Decreased White Matter Integrity Research Articles

Multimodal neuroimaging insights into the neurobiology of healthy aging across the lifespan.

The purpose of this study was to advance our understanding of the neurobiology of healthy aging, which is crucial for improving quality of life and preventing age-related diseases. Despite its importance, a comprehensive investigation of this process has yet to be fully characterized. We used a hybrid PET/MRI scanner to assess neurophysiological parameters in 80 healthy individuals aged 20-78. Cerebral amyloid-beta (Aβ) deposition and glucose metabolism were assessed using PET scans, while participants underwent simultaneous MRI scans. We found a positive correlation between Aβ-deposition and aging, and a negative correlation between glucose metabolism and aging. The insula showed the strongest negative correlation between glucose metabolism and age (Spearman's r = -0.683, 95% CI [-0.79, -0.54], p < 0.0001), while the posterior cingulate cortex had the strongest positive correlation between Aβ-deposition and age (Spearman's r = 0.479, 95% CI [0.28, 0.64], p < 0.0001). These results suggest a spatially dependent link between Aβ-deposition and metabolism in healthy older adults, indicating a compensatory mechanism in early Alzheimer's. Additionally, Aβ-deposition was linked to changes in interregional neural communication. Our study confirms previous findings on aging and offers new insights, particularly on the role of Aβ-deposition in healthy aging. We observed a linear increase in Aβ-deposition, alongside decreases in white matter integrity, cerebral blood flow, and glucose metabolism. Additionally, we identified a complex regional relationship between Aβ-deposition, glucose metabolism, and neural communication, possibly reflecting compensatory mechanisms.

Right temporal variant frontotemporal dementia: a multimodal MRI analysis

AbstractBackgroundRight temporal variant frontotemporal dementia (rtvFTD), a new recognized entity among the FTD‐spectrum, is characterized by right anterior temporal lobe (rATL) atrophy and a peculiar clinical presentation, involving face and emotions recognition, memory, and naming deficits and behavioral disturbances. Clinical diagnosis is challenging, since rtvFTD shares features with both the behavioral variant FTD (bvFTD) and the semantic variant primary progressive aphasia (svPPA), and there is no consensus yet on its designation and characterization. Although rATL neurodegeneration is a hallmark of this syndrome, only a few studies investigated patterns of gray matter (GM) atrophy. Even less is known about white matter (WM) involvement. We conducted a preliminary study on the rtvFTD neuroimaging features using multimodal magnetic resonance imaging (MRI).MethodWe compared GM volume and WM microstructural integrity in rtvFTD (n=3) and svPPA (n=3) patients, and healthy controls (HC, n=27), using voxel‐based morphometry (VBM) and tract‐based spatial statistics (TBSS). Age and disease duration were considered as covariates of no interest.ResultSvPPA patients showed GM atrophy in the left temporal structures relative to HC. rtvFTD patients compared to HC showed not only GM atrophy in the right frontal and temporal structures, but also in the insula bilaterally, and in the left temporal and orbitofrontal cortices. Direct comparison between rtvFTD and svPPA showed that rtvFTD were more atrophic than svPPA patients in the bilateral temporal and frontal regions. Moreover, rtvFTD patients had less WM integrity than controls in the corpus callosum and the right inferior fronto‐occipital, inferior longitudinal, and uncinate fasciculi, while svPPA patients had decreased WM integrity in the corpus callosum and the left inferior fronto‐occipital fasciculus.ConclusionWe found that rtvFTD patients show greater atrophy compared to svPPA patients both in the right and left hemisphere, independently of disease duration. This suggests that rtvFTD and svPPA do not mirror each other in GM loss, and that a neurodegenerative process starting in the right hemisphere must be more widespread to become clinically evident. We also demonstrate that rtvFTD patients show WM disruption in fasciculi which have been implicated in face recognition, emotion processing, and language functions, in line with the clinical picture.

