Measures Of White Matter Integrity Research Articles

Chronotype and subjective sleep quality predict white matter integrity in young people with emerging mental disorders.

Protecting brain health is a goal of early intervention. We explored whether sleep quality or chronotype could predict white matter (WM) integrity in emerging mental disorders. Young people (N = 364) accessing early-intervention clinics underwent assessments for chronotype, subjective sleep quality, and diffusion tensor imaging. Using machine learning, we examined whether chronotype or sleep quality (alongside diagnostic and demographic factors) could predict four measures of WM integrity: fractional anisotropy (FA), and radial, axial, and mean diffusivities (RD, AD and MD). We prioritised tracts that showed a univariate association with sleep quality or chronotype and considered predictors identified by ≥80% of machine learning (ML) models as 'important'. The most important predictors of WM integrity were demographics (age, sex and education) and diagnosis (depressive and bipolar disorders). Subjective sleep quality only predicted FA in the perihippocampal cingulum tract, whereas chronotype had limited predictive importance for WM integrity. To further examine links with mood disorders, we conducted a subgroup analysis. In youth with depressive and bipolar disorders, chronotype emerged as an important (often top-ranking) feature, predicting FA in the cingulum (cingulate gyrus), AD in the anterior corona radiata and genu of the corpus callosum, and RD in the corona radiata, anterior corona radiata, and genu of corpus callosum. Subjective quality was not important in this subgroup analysis. In summary, chronotype predicted altered WM integrity in the corona radiata and corpus callosum, whereas subjective sleep quality had a less significant role, suggesting that circadian factors may play a more prominent role in WM integrity in emerging mood disorders.

Estimating the prevalence of Non-Verbal Learning Disability (NVLD) from the ABCD sample.

Non-Verbal Learning Disability (NVLD) is a neurodevelopmental disorder characterized by deficits in processing visuospatial information but with age-appropriate verbal skills. This cognitive profile has been hypothesized to be associated with atypical white matter, but at the present there is a lack of evidence for this hypothesis. Currently, the condition is not characterized within the main diagnostic systems, in part because no clear set of criteria for characterizing the disorder exists. This report is the first attempt to estimate NVLD prevalence, using two sets of diagnostic criteria, in a large sample of over 11,000 children who were selected without regards to problems of specific nature, either psychological, neurological, physical and/or social. Furthermore, it examined the association between the profile of cognitive abilities and aspects of whole-brain white matter measures in children with and without symptoms associated with NVLD. Participants were drawn from the Adolescent Brain Cognitive Development (ABCD) study, a 10-year longitudinal study of 11,876 children in the U.S. The data used in the present study were drawn from the initial testing point at which the children were 9-10years old. Prevalence of NVLD based on two distinct sets of criteria, correlations between the measures used to create the criteria, correlations between criteria measures and measures of white matter integrity. The cognitive criteria included measures of visuospatial processing, reading, intelligence and social skills. By varying the cut-offs applied to social skills in conjunction with visuo-spatial difficulties, spared reading skills and intelligence scores, we calculated prevalence for two NVLD groups. White matter characteristics were measures of volume, fractional anisotropy and mean diffusivity. Based on the criteria used, the estimated prevalence of NVLD varied from 1 to 8%. Furthermore, children with NVLD showed a dissociation between measures of visuo-spatial processing not observed in non-NVLD children. At the neurological level, findings provide preliminary evidenceof associations between the cognitive profile of NVLD and abnormalities in white matters tracts. The present study documents that exists, within this large non-selected sample, a proportion of youth who show evidence of NVLD. Given those results, it appears essential to establish the best diagnostic criteria, to improve the treatment options and quality of life for children with this disorder.

