Alterations In White Matter Integrity Research Articles

Reduced white matter microstructural integrity in prediabetes and diabetes: A population-based study.

SummaryBackgroundWhite matter (WM) microstructural abnormalities have been observed in diabetes. However, evidence of prediabetes is currently lacking. This study aims to investigate the WM integrity in prediabetes and diabetes. We also assess the association of WM abnormalities with glucose metabolism status and continuous glucose measures.MethodsThe WM integrity was analyzed using cross-sectional baseline data from a population-based PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study. The cohort, including a total of 2218 cases with the mean age of 61.3 ± 6.6 years and 54.1% female, consisted of 1205 prediabetes which are categorized into two subgroups (a group of 254 prediabetes with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and the other group of 951 prediabetes without combined IFG/IGT), 504 diabetes, and 509 normal control subjects. Alterations of WM integrity were determined by diffusion tensor imaging along with tract-based spatial statistics analysis to compare diffusion metrics on WM skeletons between groups. The mixed-effects multivariate linear regression models were used to assess the association between WM microstructural alterations and glucose status.FindingsMicrostructural abnormalities distributed in local WM tracts in prediabetes with combined IFG/IGT and spread widely in diabetes. These WM abnormalities are associated with higher glucose measures.InterpretationOur findings suggest that WM microstructural abnormalities are already present at the prediabetes with combined IFG/IGT stage. Preventative strategies should begin early to maintain normal glucose metabolism and avert further destruction of WM integrity.FundingPartially supported by National Key R&D Program of China (2016YFC0901002).

Diffusion tensor imaging analysis of rheumatoid arthritis patients with neuropsychiatric features to determine the alteration of white matter integrity due to vascular events.

The pathophysiology of neuropsychiatric manifestations in rheumatoid arthritis is not well known. The magnetic resonance imaging of the brain in rheumatoid arthritis demonstrates non-specific findings, and in the majority of cases, magnetic resonance imaging fails to detect an abnormality, even in rheumatoid arthritis patients with neuropsychiatric manifestations. Therefore, we aimed to assess microstructural integrity changes of white matter in patients with rheumatoid arthritis by using different diffusion tensor imaging parameters. Eighteen rheumatoid arthritis patients (10 with neuropsychiatric symptoms and 8 without any neuropsychiatric symptoms) and 14 controls were included. The volume of the T2 hyperintense lesions was assessed. Different diffusion tensor imaging parameters such as fractional anisotropy, apparent diffusion coefficient, trace, axial diffusivity, and radial diffusivity were obtained from six different regions of white matter. Inter group significant difference was determined by one-way analysis of variance followed by Tukey's post hoc test. The accuracy of diffusion tensor imaging matrices was evaluated from the receiver operating characteristic curve. No significant difference in lesions' volume was detected between rheumatoid arthritis patients with or without neuropsychiatric symptoms. There was an increased apparent diffusion coefficient and radial diffusivity (p < 0.05) as well as decreased fractional anisotropy and axial diffusivity (p < 0.5) in rheumatoid arthritis patients with neuropsychiatric symptoms compared to controls. Moreover, the apparent diffusion coefficient (p < .05) was increased in both positive and negative MRI of patients with neuropsychiatric features compared to the control group. The sensitivity and specificity of the apparent diffusion coefficient parameters was 73% and 72%, respectively. The various anisotropic metrics were altered in rheumatoid arthritis patients with neuropsychiatric symptoms by using diffusion tensor imaging analysis, representing that central nervous system vasculitis leads to tissue hypoxia resulting in vasogenic edema. This may lead to axonal and myelin degeneration of white matter fibers and neuronal cell disruption. Key Points • Our study confirms that neurovascular events are not uncommon in RA patients with NP features. Diffusion tensor imaging (DTI) is superior to conventional MRI scan for RA patients with NP features because it distinguishes between gray and white matter structures. • RA patients with NP features are more likely to have microstructural changes detected by DTI than by DWI, and it can provide comprehensive anatomical layouts describing regional disparities in neurodegeneration. • DTI's quantitative association of NP symptoms in a large patient cohort is an important study scope.

Unraveling the mystery of white matter in depression: A translational perspective on recent advances.

BackgroundNumerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention.ObjectiveThis systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype.MethodsA systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression.ResultsAlterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities.ConclusionTranslational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.

Combinatorial panel with endophenotypes from multilevel information of diffusion tensor imaging and lipid profile as predictors for depression.

Clinical heterogeneity in major depressive disorder likely reflects the range of etiology and contributing factors in the disorder, such as genetic risk. Identification of more refined subgroups based on biomarkers such as white matter integrity and lipid-related metabolites could facilitate precision medicine in major depressive disorder. A total of 148 participants (15 genetic high-risk participants, 57 patients with first-episode major depressive disorder and 76 healthy controls) underwent diffusion tensor imaging and plasma lipid profiling. Alterations in white matter integrity and lipid metabolites were identified in genetic high-risk participants and patients with first-episode major depressive disorder. Then, shared alterations between genetic high-risk and first-episode major depressive disorder were used to develop an imaging x metabolite diagnostic panel for genetically based major depressive disorder via factor analysis and logistic regression. A fivefold cross-validation test was performed to evaluate the diagnostic panel. Alterations of white matter integrity in corona radiata, superior longitudinal fasciculus and the body of corpus callosum and dysregulated unsaturated fatty acid metabolism were identified in both genetic high-risk participants and patients with first-episode major depressive disorder. An imaging x metabolite diagnostic panel, consisting of measures for white matter integrity and unsaturated fatty acid metabolism, was identified that achieved an area under the receiver operating characteristic curve of 0.86 and had a significantly higher diagnostic performance than that using either measure alone. And cross-validation confirmed the adequate reliability and accuracy of the diagnostic panel. Combining white matter integrity in corpus callosum, superior longitudinal fasciculus and corona radiata, and unsaturated fatty acid profile may improve the identification of genetically based endophenotypes in major depressive disorder to advance precision medicine strategies.

Altered White Matter Integrity at Illness Onset in Adolescents With a First Episode of Psychosis.

BackgroundDisruption in white matter integrity has been consistently observed in individuals with psychosis. However, whether such abnormalities are already present at illness onset or are related to downstream processes remains elusive. The study of adolescents with a recent onset of psychosis provides the opportunity to evaluate white matter integrity proximally to disease onset.MethodsTwenty-six adolescents (aged 15.9 ± 1.3 years) with a first episode of psychosis (FEP) (less than 6 months duration) were compared with 26 age and sex-matched healthy controls (HC) (16.8 ± 2 years). In participants with a FEP, clinical diagnoses were confirmed after a minimum of 1 year follow-up (main categories: schizophrenia, bipolar disorder, or schizoaffective disorder). Anatomical images and diffusion tensor sequences were acquired using a 1.5T scanner. Whole brain, voxel-wise group differences in fractional anisotropy (FA) were investigated between participants with a FEP and controls.ResultsRelative to HC, FEP participants displayed decreased FA in the right posterior cingulate gyrus, encompassing the right superior and posterior corona radiata, and the right parahippocampal gyrus, including the cingulum and fornix. FEP patients showed no areas of increased FA relative to HC. The results remained significant after controlling for medication, cannabis use and intelligence.ConclusionOur findings indicate that adolescents with recent onset of psychotic disorders show decreased white matter integrity in circuits implicated in cognitive functions and emotion regulation.

Altered White Matter Integrity in Patients with Retinal Vein Occlusion: A Diffusion Tensor Imaging and Tract-Based Spatial Statistics Study.

Background To investigate microstructural alterations of white matter in retinal vein occlusion (RVO) patients by tract-based spatial statistics (TBSS) and diffusion tensor imaging (DTI). Material/Methods. DTI was performed on 14 RVO patients and 14 normal controls (HCs). We measured and recorded fractional anisotropy (FA) and radial diffusivity (RD) of white matter fibers and classified them through the receiver operating characteristic (ROC) curve and correlation analysis, respectively. Results The mean FA value of white matter in RVO patients is lower than the HCs, and the mean RD value in RVO patients increased, especially in the bilateral posterior thalamic, bilateral sagittal stratum, body of corpus callosum, cingulum, and fornix. The ROC curve of different brain regions showed high accuracy. Moreover, the mean FA and RD values were significantly correlated with visual and psychological disorders. Conclusion TBSS could be regarded as an important method to reveal the alterations of white matter in RVO patients, indicating the underlying neurological mechanism of the RVO.