Alzheimer’s-linked axonal changes accompany elevated antidromic action potential failure rate in aged mice

Alzheimer’s disease (AD) affects both grey and white matter (WM), but considerably more is known about the former. Interestingly, WM disruption has been consistently observed and thoroughly described using imaging modalities, particularly MRI which has shown WM functional disconnections between the hippocampus and other brain regions during AD pathogenesis when early neurodegeneration and synapse loss are also evident. Nonetheless, high-resolution structural and functional analyses of WM during AD pathogenesis remain scarce. Given the importance of the myelinated axons in the WM for conveying information across brain regions, such studies will provide valuable information on the cellular drivers and consequences of WM disruption that contribute to the characteristic cognitive decline of AD. Here, we employed a multi-scale approach to investigate hippocampal WM disruption during AD pathogenesis and determine whether hippocampal WM changes accompany the well-documented grey matter losses. Our data indicate that ultrastructural myelin disruption is elevated in the alveus in human AD cases and increases with age in 5xFAD mice. Unreliable action potential propagation and changes to sodium channel expression at the node of Ranvier co-emerged with this deterioration. These findings provide important insight to the neurobiological substrates and functional consequences of decreased WM integrity and are consistent with the notion that hippocampal disconnection contributes to cognitive changes in AD.

White matter changes following electroconvulsive therapy for depression: a mega-analysis

IntroductionElectroconvulsive therapy (ECT) is proposed to exert an effect on white matter (WM) microstructure, but the limited power of previous studies made it difficult to highlight consistent patterns of change in diffusion metrics.ObjectivesWe initiated a multi-site mega-analysis and sought to address whether changes in WM microstructure occur following ECT.Methods To this end, diffusion tensor imaging (DTI) data (n=58) from 4 different sites were harmonized before pooling them by using ComBat, a batch-effect correction tool that removes inter-site technical variability, preserves inter-site biological variability and maximizes statistical power. Downstream statistical analyses aimed to quantify changes in Fractional anisotropy (FA), Mean Diffusivity (MD), Radial Diffusivity (RD) and Axial Diffusivity (AD), by employing whole-brain, tract-based spatial statistics (TBSS).ResultsECT increases FA in the right splenium of the corpus callosum and the left cortico-spinal tract. Both the left superior longitudinal fasciculus and the right inferior fronto-occipital fasciculus showed increases in AD. Increases in MD and RD could be observed in overlapping white matter structures of both hemispheres. Finally, responders showed significantly smaller FA values in the left forceps major and smaller AD values in the right uncinate fasciculus compared with non-responders.ConclusionsThis is the first and largest multi-site mega-analysis to demonstrate that ECT normalizes altered WM microstructure in important brain circuits that are implicated in the pathophysiology of depression. Furthermore, responders appear to present a more decreased WM integrity at baseline, which if replicated could serve as a biomarker for ECT response.DisclosureNo significant relationships.

Regional glucose metabolic decreases with ageing are associated with microstructural white matter changes: a simultaneous PET/MR study.

Human ageing is associated with a regional reduction in cerebral neuronal activity as assessed by numerous studies on brain glucose metabolism and perfusion, grey matter (GM) density and white matter (WM) integrity. As glucose metabolism may impact energetics to maintain myelin integrity, but changes in functional connectivity may also alter regional metabolism, we conducted a cross-sectional simultaneous FDG PET/MR study in a large cohort of healthy volunteers with a wide age range, to directly assess the underlying associations between reduced glucose metabolism, GM atrophy and decreased WM integrity in a single ageing cohort. In 94 healthy subjects between 19.9 and 82.5years (mean 50.1 ± 17.1; 47M/47F, MMSE ≥ 28), simultaneous FDG-PET, structural MR and diffusion tensor imaging (DTI) were performed. Voxel-wise associations between age and grey matter (GM) density, RBV partial-volume corrected (PVC) glucose metabolism, white matter (WM) fractional anisotropy (FA) and mean diffusivity (MD), and age were assessed. Clusters representing changes in glucose metabolism correlating significantly with ageing were used as seed regions for tractography. Both linear and quadratic ageing models were investigated. An expected age-related reduction in GM density was observed bilaterally in the frontal, lateral and medial temporal cortex, striatum and cerebellum. After PVC, relative FDG uptake was negatively correlated with age in the inferior and midfrontal, cingulate and parietal cortex and subcortical regions, bilaterally. FA decreased with age throughout the entire brain WM. Four white matter tracts were identified connecting brain regions with declining glucose metabolism with age. Within these, relative FDG uptake in both origin and target clusters correlated positively with FA (0.32 ≤ r ≤ 0.71) and negatively with MD (- 0.75 ≤ r ≤ - 0.41). After appropriate PVC, we demonstrated that regional cerebral glucose metabolic declines with age and that these changes are related to microstructural changes in the interconnecting WM tracts. The temporal course and potential causality between ageing effects on glucose metabolism and WM integrity should be further investigated in longitudinal cohort PET/MR studies.

