Changes In White Matter Integrity Research Articles

Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Amygdala structural and functional reorganization as an indicator of affective dysfunction in patients with tinnitus.

The aim of this study was to systematically investigate structural and functional alterations in amygdala subregions using multimodal magnetic resonance imaging (MRI) in patients with tinnitus with or without affective dysfunction. Sixty patients with persistent tinnitus and 40 healthy controls (HCs) were recruited. Based on a questionnaire assessment, 26 and 34 patients were categorized into the tinnitus patients with affective dysfunction (TPAD) and tinnitus patients without affective dysfunction (TPWAD) groups, respectively. MRI-based measurements of gray matter volume, fractional anisotropy (FA), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), degree centrality (DC), and functional connectivity (FC) were conducted within 14 amygdala subregions for intergroup comparisons. Associations between the MRI properties and clinical characteristics were estimated via partial correlation analyses. Compared with that of the HCs, the TPAD and TPWAD groups exhibited significant structural and functional changes, including white matter integrity (WMI), fALFF, ReHo, DC, and FC alterations, with more pronounced WMI changes in the TPAD group, predominantly within the left auxiliary basal or basomedial nucleus (AB/BM), right central nucleus, right lateral nuclei (dorsal portion), and left lateral nuclei (ventral portion containing basolateral portions). Moreover, the TPAD group exhibited decreased FC between the left AB/BM and left middle occipital gyrus and right superior frontal gyrus (SFG), left basal nucleus and right SFG, and right lateral nuclei (intermediate portion) and right SFG. In combination, these amygdalar alterations exhibited a sensitivity of 65.4% and specificity of 96.9% in predicting affective dysfunction in patients with tinnitus. Although similar structural and functional amygdala remodeling were observed in the TPAD and TPWAD groups, the changes were more pronounced in the TPAD group. These changes mainly involved alterations in functionality and white matter microstructure in various amygdala subregions; in combination, these changes could serve as an imaging-based predictor of emotional disorders in patients with tinnitus.

What clinical parameter strongly associates white matter tract alterations in a Multiple Sclerosis population with voiding dysfunction? A prospective exploratory study.

To correlate clinical and urodynamics parameters in Multiple Sclerosis patients (MS) presenting Lower Urinary Tract Symptoms (LUTS) with both Expanded Disability Status Scale (EDSS) and changes in white matter integrity as seen on Diffusion Tensor Images (DTI). LUTS worsen throughout MS, as does lesion burden. We investigated which symptoms correlated best with structural changes in white matter structure. Ten adult women >18 years were recruited with stable MS for ≥3 months and voiding dysfunction defined as %PVR/BV > 20%. Patients participated in a clinical Urodynamic Study (UDS) and completed several questionnaires (i.e., HAM, AUASS, NBS-QoL). DTI images were acquired using a 7-Tesla Siemens MAGNETOM Terra MRI scanner. DTI maps were constructed, and individual patients were co-registered with the ICBM-DTI-81 white matter atlas to extract fractional anisotropy (FA) and mean diffusivity (MD). Pearson's correlation test was performed between each WMT and clinical parameters and between clinical parameters and the EDSS score as well. P-values < 0.05 were considered significant. Of the clinical parameters, %PVR/BV obtained from the average of multiple un-instrumented uroflow assessments had significant correlations to the greatest number of WMTs. Furthermore, we observed that in all recorded clinical parameters, %PVR/BV was the only significant parameter correlated to the EDSS score. This study demonstrates that %PVR/BV can be used as an objective parameter to gauge WMT changes and disease progression in MS patients. Future studies are needed to refine this model.

Electrical field strength from anodal prefrontal tDCS determines degree of white matter integrity changes in amnestic MCI patients