Prenatal depression exposure alters white matter integrity and neurodevelopment in early childhood

Prenatal exposure to maternal depression increases the risk for onset of emotional and behavioral disorders in children. We investigated the effects of exposure to prenatal depression on white matter microstructural integrity at birth and at 2-3 years, and associated neurodevelopment. Diffusion-weighted images were acquired for children of the Drakenstein Child Health Study at 2-4 weeks postpartum (n=70, 47% boys) and at 2-3 years of age (n=60, 58% boys). Tract-Based Spatial Statistics was used to compare, using an ROI based approach, diffusion tensor metrics across groups defined by presence (>19 on Beck’s Depression Inventory and/or >12 on the Edinburgh Postnatal Depression Scale) or absence (below depression thresholds) of depression, and associations with neurodevelopmental measures at age 2-3 years were determined. We did not detect group differences in white matter integrity at neonatal age, but at 2-3 years, children in the exposed group demonstrated higher fractional anisotropy, and lower mean and radial diffusivity in association tracts compared to controls. This was notable in the sagittal stratum (radial diffusivity: p<0.01). Altered white matter integrity metrics were also observed in projection tracts, including the corona radiata, which associated with cognitive and motor outcomes in exposed 2-3-year-olds (p<0.05). Our findings of widespread white matter alterations in 2-3-year-old children with prenatal exposure to depression are consistent with previous findings, as well as with neuroimaging findings in adults with major depression. Further, we identified novel associations of altered white matter integrity with cognitive development in depression-exposed children, suggesting that these neuroimaging findings may have early functional impact.

Analysis of brain structural connectivity networks and white matter integrity in patients with mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is considered a prodromal phase of Alzheimer’s disease (AD) and patients with MCI convert to AD at a rate of about 10–15% per year. Because of this high conversion rate to AD, studies of MCI may yield insight into early pathological changes in AD. Here, we used a novel approach to analyze structural connectivity and white matter (WM) integrity using fractional anisotropy (FA), intra‐cellular (IC), extra‐cellular (EC), and isotropic (ISO) maps between patients with MCI and healthy controls (HC).MethodThirty‐two HC (age mean ± S.D. = 69 ± 6 years; 22 females) and 20 MCI (71 ± 9 years; 7 females) were included in this study. All subjects completed the Mini‐Mental State Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). Multi‐shell DTI were download from ADNI (http://adni.loni.usc.edu/). Pre‐processing was performed by Mrtrix3, FSL, and ANTs. Tractography was performed with 5 million seeds using the iFOD2 algorithm. Connectome was generated from the Desikan‐Killiany parcellation file and was subsequently filtered using the COMMIT2 algorithm. A three‐compartment Stick‐Zeppelin‐Ball model was used to create the IC, the EC, and the ISO compartments, respectively. Statistical analyses (ANCOVA) were performed by connectomestats (Mrtrix3), randomise (FLS), and by an in‐house Matlab script for Spearman’s correlations.ResultThe two groups did differ in MMSE and MoCA (Mann–Whitney U test: Z=2.031; p=0.021; Z=1.683; p=0.046, respectively). Differences between HC and MCI were found principally in the fornix for FA and in several WM areas for IC and ISO (Figure 1, Table 1). Connectometry analysis found differences between groups in two distinct tracts: Tract#1 between the left‐lateraloccipital and the left‐insula (t=4.25, p=0.023) and Tract#2 between the left‐middletemporal and the left‐parsopercularis (t=3.34, p=0.013) (Figure 2). Figure 3 and Table 2 show the results for the correlations between DTI metrics and the neurological scores.ConclusionIn this study, by using a multi‐shell diffusion MRI acquisition and robust processing of DTI data, we detected alterations in WM integrity and structural connectivity in MCI subjects. Our results demonstrate the potential of these advanced diffusion MRI methods as biomarkers to distinguish MCI and HC.