A comprehensive analysis of APOE genotype effects on human brain structure in the UK Biobank

Alzheimer’s disease (AD) risk is increased in carriers of the apolipoprotein E (APOE) ε4 allele and decreased in ε2 allele carriers compared with the ε3ε3 genotype. The aim of this study was to determine whether: the APOE genotype affects brain grey (GM) or white matter (WM) structure; and if differences exist, the age when they become apparent and whether there are differential effects by sex. We used cross-sectional magnetic resonance imaging data from ~43,000 (28,494 after pre-processing) white British cognitively healthy participants (7,446 APOE ε4 carriers) aged 45–80 years from the UK Biobank cohort and investigated image-derived phenotypes (IDPs). We observed no statistically significant effects of APOE genotype on GM structure volumes or median T2* in subcortical structures, a measure related to iron content. The volume of white matter hyperintensities differed significantly between APOE genotype groups with higher volumes in APOE ε4ε4 (effect size 0.14 standard deviations [SD]) and ε3ε4 carriers (effect size 0.04 SD) but no differences in ε2 carriers compared with ε3ε3 carriers. WM integrity measures in the dorsal (mean diffusivity [MD]) and ventral cingulum (MD and intracellular volume fraction), posterior thalamic radiation (MD and isotropic volume fraction) and sagittal stratum (MD) indicated lower integrity in APOE ε4ε4 carriers (effect sizes around 0.2–0.3 SD) and ε3ε4 (effect sizes around 0.05 SD) carriers but no differences in ε2 carriers compared with the APOE ε3ε3 genotype. Effects did not differ between men and women. APOE ε4 homozygotes had lower WM integrity specifically at older ages with a steeper decline of WM integrity from the age of 60 that corresponds to around 5 years greater “brain age”. APOE genotype affects various white matters measures, which might be indicative of preclinical AD processes. This hypothesis can be assessed in future when clinical outcomes become available.

Associations of Polycystic Ovary Syndrome With Indicators of Brain Health at Midlife in the CARDIA Cohort.

Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with an adverse cardiometabolic profile early in life. Increasing evidence links cardiovascular risk factors, such as diabetes and hypertension, to accelerated cognitive aging. However, less is known about PCOS and its relationship to brain health, particularly at midlife. Our goal was to investigate possible associations between PCOS and midlife cognitive function and brain MRI findings in an ongoing prospective study. We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a geographically diverse prospective cohort study of individuals who were 18-30 years at baseline (1985-1986) and followed for 30 years. We identified women with PCOS from an ancillary study (CARDIA Women's study (CWS); n = 1,163) as those with elevated androgen levels and/or hirsutism in conjunction with symptoms of oligomenorrhea. At year 30, participants completed cognitive testing, including the Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test (RAVLT) (verbal learning and memory), Digit Symbol Substitution Test (processing speed and executive function), Stroop test (attention and cognitive control), and category and letter fluency tests (semantics and attention). A subset completed brain MRI to assess brain structure and white matter integrity. Multivariable linear regression models estimated the association between PCOS and outcomes, adjusting for age, race, education, and study center. Of the 1163 women in CWS, 907 completed cognitive testing, and of these, 66 (7.1%) met criteria for PCOS (age 54.7 years). Women with and without PCOS were similar for age, BMI, smoking/drinking status, and income. At year 30, participants with PCOS performed lower (mean z score; 95% CI) on Stroop (-0.323 (-0.69 to -7.37); p = 0.008), RAVLT (-0.254 (-0.473 to -0.034); p = 0.002), and category fluency (-0.267 (-0.480 to -0.040); p = 0.02) tests. Of the 291 participants with MRI, 25 (8.5%) met PCOS criteria and demonstrated lower total white matter fractional anisotropy, a measure of white matter integrity (coefficient (95% CI) -0.013 (-0.021 to -0.005); p = 0.002), though not abnormal white matter. Our results suggest that women with PCOS have lower cognitive performance and lower white matter integrity at midlife. Additional research is needed to confirm these findings and to determine potential mechanistic pathways including potential modifiable factors.

Association Between Hippocampal Volumes and Cognition in Cerebral Amyloid Angiopathy.