AbstractBackgroundAn electrical field (EF) strength induced by tDCS affects a therapeutic effect. Additionally, sequential tDCS has improved white matter integrity in cognitively impaired patients. However, researchers have not evaluated the impact of EF strength on white matter integrity in the prodromal stage of dementia. This study aimed to elucidate the effect of EF strength from prefrontal anodal tDCS on white matter integrity change and the modulating role of relevant genetic and pathologic factors in this effect in amnestic mild cognitive impairment (MCI) patients.MethodIn 55 amnestic MCI patients, we delivered anodal‐tDCS (2 mA/day, five times/week, for two weeks) over the left dorsolateral prefrontal cortex (DLPFC), calculated the EF strength for the left inferior frontal gyrus and DLPFC through the stimulation navigation program analysis. Additionally, we assessed the white matter integrity by diffusion tensor imaging before and after two weeks of stimulation; finally, we evaluated the modulating factors: amyloid‐beta (Aβ) deposition, APOE ε4‐allele status, and BDNF polymorphism.ResultAs the EF intensity in the left inferior frontal gyrus increased, the range of changes in white matter integrity significantly increased in left anterior thalamic radiation, corticospinal tract, inferior fronto‐occipital fasciculus, and inferior longitudinal fasciculus. Additionally, we found that greater change in white matter integrity was observed with higher regional EF strength in the APOE ε4 non‐carriers and BDNF MET non‐carrier, which could be attributed to an interaction between these modulating factors and EF intensity in the left anterior thalamic radiation and right uncinate fasciculus.ConclusionThese findings provide evidence for the precision‐medicine‐based application of tDCS in the prodromal stage of dementia, inducing the optimized therapeutic effect.

Impact of multidomain lifestyle intervention on white matter integrity: theSUPERBRAIN exploratory sub‐study

AbstractBackgroundIn the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we evaluated the impact of a 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI) on white matter integrity.MethodTotally, 152 participants, aged 60‐79 years without dementia, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 controls) underwent brain MRI at baseline and 24 weeks. The dtifit tool was used to fit the diffusion tensor model and computed diffusion scalar maps for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Individual FA, MD, AD, and RD at baseline were compared among groups using one‐way analyses of covariance (ANCOVA) with age, sex, years of education, and imaging site effects added as covariates of no interest. In addition, to compare changes in the FA, MD, AD, and RD from baseline to the study endpoint, we used two statistical analyses. First, ROI‐wise paired t‐tests were used to analyze longitudinal changes in white matter integrity for control and intervention group. The statistical significance level was set at bonferroni corrected p‐value &lt; 0.05. And then, significant brain image measures in previous paired t‐test were compared between each group pair (FMI vs. control; HMI vs. control; FMI+HMI vs. control) using ANCOVA with changes as dependent variables and age, sex, education, and site as covariates.ResultThe FA, MD, AD, and RD at each ROI at the baseline were not different among groups after bonferroni correction. In cingulum regions, the FA and AD were increased and the MD and AD were decreased significantly in the intervention group. The AD in right uncinate fasciculus was also increased in intervention group. Finally, among the significant regions in paired t‐test, compared with the control group, the FMI, HMI, and intervention group yielded significantly more beneficial effects on the AD of the cingulum regionsConclusionThe change of white matter integrity in the intervention group suggests that multidomain lifestyle intervention may be beneficial through structural neuroplastic changes in highly complex tract.