Alterations in white matter integrity in cognitively stable Down syndrome correlate with plasma neurofilament light chain: Evidence of early myelin breakdown

AbstractBackgroundAlterations in white matter (WM) integrity occur in adults with DS during the early stage of dementia. These changes may be documented by diffusion tensor imaging wherein increases in radial diffusivity (RD), a marker of dysmyelination or myelin breakdown, occur in commissural and limbic pathways in DS. Neurofilament light chain (NfL) is a support protein within large, myelinated axons specifically within the cerebral white matter and is released into blood following axonal damage and is increased in DS. In this study, we evaluated the association between plasma NfL concentrations and RD.MethodThirty cognitively stable adults with DS from the Alzheimer Disease in Down Syndrome (part of the ABC‐DS) study, (18 M, 12 F: mean age 47.1 years SD 5.2 years), underwent DTI and plasma NfL concentration measurements. Plasma NfL was assayed using the Simoa platform. Diffusion MRI connectometry was conducted using q‐space diffeomorphic reconstruction and a multiple regression model to assess the associations between plasma NfL and white matter radial diffusivity (RD). The Spearman correlation coefficient, and its 95% confidence interval (CI), was used to quantify the monotonic association between plasma NfL and RD.ResultConsistent with our hypothesis, we found positive associations between plasma NfL and RD increases, in several WM higher order association tracts, including the corpus callosum (0.46, 95% CI 0.11‐0.70, p=0.012), the cingulum bundle (L: 0.62, 0.34‐0.80, p&lt;0.001; R: 0.54 0.23‐0.76, p=0.002) and the uncinate fasciculus (L: 0.17, ‐0.20‐0.50, p=0.367; R: 0.51, 0.18‐0.73, p=0.004).ConclusionOur findings support an important link between alterations in WM myelin integrity, particularly of higher order association areas, and axonal degeneration in cognitively stable adults with Down syndrome. These findings support an important role of WM alterations in adults with DS who are at risk for and who develop AD earlier than in sporadic AD cases. WM might provide an important and novel target for intervention. Additional research is needed to understand the underlying neuropathological processes, including the potential contribution of neuronal dysfunction and/or loss to our findings. Acknowledgements: NIH grant U01AG051412. We are grateful to our participants, families, the agencies serving individuals with ID, and our dedicated staff.

Asymmetric alterations of white matter integrity in patients with insomnia disorder.

Despite the adverse consequences of insomnia disorder for both individuals and society, the underlying neurobiological processes are poorly understood. The purpose was to further understand the alterations of white matter tracts in patients with insomnia and their association with sleep variables and also to determine if diffusion tensor imaging measures would be a useful disease marker. Twenty-six patients with insomnia and 26 age-matched healthy volunteers underwent diffusion tensor imaging. We employed an automated probabilistic tractography analysis approach using TRActs Constrained by UnderLying Anatomy (TRACULA) to quantify diffusion measures in major white matter tracts. We found significantly increased fractional anisotropy in the right cingulum-angular bundle and uncinate fasciculus in patients group compared to controls. Moreover, the mean diffusivity and radial diffusivity were reduced in the right cingulum-angular bundle in patients group in comparison with controls. We also found significantly increased fractional anisotropy along the bilateral cingulum-angular bundle and right uncinate fasciculus in patients. Also, mean and radial diffusivity were reduced along the right cingulum-angular bundle in patients group compared to controls. There is a significant positive correlation between fractional anisotropy and Epworth Sleepiness Scale scores. Moreover, there are negative correlations between mean, radial and axial diffusivity and total sleep time and sleep efficiency and also positive correlations between mean, radial and axial diffusivity and duration of disease and Pittsburgh Sleep Quality Index scores. This study showed theimportanceof examining whole-tract and waypoint white matter integrity in insomnia disorder. We found asymmetric widespread white matter integrity changes in patients with insomnia.

Altered White Matter Tracts in the Somatosensory, Salience, Motor, and Default Mode Networks in 7-Year-Old Children Living with Human Immunodeficiency Virus: A Tractographic Analysis.