Accumulating evidence suggests that gray matter atrophy, often considered a marker of Alzheimer disease (AD), can also result from cerebral small vessel disease (CSVD). Cerebral amyloid angiopathy (CAA) is a form of sporadic CSVD, diagnosed through neuroimaging criteria, that often co-occurs with AD pathology and leads to cognitive impairment. We sought to identify the role of hippocampal integrity in the development of cognitive impairment in a cohort of patients with possible and probable CAA. Patients were recruited from an ongoing CAA study at Massachusetts General Hospital. Composite scores defined performance in the cognitive domains of memory, language, executive function, and processing speed. Hippocampal subfields' volumes were measured from 3T MRI, using an automated method, and multivariate linear regression models were used to estimate their association with each cognitive domain and relationship to CAA-related neuroimaging markers. One hundred twenty patients, 36 with possible (age mean [range]: 75.6 [65.6-88.9]), 67 with probable CAA (75.9 [59.0-94.0]), and 17 controls without cognitive impairment and CSVD (72.4 [62.5-82.7]; 76.4% female patients), were included in this study. We found a positive association between all investigated hippocampal subfields and memory and language, whereas specific subfields accounted for executive function (CA4 [Estimate = 5.43; 95% CI 1.26-9.61; p = 0.020], subiculum [Estimate = 2.85; 95% CI 0.67-5.02; p = 0.022]), and processing speed (subiculum [Estimate = 1.99; 95% CI 0.13-3.85; p = 0.036]). These findings were independent of other CAA-related markers, which did not have an influence on cognition in this cohort. Peak width of skeletonized mean diffusivity (PSMD), a measure of white matter integrity, was negatively associated with hippocampal subfields' volumes (CA3 [Estimate = -0.012; 95% CI -0.020 to -0.004; p = 0.034], CA4 [Estimate = -0.010; 95% CI -0.020 to -0.0007; p = 0.037], subiculum [Estimate = -0.019; 95% CI -0.042 to -0.0001; p = 0.003]). These results suggest that hippocampal integrity is an independent contributor to cognitive impairment in patients with CAA and that it might be related to loss of integrity in the white matter. Further studies exploring potential causes and directionality of the relationship between white matter and hippocampal integrity may be warranted.

APOE‐dependent and ‐independent polygenic pathways determining early Alzheimer’s Disease pathological changes in CSF and MRI

AbstractBackgroundLittle is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.MethodEPAD inclusion criteria were age>50 and Clinical Dementia Rating = 0.5 (n = 1886, Table 1). AD‐PRS was based on 85 previously identified loci, including and excluding APOE (PRSAPOE, PRSnoAPOE)[1]. Using gene‐variant and variant‐pathway mapping[2], six pathway‐specific PRSnoAPOE were identified:1) immune‐activation, 2) signal‐transduction, 3) inflammatory‐response, 4) migration, 5) amyloid‐production, and 6) clearance. Linear models were used to assess the relationship of all PRS with fluid AD biomarkers, including Aß1‐42, p‐Tau181, and t‐tau; and several imaging biomarkers, including hippocampal volume, global and lobar white matter hyperintensities (WMH) volumes, fractional anisotropy (FA) in 14 regions of interest from diffusion tensor imaging, and 10 resting‐state network connectivity from functional MRI. Models were adjusted for age, sex, site, and multiple comparisons.ResultModels’ coefficients are reported in Table 2. PRSAPOE was significantly associated with decreased Aß1‐42, and increased p‐Tau181 and t‐Tau. PRSnoAPOE showed a weaker, but still significant, negative association with Aß1‐42 levels, and a significant positive association with p‐Tau181 and t‐Tau. Aß1‐42 was only significantly associated with the migration, amyloid, and clearance pathways, while all pathways were significantly positively associated with p‐Tau181 and t‐Tau. Hippocampal volume was only significantly associated with PRSAPOE. Regarding WMH load, PRSAPOE showed a positive association with global, frontal periventricular, and parietal deep lobes. Furthermore, the clearance pathway was related to WMH load in all regions, most strongly in periventricular areas. Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Only the PRSAPOE was related to reduced functional connectivity (FC) in the default mode, control, and visual networks.ConclusionWe show that genetic risk beyond APOE facilitates the manifestation of AD related pathologies. Moreover, clearance and migration pathways were associated with neuroimaging measures of white matter integrity, while FC and hippocampal volume were associated with overall AD genetic risk.