Longitudinal change in executive function is associated with impaired top-down frontolimbic regulation during reappraisal in older adults

Networks in the prefrontal cortex (PFC) that are important for executive function are also engaged in adaptive responding to negative events. These networks are particularly vulnerable to age-related structural atrophy and an associated loss of executive function, yet existing evidence suggests preserved emotion processing ability in ageing. Using longitudinally acquired data from a battery of cognitive tasks, we defined a metric for the rate of decline of executive function. With this metric, we investigated relationships between changes in executive function and emotion reappraisal ability and brain structure, in 34 older adults, using functional and structural MRI. During task-based fMRI, participants were asked to cognitively reappraise negatively valenced images. We hypothesised one of two associations with decreasing executive function over time: 1) a decreased ability to reappraise reflected in decreased PFC and increased amygdala activation, or 2) a neural compensation mechanism characterised by increased PFC activation but no differential amygdala activation. Structurally, for a decreased reappraisal ability, we predicted a decrease in grey matter in PFC and/or a decrease of white matter integrity in amygdala-PFC pathways. Neither of the two hypotheses relating to brain function were completely supported, with the findings indicating a steeper decline in executive function associated with both increased PFC and increased left amygdala activity when reappraising negative stimuli. In addition, white matter integrity of the uncinate fasciculus, a primary white matter tract connecting the amygdala and ventromedial areas of PFC, was lower in those individuals who demonstrated a greater decrease in executive function. These findings highlight the association of diminishing cognitive ability with brain structure and function linked to emotion regulation.

Changes in Cerebral Volume and White Matter Integrity in Adults on Hemodialysis and Relationship to Cognitive Function

Introduction: Patients on hemodialysis (HD) have a significant burden of cognitive impairment. Characterizing the cerebral structural changes in HD patients compared to healthy controls and evaluating the relationship of cerebral structural integrity with cognitive performance in HD patients can help clarify the pathophysiology of the cognitive impairment in HD patients. Methods: In this cross-sectional study, in-center HD patients ≥50 years of age underwent brain structural and diffusion MRIs and cognitive assessment using the NIH Toolbox cognition battery. The cerebral imaging measures of the HD participants were compared to imaging from age-matched controls. Gray matter volume, white matter volume, and white matter integrity determined by diffusion tensor imaging parameters (including fractional anisotropy [FA]) were measured in both cohorts to determine differences in the cerebral structure between HD participants and healthy controls. The association between cognitive performance on the NIH Toolbox cognition battery and cerebral structural integrity was evaluated using multiple linear regression models. Results: We compared imaging measures form 23 HD participants and 15 age-matched controls. The HD participants had decreased gray matter volumes (526.8 vs. 589.5 cm³, p < 0.01) and worsened white matter integrity overall (FA values of 0.2864 vs. 0.3441, p < 0.01) within major white matter tracts compared to healthy controls. Decreases in white matter integrity in the left superior longitudinal fasciculus was associated with lower executive function scores (r² = 0.24, p = 0.02) and inferior longitudinal fasciculus with lower memory scores (r = 0.25 and p = 0.03 for left and r² = 0.21 and p = 0.03 for right). Conclusions: HD patients have a pattern of decreased white matter integrity and gray matter atrophy compared to controls. Decreases in white matter integrity were associated with decreased cognitive performance in the HD population.