Introduction: Even with the increased access and early initiation of combination antiretroviral therapy, children with perinatally acquired human immunodeficiency virus (CPHIV) continue to demonstrate white matter alterations. Children perinatally HIV-exposed, but uninfected (CHEU) alike show differences in white matter integrity compared with children who are HIV-unexposed and uninfected (CHUU). Objectives: Mapping white matter connections that link gray matter regions that form resting-state (RS) functional networks may demonstrate whether structural and functional connectivity alterations in HIV infection and exposure may be related. We hypothesized reduced structural connectivity in CPHIV within the default mode network (DMN), visual, ventral DMN (vDMN), somatosensory, salience, auditory, motor, executive, basal ganglia, and posterior DMN (pDMN). We also hypothesized that CHEU will have increased structural connectivity compared with CHUU in the vDMN, somatosensory, pDMN, dorsal attention, salience, auditory, motor and basal ganglia. Methods: Study participants were 61 seven-year-old CPHIV and 46 age-matched children who are HIV uninfected (CHU) (19 CHEU). We used diffusion tensor imaging-based tractography to investigate white matter connections that link gray matter regions within RS functional networks. Results: We found altered white matter integrity in the somatosensory, salience, default mode, and motor networks of CPHIV compared with CHU. The superior temporal cortex, superior frontal cortex, and putamen were affected in all four networks and have also been reported to demonstrate morphological alterations in the same cohort. In CHEU, white matter integrity was higher in the visual network, pDMN, and motor network compared with CHUU. Conclusion: Our results suggest that altered white matter integrity may influence gray matter morphology and functional network alterations. Impact statement The long-term effects of human immunodeficiency virus (HIV) and exposure on the developing brain in the combination antiretroviral therapy era are still not well known. We use diffusion tensor imaging-based tractography to explore these effects on white matter connections that link gray matter regions within functional networks. Our findings provide a context for HIV-associated white matter and connectivity abnormalities.

Alterations in white matter integrity and asymmetry in patients with benign childhood epilepsy with centrotemporal spikes and childhood absence epilepsy: An automated fiber quantification tractography study

PurposeTo investigate whether patients with benign childhood epilepsy with centrotemporal spikes (BECTS) and childhood absence epilepsy (CAE) show distinct patterns of white matter (WM) alterations and structural asymmetry compared with healthy controls and the relationship between WM alterations and epilepsy-related clinical variables. MethodsWe used automated fiber quantification to create tract profiles of fractional anisotropy (FA) and mean diffusivity (MD) in twenty-six patients with BECTS, twenty-nine patients with CAE, and twenty-four healthy controls. Group differences in FA and MD were quantified at 100 equidistant nodes along the fiber tract and these alterations and epilepsy-related clinical variables were correlated. A lateralization index (LI) representing the structural asymmetry of the fiber tract was computed and compared between both patient groups and controls. ResultsCompared with healthy controls, the BECTS group showed widespread FA reduction in 43.75% (7/16) and MD elevation in 50% (8/16) of identified fiber tracts, and the CAE group showed regional FA reduction in 31.25% (5/16) and MD elevation in 25% (4/16) of identified fiber tracts. In the BECTS group, FA and MD in the right anterior thalamic radiation positively and negatively correlated with the number of antiepileptic drugs, respectively, and MD in the right arcuate fasciculus (AF) positively correlated with seizure frequency. In the CAE group, the LI values were significantly lower in the inferior fronto-occipital fasciculus and the AF. ConclusionThe two childhood epilepsy syndromes display different patterns of WM alterations and structural asymmetry, suggesting that neuroanatomical differences may underlie the different profiles of BECTS and CAE.

White Matter Microstructure Alterations Associated With Paroxetine Treatment Response in Major Depression.

More than one-third of depressive patients do not achieve remission after the first antidepressant treatment. The “watch and wait” approach used to find the most effective antidepressant leads to an increased personal, social, and economic burden in society. In order to overcome this challenge, there has been a focus on studying neural biomarkers associated with antidepressant response. Diffusion tensor imaging measures have shown a promising role as predictors of antidepressant response by pointing to pretreatment differences in the white matter microstructural integrity between future responders and non-responders to different pharmacotherapies. Therefore, the aim of the present study was to explore whether response to paroxetine treatment was associated with differences in the white matter microstructure at baseline. Twenty drug-naive patients diagnosed with major depressive disorder followed a 6- to 12-week treatment with paroxetine. All patients completed magnetic resonance brain imaging and a clinical assessment at baseline and 6–12 weeks after treatment. Whole-brain tract-based spatial statistics was used to explore differences in white matter microstructural properties estimated from diffusion magnetic resonance imaging. Voxel-wise statistical analysis revealed a significant increase in fractional anisotropy and a decrease in radial diffusivity in forceps minor and superior longitudinal fasciculus in responders compared to non-responders. Thus, alterations in white matter integrity, specifically in forceps minor and the superior longitudinal fasciculus, are associated with paroxetine treatment response. These findings pave the way for personalized treatment strategies in major depression.