4 Interactions of Inflammation and Psychosocial Stress on White Matter Integrity Over Time in Older Black Adults

Objective:Higher levels of inflammation are associated with risk factors for Alzheimer’s disease and related dementias (ADRD) in older Black adults including psychosocial stressors (e.g., discrimination and early life adversity) and white matter alterations. Yet, limited work has investigated these risk factors together in a longitudinal neuroimaging study, despite the well-known ADRD disparity in older Black adults. Using data from the Minority Aging Research Study and African American Clinical Core of the Rush Alzheimer’s Disease Center, we examined interactions of psychosocial stressors and change in inflammation on changes in white matter integrity as measured via diffusion tensor imaging (DTI).Participants and Methods:Older Black adults (n=102) without known dementia at baseline (age=75.8±6.1 years; 87.3% female; education=15.4±2.7 years) completed blood draws at two time points (follow-up=2.4±0.7 years), neuroimaging at two or more time points (follow-up=3.7±1.8 years), and psychosocial questionnaires at one time point coinciding with the first blood draw/neuroimaging. Blood serum was assayed using highly-sensitive multiplexed sandwich ELISA for interleukin-6, c-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-a) and a change score was calculated for each inflammatory marker (T2 - T1). The Williams Everyday Discrimination Scale quantified experiences of discrimination in all participants and a 16-item questionnaire of emotional and physical trauma from age 0-18 assessed early life adversity in a participant subset (n=63). DTI-derived tract-based spatial statistics (TBSS) slope change measures for trace of the diffusion tensor, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were calculated, with the first two scans matched in time to blood assays. Linear regression models investigated interactions of each inflammatory marker change score (separately) and either discrimination or early life adversity (separately) on trace, FA, AD, and RD slopes as individual outcomes adjusting for age, sex, education, white matter hyperintensities (total volume and voxelwise), cardiovascular risk factors, statin and analgesic medications, thyroid conditions, and depression. Statistical significance was determined at p&lt;0.05 using family wise error correction and threshold free cluster enhancement.Results:Discrimination moderated the relationship between TNF-a and AD whereby those with increasing TNF-a and higher levels of discrimination had increasing levels of AD over time in white matter tracts connecting the left and right cerebellum, the left pallidum and medulla, and the left superior frontal gyrus and left thalamus. Both discrimination and early life adversity moderated associations between CRP and AD, where increases in CRP and higher psychosocial stressors (of either type) resulted in decreasing AD over time in tracts involving cingulate, frontal, and parietal regions. Discrimination and early life adversity also moderated associations between CRP and RD, where increasing CRP combined with greater psychosocial stressors resulted in decreasing RD in right hemisphere association and projection tracts connecting frontal, parietal, central, and subcortical regions.Conclusions:TNF-a and CRP interacted with measures of psychosocial stress to associate with DTI-derived TBSS slope change measures of AD and RD in differential, and at times, paradoxical ways. Findings suggest that both risk and resilience as related to brain connectivity may be co-occurring in the presence of psychosocial stressors for older Black adults.

Multimodal MRI study on the relation between WM integrity and connected GM atrophy and its effect on disability in early multiple sclerosis

BackgroundMultiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression.ObjectiveTo study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing–remitting (RR) MS in relation to clinical progression.MethodsHealthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners.ResultsWe included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups.DiscussionLower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.

Learning Spectral Fractional Anisotropy and Mean Diffusivity Features as Neuroimaging Biomarkers for Tracking White Matter Integrity Changes in Myotonic Dystrophy Type 1 Patients using Deep Convolutional Neural Networks.

Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social cognition. Fractional anisotropy and mean diffusivity along-tract data calculated using diffusion tensor imaging techniques play a vital role in assessing white matter microstructural changes associated with neurodegeneration caused by DM1. In this work, a novel spectrogram-based deep learning method is proposed to characterize white matter network alterations in DM1 with the goal of building a deep learning model as neuroimaging biomarkers of DM1. The proposed method is evaluated on fractional anisotropies and mean diffusivities along-tract data calculated for 25 major white matter tracts of 46 DM1 patients and 96 unaffected controls. The evaluation data consists of a total of 7100 spectrogram images. The model achieved 91% accuracy in identifying DM1, a significant improvement compared to previous methods.Clinical relevance- Clinical care of DM1 is particularly challenging due to DM1 multisystem involvement and the disease variability. Patients with DM1 often experience neurological and psychological symptoms, such as excessive sleepiness and apathy, that greatly impact their quality of life. Some of DM1 CNS symptoms may be responsive to treatment. The goal of this research is to gain a deeper understanding of the impact of DM1 on the CNS and to develop a deep learning model that can serve as a biomarker for the disease, with the potential to be used in future clinical trials as an outcome measure.

White matter fractional anisotropy in a nonhuman primate model of early Alzheimer’s Disease‐like neuropathology: Relationships with social status and physiologic measures of stress responses