APOE‐dependent and ‐independent polygenic pathways determining early Alzheimer’s Disease pathological changes in CSF and MRI

AbstractBackgroundLittle is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.MethodEPAD inclusion criteria were age>50 and Clinical Dementia Rating≤0.5 (n = 1886, Table 1). AD‐PRS was based on 85 previously identified loci, including and excluding APOE (PRSAPOE, PRSnoAPOE)[1]. Using gene‐variant and variant‐pathway mapping[2], six pathway‐specific PRSnoAPOE were identified:1) immune‐activation, 2) signal‐transduction, 3) inflammatory‐response, 4) migration, 5) amyloid‐production, and 6) clearance. Linear models were used to assess the relationship of all PRS with fluid AD biomarkers, including Aβ1‐42, p‐Tau181, and t‐tau; and several imaging biomarkers, including hippocampal volume, global and lobar white matter hyperintensities (WMH) volumes, fractional anisotropy (FA) in 14 regions of interest from diffusion tensor imaging, and 10 resting‐state network connectivity from functional MRI. Models were adjusted for age, sex, site, and multiple comparisons.ResultModels’ coefficients are reported in Table 2. PRSAPOE was significantly associated with decreased Aβ1‐42, and increased p‐Tau181 and t‐Tau. PRSnoAPOE showed a weaker, but still significant, negative association with Aβ1‐42 levels, and a significant positive association with p‐Tau181 and t‐Tau. Aβ1‐42 was only significantly associated with the migration, amyloid, and clearance pathways, while all pathways were significantly positively associated with p‐Tau181 and t‐Tau.Hippocampal volume was only significantly associated with PRSAPOE. Regarding WMH load, PRSAPOE showed a positive association with global, frontal periventricular, and parietal deep lobes. Furthermore, the clearance pathway was related to WMH load in all regions, most strongly in periventricular areas.Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Only the PRSAPOE was related to reduced functional connectivity (FC) in the default mode, control, and visual networks.ConclusionWe show that genetic risk beyond APOE facilitates the manifestation of AD related pathologies. Moreover, clearance and migration pathways were associated with neuroimaging measures of white matter integrity, while FC and hippocampal volume were associated with overall AD genetic risk.

Brain Structure and Cognitive Dysfunction in Myotonic Dystrophy Type 2 (BraCE‐DM2)

AbstractBackgroundMyotonic dystrophy type 2 (DM2) is a pleiotropic multisystemic disease. Although progressive muscle weakness is the main symptom in DM2, almost two‐third of the patients report cognitive deficits as one of the most disabling symptoms. Emerging evidence has identified tau mis‐splicing and tangle pathology in DM2, which has prompted interest in elucidating the role of tau in DM2‐related cognitive impairment. Previous studies suggest that cerebral white matter (WM) is primarily affected in DM2. However, quantitative brain imaging studies incorporate with cognitive measures are extremely limited.Method3T brain MRIs were acquired in 10 adults with DM2 and 10 gender and age‐matched controls. Brain morphometry and WM integrity were assessed using T1‐MPRAGE and diffusion tensor imaging (DTI) sequences. DTI scalars, including fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and median diffusivity (MD) were compared between groups. A comprehensive battery of cognitive and behavioral measures was performed and correlated with MRI measures (Spearman’s Correlation).ResultOf 20 participants (60% female), mean age (62.2 vs. 62.6 years) and education (16.4 vs. 17.5 years) were similar between the two groups. Compared to controls, the DM2 group showed a significant reduction in global measures of cerebral gray matter (GM) volume in both cortex and deep gray structures (mean difference, ‐0.03; p<0.01), but not the WM volume. Widespread abnormalities in DTI measures (lower FA, higher RD) were among the most robust findings in DM2 (mean differences of FA, 0.04; p<0.01 and RD, 0.00004; p<0.01), indicating that the pathology is within WM microstructures. Overall, the DM2 group scored lower than controls in all cognitive domains, particularly executive function (mean difference, ‐12.5; p = 0.04). We found a strong correlation between cerebral FA and a test of executive function (rho = 0.71, p = 0.02). Cerebral FA also showed a moderate correlation with processing speed (rho = 0.50) and apathy evaluation scale (rho = ‐0.43).ConclusionOur pilot data demonstrate robust differences of brain structure, explicitly measures of WM integrity and cerebral GM volume between the DM2 group vs. controls. The strong correlation between cerebral FA and executive function also supports the notion that WM integrity plays an important role in cognitive dysfunction in DM2.

