = 0.071 [0.013]; p = 1.6 × 10−8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10−9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03–1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00–1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; β [SE] = 0.106 [0.016]; p = 1.2 × 10−11 and rs7596872; β [SE] = 0.143 [0.021]; p = 3.4 × 10−12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. Conclusions Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.

Background Once a patient or a knowledgeable informant has noticed decline in memory or other cognitive functions, initiation of early dementia assessment is recommended. Hippocampus and cholinergic basal forebrain (BF) volumetry supports the detection of prodromal and early stages of Alzheimer's disease (AD) dementia in highly selected patient populations. Objective To compare effect size and diagnostic accuracy of hippocampus and BF volumetry between patients recruited in highly specialized versus primary care and to assess the effect of white matter lesions as a proxy for cerebrovascular comorbidity on diagnostic accuracy. Methods We determined hippocampus and BF volumes and white matter lesion load from MRI scans of 71 participants included in a primary care intervention trial (clinicaltrials.gov identifier: NCT01401582) and matched 71 participants stemming from a memory clinic. Samples included healthy controls and people with mild cognitive impairment (MCI), AD dementia, mixed dementia, and non-AD related dementias. Results Volumetric measures reached similar effect sizes and cross-validated levels of accuracy in the primary care and the memory clinic samples for the discrimination of AD and mixed dementia cases from healthy controls. In the primary care MCI cases, volumetric measures reached only random guessing levels of accuracy. White matter lesions had only a modest effect on effect size and diagnostic accuracy. Conclusions Hippocampus and BF volumetry may usefully be employed for the identification of AD and mixed dementia, but the detection of MCI does not benefit from the use of these volumetric markers in a primary care setting.

Introduction White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. Participants and methods Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. Results Mutation carriers were more likely to have microbleeds than non-carriers (p

Prediction of functional outcome after stroke based on initial presentation remains an open challenge, suggesting that an important aspect is missing from these prediction models. There exists the notion of a protective mechanism called brain reserve, which may be utilized to understand variations in disease outcome. In this work, we expand the concept of brain reserve (effective reserve) to improve prediction models of functional outcome after acute ischemic stroke (AIS). Consecutive AIS patients with acute brain magnetic resonance imaging (, European Commission. Framework Programme for Research and Innovation. Marie Sklodowska-Curie Actions (Grant 753896), National Institute of Neurological and Communicative Disorders and Stroke (Grant K23NS064052), National Institute of Neurological and Communicative Disorders and Stroke (Grant R01NS082285), National Institute of Neurological and Communicative Disorders and Stroke (Grant R01NS086905)