4190 White Matter Integrity in Hemodialysis Patients

OBJECTIVES/GOALS: The purpose of this study is to understand how hemodynamics during dialysis in End-Stage Renal Disease (ESRD) patients on hemodialysis (HD) affect white matter health and how those effects cause cognitive impairments. METHODS/STUDY POPULATION: We collected demographic data, comorbidities, intradialytic measurements of blood pressure and cerebral oximetry, cognitive measures in several domains using NIH Toolbox Cognition Battery, diffusion-weighted and anatomical MRIs for 20 participants on HD. Specific tracts were identified using tractography and were used to calculate the average DTI measurements in each tract. Regression analysis was used to examine the relationship between mean DTI measurements of white matter integrity and cognitive performance scores. In addition, we compared diffusion MRI and T1 anatomical images of 16 healthy age-matched controls from a previous study. RESULTS/ANTICIPATED RESULTS: In our cohort 18 participants had imaging data that could be used in the analysis. We found widespread decreases in DTI white matter integrity compared to healthy age-matched controls, mean whole-brain fractional anisotropy was .3218 in the HD cohort and .3472 in controls p = .0018. Decreased integrity was found in most of the tracts identified but more decreased in tracts implicated in cognition. Partial regression analysis identified significant relationships between the white matter integrity of the left superior longitudinal fasciculus and overall fluid cognitive performance, R = .5525, p = .0174 before multiple comparisons correction when controlling for differences due to age. DISCUSSION/SIGNIFICANCE OF IMPACT: We found a widespread decrease in white matter integrity and significant correlations between cognitive performance and specific tract integrity in our HD cohort using regions identified by tractography imaging analysis. This analysis shows that HD patients have decreased white matter health and identifies several tracts that are important for cognitive performance in HD patients.

T48. DEVIATIONS IN MICRO AND MACRO WHITE MATTER STRUCTURES IN PSYCHOSIS PRONENESS

BackgroundPsychotic disorders are characterized by neurobiological deviations, including in the macro and microstructure of white matter. White matter alterations are also seen in psychosis-proneness and in individuals who have a high risk of psychosis. For example, studies have indicated decreases in white matter integrity in the genu/forceps minor of corpus callosum (CC) in the latter populations. Anterior corona radiata (ACR) is one crucial white-matter tract connecting the anterior cingulate cortex to the striatum. Indeed, reductions in the white matter structure of anterior genu of CC significantly predict the transition from ultra-high risk to psychosis. However, there is a gap in the literature related to observing the psychosis-proneness by applying both micro and macrostructural brain analyses, and most of the microstructural white matter studies in psychosis focus on fractional anisotropy (FA) and not include mean diffusivity (MD). Thus, the current study aims to assess whether white matter deviations in CG, ACR, and CC, are associated with psychosis proneness by combining both tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM) analyses in a sample of participants with psychosis proneness (PP) and without psychosis proneness (NPP).MethodsThe study included 53 participants (29 PP vs. 24 NPP) whose ages were between 17 and 24 years. Participants were split into two groups based on their scores on Structured Interview for Schizotypy assessment, a well-validated instrument of psychosis proneness. White matter integrity was analyzed via diffusion tensor imaging (DTI) and white matter volume (WMV) via VBM. Two sample t-test was used in GLM for both DTI and VBM analyses. FA, MD, and VMV were compared between two groups to observe micro and macro white matter structure alterations in the region of interest.ResultsDTI analysis revealed decreased FA values in the right ACR and right genu of the CC in the psychosis-proneness group (F(1,52)= 7.37, p= 0.009). Moreover, VBM showed a significant WMV decreases in the right CG, Brodmann areas 8, 9, and 32 in the PP group (F(1,52)= 50.85, uncorrected p<0.01). However, MD did not differ between the two groups (F(1,51)= 3.65, p=0.06)DiscussionThese findings suggest that PP associated with decreased white matter integrity in ACR, genu of CC, and also reduced white matter volumes in the right CG, Brodmann areas 8, 9, and 32. Significant FA decreases might result from alterations in radial or axial diffusivity since we did not observe significant MD differences between two groups. The current findings suggested that participants with PP had both macro and micro white matter structure disruptions, mostly in frontal parts of the right cerebrum, compared to no PP group.

Decreases in White Matter Integrity of Ventro-Limbic Pathway Linked to Post-Traumatic Stress Disorder in Mild Traumatic Brain Injury.

Post-traumatic stress disorder (PTSD) is commonly observed in military service members with mild traumatic brain injury (mTBI); however, the relationship between mTBI and PTSD is complex and not well understood. The present study aims to elucidate a link between the degree of alteration in limbic system-related white matter tracts and PTSD symptoms in an mTBI population. Diffusion-tensor imaging (DTI) with probabilistic tractography of the fronto-limbic pathways revealed decreased white matter integrity in the uncinate fasciculus in those with co-morbid mTBI and PTSD (n = 34), relative to those with only mTBI (n = 35). Additionally, fractional anisotropy (FA) and radial diffusivity (RD) measures in the bilateral uncinate fasciculus correlated with Post-Traumatic Stress Disorder Checklist Civilian version (PCL-C) scores, and primarily within the avoidance and re-experiencing domains. Findings from this study suggest the degree of traumatic injury within the limbic system could be directly related to post-traumatic stress and post-concussive symptoms, with disrupted white matter leading to significant PTSD outcomes.