Structural abnormalities in the Fronto-Parietal Network: Linking white matter integrity to sustained attention deficits in Schizophrenia

Schizophrenia is associated with a range of cognitive deficits, among which impairments in sustained attention are particularly significant. Previous research has investigated functional changes in the fronto-parietal network (FPN) related to attentional control in schizophrenia. However, the role of structural connectivity within the FPN in sustained attention deficits remains under-explored. Utilizing diffusion tensor imaging (DTI), this study investigated white matter integrity in 75 participants, comprising 37 individuals with schizophrenia (SZ) and 38 healthy controls (HC). Psychomotor vigilance task (PVT) performance was assessed to gauge sustained attention. The SZ group showed a significant reduction in fractional anisotropy (FA) and streamline counts within white matter tracts connecting frontal and parietal regions, compared to the HC group. Further, significant negative correlations were found between PVT performance and white matter integrity measures within the SZ group, specifically in the left FPN. Our findings indicate that structural abnormalities in the FPN are associated with sustained attention deficits in schizophrenia. These results contribute to our understanding of the neurobiological mechanisms underlying cognitive impairments in schizophrenia and offer potential avenues for targeted therapeutic interventions. Further research is warranted to validate these outcomes and explore their clinical implications.

Local structural and functional MRI markers of compulsive behaviors and obsessive-compulsive disorder diagnosis within striatum-based circuits.

Obsessive-compulsive disorder (OCD) is a classic disorder on the compulsivity spectrum, with diverse comorbidities. In the current study, we sought to understand OCD from a dimensional perspective by identifying multimodal neuroimaging patterns correlated with multiple phenotypic characteristics within the striatum-based circuits known to be affected by OCD. Neuroimaging measurements of local functional and structural features and clinical information were collected from 110 subjects, including 51 patients with OCD and 59 healthy control subjects. Linked independent component analysis (LICA) and correlation analysis were applied to identify associations between local neuroimaging patterns across modalities (including gray matter volume, white matter integrity, and spontaneous functional activity) and clinical factors. LICA identified eight multimodal neuroimaging patterns related to phenotypic variations, including three related to symptoms and diagnosis. One imaging pattern (IC9) that included both the amplitude of low-frequency fluctuation measure of spontaneous functional activity and white matter integrity measures correlated negatively with OCD diagnosis and diagnostic scales. Two imaging patterns (IC10 and IC27) correlated with compulsion symptoms: IC10 included primarily anatomical measures and IC27 included primarily functional measures. In addition, we identified imaging patterns associated with age, gender, and emotional expression across subjects. We established that data fusion techniques can identify local multimodal neuroimaging patterns associated with OCD phenotypes. The results inform our understanding of the neurobiological underpinnings of compulsive behaviors and OCD diagnosis.

Resistance Training Maintains White Matter and Physical Function in Older Women with Cerebral Small Vessel Disease: An Exploratory Analysis of a Randomized Controlled Trial.

As the aging population grows, there is an increasing need to develop accessible interventions against risk factors for cognitive impairment and dementia, such as cerebral small vessel disease (CSVD). The progression of white matter hyperintensities (WMHs), a key hallmark of CSVD, can be slowed by resistance training (RT). We hypothesize RT preserves white matter integrity and that this preservation is associated with improved cognitive and physical function. To determine if RT preserves regional white matter integrity and if any changes are associated with cognitive and physical outcomes. Using magnetic resonance imaging data from a 12-month randomized controlled trial, we compared the effects of a twice-weekly 60-minute RT intervention versus active control on T1-weighted over T2-weighted ratio (T1w/T2w; a non-invasive proxy measure of white matter integrity) in a subset of study participants (N = 21 females, mean age = 69.7 years). We also examined the association between changes in T1w/T2w with two key outcomes of the parent study: (1) selective attention and conflict resolution, and (2) peak muscle power. Compared with an active control group, RT increased T1w/T2w in the external capsule (p = 0.024) and posterior thalamic radiations (p = 0.013) to a greater degree. Increased T1w/T2w in the external capsule was associated with an increase in peak muscle power (p = 0.043) in the RT group. By maintaining white matter integrity, RT may be a promising intervention to counteract the pathological changes that accompany CSVD, while improving functional outcomes such as muscle power.