Evaluation and categorisation of individual patients based on white matter profiles: Single-patient diffusion data interpretation in neurodegeneration

The majority of radiology studies in neurodegenerative conditions infer group-level imaging traits from group comparisons. While this strategy is helpful to define phenotype-specific imaging signatures for academic use, the meaningful interpretation of single scans of individual subjects is more important in everyday clinical practice. Accordingly, we present a computational method to evaluate individual subject diffusion tensor data to highlight white matter integrity alterations. Fifty white matter tracts were quantitatively evaluated in 132 patients with amyotrophic lateral sclerosis (ALS) with respect to normative values from 100 healthy subjects. Fractional anisotropy and radial diffusivity alterations were assessed individually in each patient. The approach was validated against standard tract-based spatial statistics and further scrutinised by the assessment of 78 additional data sets with a blinded diagnosis. Our z-score-based approach readily detected white matter degeneration in individual ALS patients and helped to categorise single subjects with a 'blinded diagnosis' as likely ‘ALS’ or ‘control’. The group-level inferences from the z-score-based approach were analogous to the standard TBSS output maps. The benefit of the z-score-based strategy is that it enables the interpretation of single DTI datasets as well as the comparison of study groups. Outputs can be summarised either visually by highlighting the affected tracts, or, listing the affected tracts in a text file with reference to normative data, making it particularly useful for clinical applications. While individual diffusion data cannot be visually appraised, our approach provides a viable framework for single-subject imaging data interpretation.

Central white matter integrity alterations in 2-3-year-old children following prenatal alcohol exposure

BackgroundPrenatal alcohol exposure (PAE) remains a potentially preventable, but pervasive risk factor to neurodevelopment. Yet, evidence is lacking on the impact of alcohol on brain development in toddlers. This study aimed to investigate the impact of PAE on brain white matter integrity in 2–3-year-old children. MethodsChildren (n = 83, 30–37 months old) of the Drakenstein Child Health Study birth cohort, underwent diffusion MRI on a 3 T Siemens scanner during natural sleep. Parameters were extracted in children with PAE (n = 25, 56 % boys) and unexposed controls (n = 58, 62 % boys) using Tract-based Spatial Statistics, and compared by group. The contribution of maternal tobacco smoking to white matter differences was also explored. ResultsChildren with PAE had altered fractional anisotropy, radial diffusivity and axial diffusivity in brain stem, limbic and association tracts compared to unexposed controls. Notably lower fractional anisotropy was found in the uncinate fasciculus, and lower mean and radial diffusivity were found in the fornix stria terminalis and corticospinal tract (FDR corrected p < 0.05). There was a significant interaction effect of PAE and prenatal tobacco exposure which lowered mean, radial and axial diffusivity in the corticospinal tract significantly in the PAE group but not controls. ConclusionWidespread altered white matter microstructural integrity at 2–3 years of age is consistent with findings in neonates in the same and other cohorts, indicating persistence of effects of PAE through early life. Findings also highlight that prenatal tobacco exposure impacts the association of PAE on white matter alterations, amplifying effects in tracts underlying motor function.

Signatures of white-matter microstructure degradation during aging and its association with cognitive status

Previous studies have shown an association between cognitive decline and white matter integrity in aging. This led to the formulation of a “disconnection hypothesis” in the aging-brain, which states that the disruption in cortical network communication may explain the cognitive decline during aging. Although some longitudinal studies have already investigated the changes occurring in white matter microstructure, most focused on specific white matter tracts. Our study aims to characterize the longitudinal whole-brain signatures of white matter microstructural change during aging. Furthermore, we assessed the relationship between distinct longitudinal alterations in white matter integrity and cognition. White matter microstructural properties were estimated from diffusion magnetic resonance imaging, and cognitive status characterized from extensive neurocognitive testing. The same individuals were evaluated at two timepoints, with a mean interval time of 52.8 months (SD = 7.24) between first and last assessment. Our results show that age is associated with a decline in cognitive performance and a degradation in white matter integrity. Additionally, significant associations were found between diffusion measures and different cognitive dimensions (memory, executive function and general cognition). Overall, these results suggest that age-related cognitive decline is related to white matter alterations, and thus give support to the “disconnected hypothesis” of the aging brain.