Altered white matter integrity in adults with autism spectrum disorder and an IQ >100: a diffusion tensor imaging study.

White matter (WM) alterations have been reported in children and adults with autism spectrum disorder (ASD). In particular, impaired connectivity of limbic structures may be related to social deficits. Heterogeneous findings could be explained in terms of differences in sample characteristics and methodology. In this context, non-syndromic forms might differ substantially in WM structure from secondary ASD forms. In an attempt to recruit a homogeneous study sample, we included adults with high-functioning ASD and an IQ > 100 to decrease the influence of syndromic forms being often associated with cognitive deficits. Diffusion tensor imaging (DTI) was performed in 30 participants with ASD and 30 pairwise-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) as surrogate imaging markers for WM integrity were calculated. We found a significant FA decrease in the ASD group in the genu and body of the corpus callosum (CC). Increased MD was detected in the subgenual anterior cingulate cortex (sACC). The finding of decreased WM integrity in the genu of the CC is in line with earlier studies reporting a decreased number of interhemispheric fibers in the frontal lobe of ASD. Alterations in the sACC might be associated with 'Theory of mind' deficits.

In vivo imaging of oxidative stress and fronto-limbic white matter integrity in young adults with mood disorders.

Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18-30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment.

White Matter Associations With Performance Validity Testing in Veterans With Mild Traumatic Brain Injury: The Utility of Biomarkers in Complicated Assessment.

Failure on performance validity tests (PVTs) is common in Veterans with histories of mild traumatic brain injury (mTBI), leading to questionable validity of clinical presentations. Using diffusion tensor imaging, we investigated white matter (WM) integrity and cognition in 79 Veterans with history of mTBI who passed PVTs (n = 43; traumatic brain injury [TBI]-passed), history of mTBI who failed at least 1 PVT (n = 13; TBI-failed), and military controls (n = 23; MCs) with no history of TBI. The TBI-failed group demonstrated significantly lower cognitive scores relative to MCs and the TBI-passed group; however, no such differences were observed between MCs and the TBI-passed group. On a global measure of WM integrity (ie, WM burden), the TBI-failed group showed more overall WM abnormalities than the other groups. However, no differences were observed between the MCs and TBI-passed group on WM burden. Interestingly, regional WM analyses revealed abnormalities in the anterior internal capsule and cingulum of both TBI subgroups relative to MCs. Moreover, compared with the TBI-passed group, the TBI-failed group demonstrated significantly decreased WM integrity in the corpus callosum. Findings revealed that, within our sample, WM abnormalities are evident in those who fail PVTs. This study adds to the burgeoning PVT literature by suggesting that poor PVT performance does not negate the possibility of underlying WM abnormalities in military personnel with history of mTBI.

Beyond the Arcuate Fasciculus: Damage to Ventral and Dorsal Language Pathways in Aphasia.

Previous regional-based diffusion tensor imaging (DTI) studies focused on impairment of the arcuate fasciculus in aphasia; little is known about the extent to which aphasia severity is affected by damage to both ventral and dorsal language white matter (WM) pathways. To understand whether disconnection of these pathways contributes to clinical symptoms, we assessed the relationship between the alterations of WM integrity and clinical characteristics in acute aphasia after stroke. Eighteen patients with acute aphasia and age-, gender-, and education-matched healthy controls underwent language assessment and DTI scanning. The whole brain unbiased tract-based spatial statistics method was employed to quantitate WM integrity (fractional anisotropy) for both groups. Linear correlation analyses were performed to evaluate the relationship between WM integrity and clinical features. The aphasic patients showed decreased WM integrity in the left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus (IFOF/ILF) and the left uncinate fasciculus, which represents components of ventral language pathway, and the left superior longitudinal fasciculus (SLF), which relates to dorsal language pathway. In addition, WM integrity of the left IFOF and SLF showed a positive correlation with aphasia quotient, performance quotient, and cortical quotient, respectively. These findings suggested that impaired WM integrity in both language pathways not only contributed to language performance, but also to general cognitive status. We suggest that aphasia involves a breakdown of multiple connections of dorsal and ventral streams that directly contributes to language deficits. Damage to these dual-streams may serve as a neuromarker for aphasias after stroke.