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

Immuno-epigenetic signature derived in saliva associates with the encephalopathy of prematurity and perinatal inflammatory disorders

BackgroundPreterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. MethodsUsing salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 – 34.84 weeks, n = 103 term, gestational age at birth 37.00 – 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. ResultsHigher DNAm CRP was linked to preterm status (-0.0107 ± 0.0008, compared with −0.0118 ± 0.0006 among term infants; p < 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p < 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippocampi and amygdalae (β range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (β range |0.206| to |0.371|), independent of other confounding exposures. ConclusionsInflammatory-related DNAm captures the allostatic load of inflammatory burden in preterm infants. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.

Posterior white matter integrity and self-reported posterior cortical symptoms using the Colorado Posterior Cortical Questionnaire.

The Colorado Posterior Cortical Questionnaire (CPC-Q) is a self-report, 15-item screening questionnaire for posterior cortical symptoms, including visuospatial and visuoperceptual difficulties. Changes in white matter connectivity may precede obvious gray matter atrophy in neurodegenerative conditions, especially posterior cortical atrophy. Integration of CPC-Q scores and measures of white matter integrity could contribute to earlier detection of posterior cortical syndromes. We investigated the relationships between posterior cortical symptoms as captured by the CPC-Q and diffusion tensor imaging fractional anisotropy (DTI FA) of white matter regions of interest localized to posterior brain regions (posterior thalamic radiations, splenium of corpus callosum, tapetum). Comparisons were also made by diagnostic group [healthy older adult (n = 31), amnestic Alzheimer's disease (AD, n = 18), and posterior cortical atrophy (PCA, n = 9)] and by SENAS battery visuospatial composite score quartile. Exploratory comparisons of all available individual white matter region DTI FA to CPC-Q, as well as comparisons of DTI FA between diagnostic groups and visuospatial quartiles, were also made. CPC-Q score was correlated with the average DTI FA for the averaged posterior white matter regions of interest (r = -0.31, p = 0.02). Posterior thalamic radiation DTI FA was most strongly associated with CPC-Q (r = -0.34, p = 0.01) and visuospatial composite (r = 0.58, p < 0.01) scores and differed between the PCA and AD groups and the lower and higher visuospatial quartiles. The DTI FA of body and splenium of the corpus callosum also demonstrated this pattern but not the DTI FA of the tapetum. The integrity of posterior white matter tracts is associated with scores on the CPC-Q, adding to the validation evidence for this new questionnaire. White matter regions that may be related to posterior cortical symptoms detected by the CPC-Q, and distinct from those affected in amnestic syndromes, include the posterior thalamic radiations and body and splenium of the corpus callosum. These findings are in line with previous neuroimaging studies of PCA and support continued research on white matter in posterior cortical dysfunction.

Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk.

Many factors outside of cardiovascular health can impact the structure of white matter. Identification of reliable and clinically meaningful biomarkers of the neural effects of systemic and cardiovascular health are needed to refine etiologic predictions. We examined whether the corpus callosum demonstrates regional vulnerability to systemic cardiovascular risk factors. Three hundred and ninety-four older adults without dementia completed brain MRI, neurobehavioral evaluations, and blood draws. A subset (n = 126, n = 128) of individuals had blood plasma analyzed for inflammatory markers of interest (IL-6 and TNF-alpha). Considering diffusion tensor imaging (DTI) is a particularly reliable measure of white matter integrity, we utilized DTI to examine fractional anisotropy (FA) of anterior and posterior regions of the corpus callosum. Using multiple linear regression models, we simultaneously examined FA of the genu and the splenium to compare their associations with systemic and cardiovascular risk factors. Lower FA of the genu but not splenium was associated with greater systemic and cardiovascular risk, including higher systolic blood pressure (β = -0.17, p = .020), hemoglobin A1C (β = -0.21, p = .016) and IL-6 (β = -0.34, p = .005). FA of the genu was uniquely associated with cognitive processing speed (β = 0.20, p = .0015) and executive functioning (β = 0.15, p = .012), but not memory performances (β = 0.05, p = .357). Our results demonstrated differential vulnerability of the corpus callosum, such that frontal regions showed stronger, independent associations with biomarkers of systemic and cardiovascular health in comparison to posterior regions. Posterior white matter integrity may not reflect cardiovascular health. Clinically, these findings support the utility of examining the anterior corpus callosum as an indicator of cerebrovascular health.