AbstractBackgroundPsychosocial stress is associated with micro‐ and macrostructural brain changes that may increase risk of Alzheimer’s disease (AD). White matter (WM) appears particularly vulnerable, and changes in white matter integrity are an early sign of AD pathogenesis. Cynomolgus macaques (Macaca fascicularis) have complex central nervous systems and naturally develop early AD‐like neuropathology with age. Female macaques form social status hierarchies in which subordinates exhibit behavioral and physiological signs of stress, and increased stress‐related pathologies similar to humans. Nonhuman primate studies provide a useful platform in which to assess relationships between stress and brain health is a well‐controlled environment with limited outside influences. Thus, these nonhuman primates are useful translational models for studying relationships of psychosocial stress with early AD‐like neuropathology.MethodUsing diffusion tensor imaging, we examined the relationship between psychosocial stress and fractional anisotropy (index of WM microstructural integrity (FA)) in 38 middle‐aged female cynomolgus macaques living in small social groups. Subjects were classified as either dominant or subordinate based upon the outcomes of agonistic interactions. FA in several regions of interest (ROIs): splenium, body, and genu of the corpus callosum (CC), frontal, temporal, occipital, and total cerebral and cerebellar white matter was assessed in relation to social status and several contemporaneous measures of stress physiology (blood pressure, resting cortisol, and heart rate variability (HRV)).ResultRepeated measures ANOVA using left and right ROIs as a repeated measure showed that dominants had significantly higher FA than subordinates in the genu and splenium of the CC, and the occipital and frontal cortices (all p&lt;0.05). Dominants also had higher FA, on average, in the body of CC (p = 0.07) and cerebrum (p = 0.10), although these differences were not significant. Dominants and subordinates did not differ in temporal or cerebellar FA (both p&gt;0.7). FA was inversely correlated with blood pressure, directly correlated with HRV (p’s&lt;0.05), but not correlated with serum cortisol.ConclusionPsychosocial stress of subordination, as well as physiologic indices of stress responses, was associated with diminished WM integrity in several brain regions. These studies lay the groundwork for investigations of interventions on psychosocial stress to reduce AD risk later in life.

White Matter and Gray Matter Changes Related to Cognition in Community populations (P12-6.008)

<h3>Objective:</h3> To investigate the global and topographic changes of white matter integrity and cortical structure related to cognitive impairments in a community-based population. <h3>Background:</h3> Further studies in associations of cortical and subcortical changes with cognitive function would better explain the pathology of cognitive impairment. <h3>Design/Methods:</h3> A cross-sectional analysis was performed based on 995 subjects (aged 56.8±9.1 years, 34.8% males) from the Shunyi study, a community-dwelling cohort. Cognitive status was accessed by a series of neurocognitive tests including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), category Verbal Fluency Test (VFT), Digit Span Test (DST), and Trail Making Tests A and B (TMT-A and TMT-B). Structural and diffusional MRI data were acquired. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and peak width of skeletonized mean diffusivity (PSMD). Cortical surface area, thickness, and volume were measured using Freesurfer. Probabilistic tractography was further conducted to track the white matter fibers connecting to the cortical regions related to cognition. General linear models were used to investigate the association between brain structure and cognition. <h3>Results:</h3> Global mean FA and MD were associated with VFT performances (FA, β=0.119, p&lt;0.001; MD, β=−0.128, p&lt;0.001). Global cortical surface area, thickness, and volume were not related to cognitive scores. In tract-based spatial statistics, disrupted white matter integrity was related to cognitive impairment mainly in visuomotor processing speed and executive function (TMT-A and VFT), rather than short-term memory (DST). In the whole brain vertex-wise analysis, surface area in the left orbitofrontal cortex and left central sulcus were positively associated with MMSE and MoCA scores. These associations were independent of the connecting white matter tract. <h3>Conclusions:</h3> Disrupted white matter integrity and regional cortical surface area were related to cognition in community-dwelling populations. The associations of cortical surface area and cognition were independent of the connecting white matter tract. <b>Disclosure:</b> Mrs. Li has nothing to disclose. Jing Yuan has nothing to disclose. Fei Han has nothing to disclose. Lixin Zhou has nothing to disclose. Jun Ni has nothing to disclose. Ming Yao has nothing to disclose. Shuyang Zhang has nothing to disclose. Zhengyu Jin has nothing to disclose. Liying Cui has nothing to disclose. Feifei Zhai has nothing to disclose. Yi-Cheng Zhu has nothing to disclose.

Effects of manual therapy combined with therapeutic exercise versus routine physical therapy on brain biomarkers in patients with chronic non-specific neck pain in Thailand: a study protocol for a single-blinded randomised controlled trial

IntroductionStructural brain alterations in pain-related areas have been demonstrated in patients with non-specific neck pain. While manual therapy combined with therapeutic exercise is an effective management for neck pain, its...

White matter and gray matter changes related to cognition in community populations.