Connectivity in Autism: A Review of MRI Connectivity Studies.

Autism spectrum disorder (ASD) affects 1 in 50 children between the ages of 6 and 17 years. The etiology of ASD is not precisely known. ASD is an umbrella term, which includes both low- (IQ < 70) and high-functioning (IQ > 70) individuals. A better understanding of the disorder and how it manifests in individual subjects can lead to more effective intervention plans to fulfill the individual's treatment needs.Magnetic resonance imaging (MRI) is a non-invasive investigational tool that can be used to study the ways in which the brain develops or deviates from the typical developmental trajectory. MRI offers insights into the structure, function, and metabolism of the brain. In this article, we review published studies on brain connectivity changes in ASD using either resting state functional MRI or diffusion tensor imaging.The general findings of decreases in white matter integrity and in long-range neural coherence are well known in the ASD literature. Nevertheless, the detailed localization of these findings remains uncertain, and few studies link these changes in connectivity with the behavioral phenotype of the disorder. With the help of data sharing and large-scale analytic efforts, however, the field is advancing toward several convergent themes, including the reduced functional coherence of long-range intra-hemispheric cortico-cortical default mode circuitry, impaired inter-hemispheric regulation, and an associated, perhaps compensatory, increase in local and short-range cortico-subcortical coherence.

Myelination-related genes are associated with decreased white matter integrity in schizophrenia

Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity--as measured by fractional anisotropy (FA)--is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA.

Cognitive and Brain Structural Changes in a Lung Cancer Population

No study has examined structural brain changes specifically associated with chemotherapy in a lung cancer population. The aim of this cross-sectional study was to assess differences in brain structure between small-cell lung cancer patients (C+) following chemotherapy, non-small-cell lung cancer patients (C-) before chemotherapy and healthy controls (HC). Twenty-eight small-cell lung cancer patients underwent a neuropsychological assessment and a structural magnetic resonance imaging, including T1-weighted and diffusion tensor imaging to examine gray matter density and white matter (WM) integrity, respectively, 1 month following completion of platinum-based chemotherapy. This group was compared with 20 age and education-matched non-small-cell lung cancer patients before receiving chemotherapy and 20 HC. Both C+ and C- groups exhibited cognitive impairment compared with the HC group. The C+ group performed significantly worse than HC in verbal fluency and visuospatial subtests; C- performed significantly worse than both C+ and HC in verbal memory. Voxel-based morphometry analysis revealed lower gray matter density in the insula and parahippocampal gyrus bilaterally, and left anterior cingulate cortex in C+ compared with HC. Diffusion tensor imaging indices showed focal decreased WM integrity in left cingulum and bilateral inferior longitudinal fasciculus in the C+ group and more widespread decreased integrity in the C- group compared with the HC group. This study demonstrates that lung cancer patients exhibit cognitive impairment before and after chemotherapy. Before the treatment, C- showed verbal memory deficits as well as a widespread WM damage. Following treatment, the C+ group performed exhibited lower visuospatial and verbal fluency abilities, together with structural gray matter and WM differences in bilateral regions integrating the paralimbic system.

Brain function during cognitive flexibility and white matter integrity in alcohol-dependent patients, problematic drinkers and healthy controls.

Cognitive flexibility has been associated with prefrontal white matter (WM) integrity in healthy controls (HCs), showing that lower WM integrity is associated with worse performance. Although both cognitive flexibility and WM integrity have been found to be aberrant in alcohol-dependent (AD) patients, the relationship between the two has never been tested. In this study, we investigated the association between WM tract density and cognitive flexibility in patients with AD (n = 26) and HCs (n = 22). In order to assess the influence of AD severity, we also included a group of problematic drinkers (PrDs; n = 23) who did not meet the AD criteria. Behavioral responses and brain activity during a cognitive flexibility task were measured during functional magnetic resonance imaging. Probabilistic fiber tracking was performed between the dorsolateral prefrontal cortex and the basal ganglia; two crucial regions for task switching. Finally, the task-related functional connectivity between these areas was assessed. There were no significant group differences in the task performance. However, compared with HCs, AD patients and PrDs showed decreased WM integrity and increased prefrontal brain activation during task switching. Evidence is presented for a compensatory mechanism, involving recruitment of additional prefrontal resources in order to compensate for WM and neural function impairments in AD patients and PrDs. Although present in both alcohol groups, the PrDs were more successful in invoking this compensatory mechanism when compared to the AD patients. We propose that this may therefore serve as a protective factor, precluding transition from problematic drinking into alcohol dependence.