Altered microstructural pattern of the cortex and basal forebrain cholinergic system in wilson's disease: an automated fiber quantification tractography study.

Basal forebrain (BF) cholinergic projection neurons form a highly extensive input to the cortex. Failure of BF cholinergic circuits is responsible for the cognitive impairment associated with Wilson's disease (WD), but whether and how the microstructural changes in fiber projections between the BF and cerebral cortex influence prospective memory (PM) remain poorly understood. We collected diffusion tensor imaging (DTI) data from 21 neurological WD individuals and 26 healthy controls (HCs). The experiment reconstructed the probabilistic streamlined tractography of 18 white matter tracts using an automated fiber quantification (AFQ) toolkit. Tract properties (FA, MD, RD, and AD) were computed for 100 points along each tract for each participant, and the differences between the groups were examined. Subsequently, correlation analysis was performed to evaluate whether abnormal microstructural white matter integrity measures correlate with PM performance. Additional investigations used a tract-based spatial statistics (TBSS) approach to identify regions with altered white matter structure between groups and verify the reliability of the AFQ results. The highest nonoverlapping DTI-related differences were detected in the anterior thalamic radiation (ATR), corticospinal tract (CST), corpus callosum, association fibers, and limbic system fibers. Additionally, PM parameters of the patient group were highly correlated with white matter microstructure changes in the inferior longitudinal fasciculus. Our study highlights that the performance of projections between cholinergic input and output areas-the cerebral cortex and BF-may serve as neural biomarkers of PM and disease prognosis.

Aerobic exercise is associated with region-specific changes in volumetric, tensor-based, and fixel-based measures of white matter integrity in healthy older adults

White matter integrity and cognition have been found to decline with advancing adult age. Aerobic exercise may be effective in counteracting these declines. Generally, white matter integrity has been quantified using a volumetric measure (WMV) and with tensor-based parameters, such as fractional anisotropy (FA) and mean diffusivity (MD), the validity of which appears to be compromised in the presence of crossing fibers. Fixel-based analysis techniques claim to overcome this problem by yielding estimates of fiber density (FD), cross-section (FC), and their product (FDC) in multiple directions per voxel. In a sample of 61 healthy older adults (63–76 years old), we quantified changes in white matter integrity following an aerobic exercise intervention with the commonly used volumetric and tensor-based metrics (WMV, FA, MD) and with fixel-based metrics (FD, FC, FDC). We investigated the associations of changes in these white matter parameters with changes in cardiovascular fitness and Digit Symbol Substitution task (DSST) performance, a marker of perceptual speed. In line with previous findings, we observed maintained WMV in the corpus callosum of exercisers, and positive change-change correlations between WMV and fitness, and between WMV and perceptual speed. For FA and MD, group differences in change opposite to those hypothesized were found in the corpus callosum, posterior corona radiata, and superior longitudinal fasciculus at an uncorrected significance threshold. Likewise, regions in superficial WM in the prefrontal cortex showed group differences in FD and FDC change, uncorrected, with more positive change in controls and more negative change in exercisers. Finally, changes in FD and FDC were found to be inversely correlated to changes in fitness and DSST performance. The present results corroborate previous findings of WMV changes, but cast doubt on current physiological interpretations of both tensor-based and fixel-based indicators of white matter properties in the context of exercise intervention studies.

White matter integrity as a mediator between socioeconomic status and executive function.