Pretreatment abnormalities in white matter integrity predict one-year clinical outcome in first episode schizophrenia

Schizophrenia is a serious mental illness for which the mainstay of treatment is antipsychotics. Up to 30% of schizophrenia patients show limited response to antipsychotics. Identifying these patients before treatment could guide individualized treatment for improving outcomes in those not likely to show robust benefit from antipsychotics. Diffusion tensor imaging was performed with 56 drug-naïve first-episode schizophrenia patients and 69 matched healthy controls. Patients were followed clinically after one-year of antipsychotic treatment and classified at that point into groups of 17 poor outcome and 39 good outcome patients based on whether they showed at least a 50% reduction of Positive and Negative Syndrome Scale (PANSS) scores from baseline. Tract-based spatial statistics were applied to assess white matter microstructure in the two patient subgroups and healthy controls. Poor outcome patients showed reduced pretreatment fractional anisotropy (FA) in left cingulum and anterior thalamic radiation and increased FA in right superior and inferior longitudinal fasciculus compared with good outcome patients. FA in each of these four tracts was decreased in both patient subgroups relative to healthy controls. Considered together, the four altered tracts showed promising ability to differentiate poor from good outcome patients (sensitivity = 74.4%, specificity = 95.2%, AUC = 0.90, p < 0.001), and superior prediction of clinical outcome to baseline PANSS scores (p < 0.015). Prediction of outcomes using DTI features was not related to duration of untreated psychosis. Baseline alterations in white matter integrity may identify schizophrenia patients less likely to respond to treatment, which could be useful information for stratification in clinical trials and for individualized treatment planning.

Integrity of the uncinate fasciculus is associated with emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders involving emotional disruptions. One such pathway – the uncinate fasciculus – connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity with the orbitofrontal cortex remains unknown. Here we asked if the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution fMRI, we found that reduced integrity of the UF is related to elevated BOLD fMRI activation of the DG/CA3 subregions of the hippocampus during emotional lure discrimination. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that greater activation in this network (possibly driven by CA3 recurrent collaterals) is associated with memory errors. Based on this work we suggest that the UF is one pathway that may allow the OFC to exert control on this network and improve discrimination of emotional experiences, although further work is necessary to fully evaluate this possibility. This work provides novel insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

Cerebral small vessel disease genomics and its implications across the lifespan

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.

Gray and white matter abnormalities in primary trigeminal neuralgia with and without neurovascular compression

PurposePrevious researches have reported gray and white matter microalterations in primary trigeminal neuralgia (TN) with neurovascular compression (NVC). The central mechanism underlying TN without NVC are unknown but may include changes in specific brain regions or circuitries. This study aimed to investigate abnormalities in the gray matter (GM) and white matter (WM) of the whole brain and the possible pathogenetic mechanism underlying this disease.MethodsWe analyzed brain morphologic images of TN patients, 23 with NVC (TN wNVC) and 22 without NVC (TN wNVC) compared with 45 healthy controls (HC). All subjects underwent 3T-magnetic resonance imaging and pain scale evaluation. Voxel-based morphometry (VBM) and surface-based morphometry (SBM) were used to investigate whole brain grey matter quantitatively; graph theory was applied to obtain network measures based on extracted DTI data based on DTI data of the whole brains. Sensory and affective pain rating indices were assessed using the visual analog scale (VAS) and short-form McGill Pain Questionnaire (SF-MPQ).ResultsThe VBM and SBM analyses revealed widespread decreases in GM volume and cortical thickness in TN wNVC compared to TN woNVC, and diffusion metrics measures and topology organization changes revealed DTI showed extensive WM integrity alterations. However, above structural changes differed between TN wNVC and TN woNVC, and were related to specific chronic pain modulation mechanism.ConclusionAbnormalities in characteristic regions of GM and WM structural network were found in TN woNVC compared with TN wNVC group, suggesting differences in pathophysiology of two types of TN.