Further studies are needed to improve the understanding of the pathological process underlying cognitive impairments. The purpose of this study is to investigate the global and topographic changes of white matter integrity and cortical structure related to cognitive impairments in a community-based population. A cross-sectional analysis was performed based on 995 subjects (aged 56.8 ± 9.1 years, 34.8% males) from the Shunyi study, a community-dwelling cohort. Cognitive status was accessed by a series of neurocognitive tests including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), category Verbal Fluency Test (VFT), Digit Span Test (DST), and Trail Making Tests A and B (TMT-A and TMT-B). Structural and diffusional MRI data were acquired. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and peak width of skeletonized mean diffusivity (PSMD). Cortical surface area, thickness, and volume were measured using Freesurfer. Probabilistic tractography was further conducted to track the white matter fibers connecting to the cortical regions related to cognition. General linear models were used to investigate the association between brain structure and cognition. Global mean FA and MD were significantly associated with performances in VFT (FA, β 0.119, p < 0.001; MD, β -0.128, p < 0.001). Global cortical surface area, thickness, and volume were not related to cognitive scores. In tract-based spatial statistics analysis, disruptive white matter integrity was related to cognition impairment, mainly in visuomotor processing speed, semantic memory, and executive function (TMT-A and VFT), rather than verbal short-term memory and working memory (DST). In the whole brain vertex-wise analysis, surface area in the left orbitofrontal cortex, right posterior-dorsal part of the cingulate gyrus, and left central sulcus were positively associated with MMSE and MoCA scores, and the association were independent of the connecting white matter tract. Disrupted white matter integrity and regional cortical surface area were related to cognition in community-dwelling populations. The associations of cortical surface area and cognition were independent of the connecting white matter tract.

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 Fractional Anisotropy in a Nonhuman Primate Model of Early Alzheimer’s Disease‐like Neuropathology: Relationships with Social Status and Physiologic Measures of Stress Responses

AbstractBackgroundPsychosocial stress is associated with micro‐ and macrostructural brain changes that may increase risk of Alzheimer’s disease (AD). White matter (WM) appears particularly vulnerable, and changes in white matter integrity are an early sign of AD pathogenesis. Cynomolgus macaques (Macaca fascicularis) have complex central nervous systems and naturally develop early AD‐like neuropathology with age. Female macaques form social status hierarchies in which subordinates exhibit behavioral and physiological signs of stress, and increased stress‐related pathologies similar to humans. Nonhuman primate studies provide a useful platform in which to assess relationships between stress and brain health is a well‐controlled environment with limited outside influences. Thus, these nonhuman primates are useful translational models for studying relationships of psychosocial stress with early AD‐like neuropathology.MethodUsing diffusion tensor imaging, we examined the relationship between psychosocial stress and fractional anisotropy (index of WM microstructural integrity (FA)) in 38 middle‐aged female cynomolgus macaques living in small social groups. Subjects were classified as either dominant or subordinate based upon the outcomes of agonistic interactions. FA in several regions of interest (ROIs): splenium, body, and genu of the corpus callosum (CC), frontal, temporal, occipital, and total cerebral and cerebellar white matter was assessed in relation to social status and several contemporaneous measures of stress physiology (blood pressure, resting cortisol, and heart rate variability (HRV)).ResultRepeated measures ANOVA using left and right ROIs as a repeated measure showed that dominants had significantly higher FA than subordinates in the genu and splenium of the CC, and the occipital and frontal cortices (all p&lt;0.05). Dominants also had higher FA, on average, in the body of CC (p=0.07) and cerebrum (p=0.10), although these differences were not significant. Dominants and subordinates did not differ in temporal or cerebellar FA (both p&gt;0.7). FA was inversely correlated with blood pressure, directly correlated with HRV (p’s&lt;0.05), but not correlated with serum cortisol.ConclusionPsychosocial stress of subordination, as well as physiologic indices of stress responses, was associated with diminished WM integrity in several brain regions. These studies lay the groundwork for investigations of interventions on psychosocial stress to reduce AD risk later in life.