Lower socioeconomic status (SES) is associated with poorer executive function, but the neural mechanisms of this association remain unclear. As healthy brain communication is essential to our cognitive abilities, white matter integrity may be key to understanding socioeconomic disparities. Participants were 201 African American and White adults (ages 33-72) from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) SCAN study. Diffusion tensor imaging was used to estimate regional fractional anisotropy as a measure of white matter integrity. Adjusting for age, analyses examined if integrity of the anterior limb of the internal capsule (ALIC), external capsule (EC), superior longitudinal fasciculus (SLF), and cingulum mediated SES-executive function relations. Lower SES was related to poorer cognitive performance and white matter integrity. Lower Trails B performance was related to poorer integrity of the ALIC, EC, and SLF, and lower Stroop performance was associated with poorer integrity of the ALIC and EC. ALIC mediated the SES-Trails B relation, and EC mediated the SES-Trails B and SES-Stroop relations. Sensitivity analyses revealed that (1) adjustment for race rendered the EC mediations non-significant, (2) when using poverty status and continuous education as predictors, results were largely the same, (3) at least some of the study's findings may generalize to processing speed, (4) mediations are not age-dependent in our sample, and (5) more research is needed to understand the role of cardiovascular risk factors in these models. Findings demonstrate that poorer white matter integrity helps explain SES disparities in executive function and highlight the need for further clarification of the biopsychosocial mechanisms of the SES-cognition association.

Brain spectroscopic measures of glutamatergic and neuronal metabolism and glial activation influence white matter integrity in bipolar depression

Bipolar disorder (BD) is associated with alterations in white matter (WM) microstructure, glutamatergic neurotransmission, and glia activity. Previous studies showed higher concentrations of glutamate (Glu), glutamate+glutamine (Glx), and reduced N-acetyl-aspartate (NAA) in BD. We investigated brain concentrations of Glu, Glx, NAA, mI as indirect marker of microglia activation, and Glx/NAA ratio as index of neuronal damage through 1H-MR, and WM integrity with Tract-Based Spatial Statistics in 93 depressed BD patients and 58 healthy controls (HC).We tested for linear effects of cited spectroscopic metabolites on DTI measures of WM integrity with general linear models for each group, then performing a conjunction analysis of Glx/NAA and mI concentration on the same measures. Statistical analyses (whole sample) revealed higher concentration of Glx/NAA, Glx and mI in BD patients compared to HC, and a positive association between mI and the ratio. DTI analyses (87 BD and 35 HC) showed a significant association of Glx/NAA ratio, and mI with WM microstructure. Conjunction analysis revealed a joint negative association between Glx/NAA and mI with fractional anisotropy.This is the first study showing an association between brain metabolites involved in neuronal damage, and glial activation and the alterations in WM consistently reported in BD.

Impact of Childhood Trauma Exposure, Genetic Variation in Endocannabinoid Signaling, and Anxiety on Frontolimbic Pathways in Children.

Introduction: The endocannabinoid (eCB) system plays a key role in modulating brain development, including myelination processes. Recent studies link a common variant (C385A, rs324420) in the fatty acid amide hydrolase (FAAH) gene to higher circulating eCB levels, lower anxiety, and altered frontolimbic development. Frontolimbic pathways, which demonstrate a protracted maturational course across childhood and adolescence, are associated with anxiety, and are vulnerable to environmental stressors such as trauma exposure. Here, we examined the impact of trauma exposure, FAAH genotype, and anxiety on frontolimbic white matter microstructure in children. Materials and Methods: We leveraged baseline data from the Adolescent Brain Cognitive Development (ABCD) study (n=9969; mean±standard deviation age=9.92±0.62 years; 47.1% female). Saliva samples were used for genotyping, and caregivers reported on their child's anxiety symptoms and trauma exposure. Fractional anisotropy (FA), a nonspecific measure of white matter integrity, was estimated for frontolimbic tracts. Results: Thirty-six percent of youth experienced one or more potentially traumatic events according to DSM-5 Criterion A (64% controls), and 45% were FAAH A-allele carriers (55% noncarriers). Relative to controls, trauma-exposed youth demonstrated higher anxiety and higher FA of the left uncinate. The FAAH A-allele (vs. CC) was associated with lower FA in the left fornix and left parahippocampal cingulum, and there was an indirect effect of FAAH genotype on anxiety through FA of the left fornix. Moreover, genotype moderated the association between FA of the left cingulum and anxiety. Conclusions: Our findings demonstrate distinct effects of trauma exposure and the FAAH C385A variant on frontolimbic pathways and subsequent anxiety risk in preadolescent children. This line of work may provide important insights into neurodevelopmental mechanisms leading to anxiety risk, and potential targets for intervention.