Changes in white matter integrity before conversion from mild cognitive impairment to Alzheimer's disease.

BackgroundMild cognitive impairment (MCI) may represent an early stage of dementia conferring a particularly high annual risk of 15–20% of conversion to Alzheimer’s disease (AD). Recent findings suggest that not only gray matter (GM) loss but also a decline in white matter (WM) integrity may be associated with imminent conversion from MCI to AD.ObjectiveIn this study we used Voxel-based morphometry (VBM) to examine if gray matter loss and/or an increase of the apparent diffusion coefficient (ADC) reflecting mean diffusivity (MD) are an early marker of conversion from MCI to AD in a high risk population.MethodRetrospective neuropsychological and clinical data were collected for fifty-five subjects (MCI converters n = 13, MCI non-converters n = 14, healthy controls n = 28) at baseline and one follow-up visit. All participants underwent diffusion weighted imaging (DWI) and T1-weighted structural magnetic resonance imaging scans at baseline to analyse changes in GM density and WM integrity using VBM.ResultsAt baseline MCI converters showed impaired performance in verbal memory and naming compared to MCI non-converters. Further, MCI converters showed decreased WM integrity in the frontal, parietal, occipital, as well as the temporal lobe prior to conversion to AD. Multiple regression analysis showed a positive correlation of gray matter atrophy with specific neuropsychological test results.ConclusionOur results suggest that additionally to morphological changes of GM a reduced integrity of WM indicates an imminent progression from MCI stage to AD. Therefore, we suggest that DWI is useful in the early diagnosis of AD.

LOW GLUCOSE UTILIZATION AND HIGH LACTATE PRODUCTION IN THE ALZHEIMER'S DISEASE BRAIN

Background: Age-related changes in the cerebral white matter (WM) have been demonstrated in cognitively intact elderly, and are associated with cognition. The etiology of microstructuralWMdegeneration and its relation to cerebral blood flow (CBF) and white matter hyperintensities (WMH) are uncertain.Methods: 61 cognitively intact elderly volunteers (mean age 85, CDR 0) underwent 3T MRI Q2TIPS pulsed arterial spin labeling (PASL), diffusion tensor imaging (DTI), and cognitive assessment. Voxelwise Tract-Based Spatial Statistics (TBSS) was performed. A general linear model using permutation-based nonparametric testing (FSLRANDOMIZE) examined regional associations betweenWMCBF,WMHs, and microstructural measures. WMHs and WM CBF were examined in relation to fractional anisotropy using both voxel-based and mean WMH volume and WM CBF values. Region of interest (ROI) analyses included atlas-based segmentation of the corpus callosum (CC), limited to the TBSS-derived WM skeleton, and examined CC integrity in relation to cognitive function. Analyses were corrected for partial volume effects and adjusted for age and gender. Matched pairs t-test examined differences in anterior and poster WM integrity.Results: In TBSS voxel-based analysis, associations between WM integrity and WMHs were observed in regions commonly associated with small vessel ischemic disease, along the periventricular WM tracts. WM integrity was significantly decreased in relation to lowerWMperfusion in similar regions. Findings were largely replicated when WMH and WM CBF were entered into the model as mean values, rather than voxel-wise analysis. In addition, clusters of decreased WM integrity were seen in areas of normal appearing white matter in the anterior and posterior cc and WM tracts in the frontal and parietal lobes. ROI analyses showed greater WM integrity disruption in the anterior compared with posterior CC. Anterior CC integrity was associated with performance on executive and memory function tests. Conclusions: Greater WMH and lower WM perfusion are independently associated with decreased WM integrity both within and outside of commonly observedWMlesions.Anterior> poster cc involvement may represent greater susceptibility of this region to hypoperfusion.WMCBF may serve as a potentiallymodifiable target in trials aimed at preserving cognitive function in elderly individuals, prior to cognitive impairment.