In‐season docosahexaenoic acid supplementation does not prevent white matter damage during a single American football season: Implications for neurodegeneration prevention

AbstractBackgroundRepetitive sub‐concussive head impacts (RSHIs) are common in American football, result in changes to white matter microstructural integrity, and are suggested as a potential risk factor for neurodegenerative diseases, including Alzheimer’s disease. RSHI‐induced white matter degradation may accelerate neurodegenerative processes, necessitating effective preventative and therapeutic approaches in this population. Prior studies indicate potential neuroprotective and remyelinating effects of docosahexaenoic acid (DHA). Here, we conducted a double‐blind, randomized, placebo‐controlled trial to assess the effects DHA supplementation during a National Collegiate Athletic Association football season on neuroimaging measures of white matter integrity.MethodThirty‐eight participants were randomized to treatment (6g DHA/EPA) or placebo (6g oleic/linoleic acid) group for seven months of five‐times‐per‐week supplementation. 27 participants completed the trial and had complete neuroimaging datasets (n = 16 placebo; n = 11 treatment). White matter integrity changes from preseason to immediately post‐season were quantified using voxel‐wise fractional anisotropy and diffusivity (mean, axial, radial) as well as deterministic tractography using quantitative anisotropy (QA). Gray matter volume as well as intra‐regional, edge‐wise, and network level functional connectivity were obtained as secondary measures along with serum neurofilament light (NfL) as a peripheral biomarker of axonal damage.ResultThere were no voxel‐wise, between‐group differences in voxel‐wise DTI analyses. Compared to placebo, the treatment group had increased QA in ascending corticostriatal fibers and decreased QA in long association and commissural fibers. Increased mean (ρ = 0.47), axial (ρ = 0.44), and radial (ρ = 0.51) diffusivity and decreased QA (ρ = ‐0.52) in the corpus callosum and bilateral corona radiata were correlated with increasing NfL levels during the season irrespective of treatment group. Default mode/frontoparietal network connectivity (g = 0.96, p = 0.024) was greater in the treatment group.ConclusionIn‐season DHA supplementation was insufficient to prevent or protect against axonal damage as it occurred during the season. However, there may be neuroprotective effects on functional connectivity despite structural damage. If RSHIs are a risk factor for future neurodegeneration, then alternative therapeutic merit further investigation. These present outcomes do not support the use of in‐season DHA supplementation as a preventive strategy to reduce brain injury resulting from collegiate football.AcknowledgementStudy funded by the Center for Innovation in Brain Science, University of Arizona. DHA provided by Pharmavite

Evidence of White Matter Integrity Changes in the Anterior Cingulum Among Shift Workers: A Cross-Sectional Study.

IntroductionWe investigated the white matter integrity in shift and non-shift workers and its associations with sleep and activity.MethodsDiffusion tensor imaging (DTI) was performed on 61 shift workers and 31 non-shift workers. Their sleep and activity profiles were assessed using the Pittsburgh Sleep Quality Index (PSQI), sleep diaries, and actigraphy. Fractional anisotropy (FA) (a measure of white matter integrity) was calculated using DTI tractography.ResultsShift workers exhibited higher FA values in the bilateral anterior cingulum than did non-shift workers. An increased FA in the right anterior cingulum was correlated with poor sleep quality (ie, a high PSQI score) in shift workers. An increased FA in the right anterior cingulum was also correlated with higher actigraphic activity indices (the mesor and M10 indices) in shift workers.DiscussionThe white matter integrity of the anterior cingulum was altered in shift workers, perhaps in association with sleep and activity disturbances.

Investigating longitudinal changes to frontal cortico-striatal tracts in Huntington’s disease: the IMAGE-HD study

The striatum is the principal site of disease pathology in Huntington’s disease and contains neural connections to numerous cortical brain regions. Studies examining abnormalities to neural connections find that white matter integrity is compromised in HD; however, further regional, and longitudinal investigation is required. This paper is the first longitudinal investigation into region-based white-matter integrity changes in Huntington’s Disease. The aim of this study was to better understand how disease progression impacts white matter tracts connecting the striatum to the prefrontal and motor cortical regions in HD. We used existing neuroimaging data from IMAGE-HD, comprised of 25 pre-symptomatic, 27 symptomatic, and 25 healthy controls at three separate time points (baseline, 18-months, 30-months). Fractional anisotropy, axial diffusivity and radial diffusivity were derived as measures of white matter microstructure. The anatomical regions of interest were identified using the Desikan-Killiany brain atlas. A Group by Time repeated measures ANCOVA was conducted for each tract of interest and for each measure. We found significantly lower fractional anisotropy and significantly higher radial diffusivity in the symptomatic group, compared to both the pre-symptomatic group and controls (the latter two groups did not differ from each other), in the rostral middle frontal and superior frontal tracts; as well as significantly higher axial diffusivity in the rostral middle tracts only. We did not find a Group by Time interaction for any of the white matter integrity measures. These findings demonstrate that whilst the microstructure of white matter tracts, extending from the striatum to these regions of interest, are compromised during the symptomatic stages of Huntington’s disease, 36-month follow-up did not show progressive changes in these measures. Additionally, no correlations were found between clinical measures and tractography changes, indicating further investigations into the relationship between tractography changes and clinical symptoms in Huntington’s disease are required.

White matter characteristics in the early and late stages of bipolar disorder: A diffusion tensor imaging study

BackgroundBipolar disorder (BD) is characterized by recurrent mood episodes that may progress over time. Staging models may be used to follow the long-term course of BD. BD is associated with microstructural changes in white matter (WM). This study aims to compare the WM integrity within patients groups who are in different stages of BD and healthy controls and investigate whether WM integrity changes may be a biomarker that can be used in the clinical staging of BD. MethodsThe study sample included euthymic 54 patients diagnosed with BD according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) and 27 healthy volunteers. Early-stage patients (n = 26) were determined as patients who have not had any mood episodes after the first manic episode, and late-stage patients (n = 28) determined as patients with recurrent mood episodes. MRI was performed using a 1.5 Tesla MR system and DTI sequences were acquired. ResultsRegion of interest (ROI) analyses showed that late-stage patients had significantly reduced fractional anisotropy (FA) in the right sagittal stratum and genu of the corpus callosum compared with healthy controls and early-stage patients. Regression models show that corpus callosum genu and right sagittal stratum FA values are predictive for the late-stage patient group. LimitationsThere are some limitations of the ROI method. The cross-sectional design is another limitation of this study. ConclusionsWM integrity of corpus callosum genu and right sagittal stratum may be a biomarker for clinical staging of BD. Identifying stage-specific biomarkers may help us predict the neuroprogressive course of BD. Longitudinal studies would be required to detect stage-specific biomarkers.

The association between control of interference and white-matter integrity: A cross-sectional and longitudinal investigation

Proactive interference (PI) occurs when old information interferes with newly acquired information and has been suggested as a major cause of forgetting in working memory. In this study, we investigate cross-sectional (N = 267) and longitudinal (N = 148) associations between PI and white-matter integrity (WMI) using diffusion-weighted imaging in an adult life-span sample (25–80 years; Mage = 60.15; 138 female). Older age was related to higher PI and lower WMI. Cross-sectional analyses showed associations between PI and WMI spanning several white-matter tracts as well as globally, suggesting that the age-related decline in PI may be driven primarily by global changes in WMI. Furthermore, longitudinal changes in PI were shown to be negatively correlated with concurrent changes in WMI in the fornix. Mediation analyses showed that WMI mediated the relationship between age and PI only in older adults, indicating that WMI becomes increasingly connected to cognitive functioning with increasing age. This is the first demonstration of WMI decline contributing to the age-related decline in PI.

White matter integrity changes and neurocognitive functioning in adult-late onset DM1: a follow-up DTI study

Myotonic Dystrophy Type 1 (DM1) is a multisystemic disease that affects gray and white matter (WM) tissues. WM changes in DM1 include increased hyperintensities and altered tract integrity distributed in a widespread manner. However, the precise temporal and spatial progression of the changes are yet undetermined. MRI data were acquired from 8 adult- and late-onset DM1 patients and 10 healthy controls (HC) at two different timepoints over 9.06 years. Fractional anisotropy (FA) and mean diffusivity (MD) variations were assessed with Tract-Based Spatial Statistics. Transversal and longitudinal intra- and intergroup analyses were conducted, along with correlation analyses with clinical and neuropsychological data. At baseline, reduced FA and increased MD values were found in patients in the uncinate, anterior-thalamic, fronto-occipital, and longitudinal tracts. At follow-up, the WM disconnection was shown to have spread from the frontal part to the rest of the tracts in the brain. Furthermore, WM lesion burden was negatively correlated with FA values, while visuo-construction and intellectual functioning were positively correlated with global and regional FA values at follow-up. DM1 patients showed a pronounced WM integrity loss over time compared to HC, with a neurodegeneration pattern that suggests a progressive anterior–posterior disconnection. The visuo-construction domain stands out as the most sensitive neuropsychological measure for WM microstructural impairment.