Cerebral White Matter Integrity Research Articles

White matter abnormalities associated with military PTSD in the context of blast TBI

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common among recent military veterans and involve substantial symptom overlap, making clinical distinction and effective intervention difficult. Emerging evidence of cerebral white matter abnormalities associated with mTBI may provide a biological measure to inform diagnosis and treatment, but the potentially confounding effects between PTSD and mTBI have largely gone unexamined. We collected diffusion imaging data from 133 recently-deployed American service members who developed PTSD and/or sustained mTBI, or had neither condition. Effects of PTSD and mTBI on traditional tensor-based measures of cerebral white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]) were compared in anatomical regions of interest and individual voxels throughout the brain. Generalized FA (GFA), which allows for multiple fiber orientations per voxel, was also included to improve sensitivity in white matter areas containing crossing or diverging axon bundles. PTSD was consistently associated with high GFA in select brain regions, greater likelihood of regions and voxels with abnormally low MD, and a greater number of voxels with abnormally high FA, while mTBI was associated with fewer high MD regions. Overall, PTSD was associated with more restricted diffusion (low MD) and greater anisotropy (high GFA) in regions of crossing/diverging fibers poorly characterized by a single tensor (FA), suggesting that interstitial fibers may be involved. Contrary to earlier results in a sample without PTSD, mTBI was not associated with anisotropy abnormalities, perhaps indicating the cooccurrence of PTSD and mTBI requires special consideration with regard to structural brain connectivity.

Regional cortical thickness and subcortical volume changes in patients with metabolic syndrome

Although previous studies have demonstrated an association between metabolic syndrome (MS) and changes in the integrity of cerebral white matter, no study has evaluated cortical thickness or subcortical volumes in MS with MRI. The purpose of our study was to investigate changes in cortical thickness and subcortical volume in an asymptomatic MS population. A total of 86 asymptomatic subjects (40 patients with MS and 46 subjects without MS) underwent 3T brain MRI scanning, and cortical thickness was compared between the groups across multiple locations. The subcortical volumes were also compared on a structure-by-structure basis. ANCOVA adjusted for age, education, total intracranial volume (TIV), and gender revealed significant volume reductions in the right nucleus accumbens in the MS group compared with the control group. The MS group showed a significant reduction in mean cortical thickness and volume in both hemispheres compared with controls. A group comparison analysis of the regional cortical thickness between the two groups also revealed significant reductions in cortical thickness in the MS group in the left insular, superior parietal, postcentral, entorhinal, and right superior parietal cortices compared with those of the control group (all comparisons p < 0.05, FDR corrected). We demonstrated a significant reduction in cortical and subcortical areas in MS patients, especially in areas involved in body weight control and cognitive function. Our results suggest an initial neurodegenerative process according to metabolic syndrome even in the preclinical stage, and further prospective studies are required to evaluate this process.

P025: Association between cardiac baroreflex sensitivity and cerebral white matter integrity in older adults

P025: Association between cardiac baroreflex sensitivity and cerebral white matter integrity in older adults

Global versus tract-specific components of cerebral white matter integrity: relation to adult age and perceptual-motor speed.

Although age-related differences in white matter have been well documented, the degree to which regional, tract-specific effects can be distinguished from global, brain-general effects is not yet clear. Similarly, the manner in which global and regional differences in white matter integrity contribute to age-related differences in cognition has not been well established. To address these issues, we analyzed diffusion tensor imaging measures from 52 younger adults (18-28) and 64 older adults (60-85). We conducted principal component analysis on each diffusion measure, using data from eight individual tracts. Two components were observed for fractional anisotropy: the first comprised high loadings from the superior longitudinal fasciculi and corticospinal tracts, and the second comprised high loadings from the optic radiations. In contrast, variation in axial, radial, and mean diffusivities yielded a single-component solution in each case, with high loadings from most or all tracts. For fractional anisotropy, the complementary results of multiple components and variability in component loadings across tracts suggest regional variation. However, for the diffusivity indices, the single component with high loadings from most or all of the tracts suggests primarily global, brain-general variation. Further analyses indicated that age was a significant mediator of the relation between each component and perceptual-motor speed. These data suggest that individual differences in white matter integrity and their relation to age-related differences in perceptual-motor speed represent influences that are beyond the level of individual tracts, but the extent to which regional or global effects predominate may differ between anisotropy and diffusivity measures.

SU‐E‐J‐143: Short‐ and Near‐Term Effects of Proton Therapy On Cerebral White Matter

Purpose:To assess early effects of proton therapy on the structural integrity of cerebral white matter in relation to the subsequent near‐term development of such effects.Methods:Sixteen children (aged 2–19 years) with craniopharyngioma underwent proton therapy of 54 Cobalt Gray Equivalent (CGE) in a prospective therapeutic trial. Diffusion tensor imaging (DTI) was performed at baseline before proton therapy and every 3 months thereafter. Tract‐based spatial statics analysis of DTI data was performed to derive the fractional anisotropy (FA) and radial diffusivity (RD) in 26 volumes of interest (VOIs). The dose distributions were spatially normalized to identify VOIs prone to high doses. The longitudinal percentage changes of the FA and RD in these VOIs at 3 and 12 months from the baseline were calculated, and their relationships were evaluated.Results:The average dose was highest to the cerebral peduncle (CP), corticospinal tract (CST) in the pons, pontine crossing tract (PCT), anterior/posterior limbs of the internal capsule (ALIC/PLIC), and genu of the corpus callosum (GCC). It ranged from 33.3 GCE (GCC) to 49.7 GCE (CP). A mild but statistically significant (P&lt;0.05) decline of FA was observed 3 months after proton therapy in all VOIs except the PLIC and ranged from −1.7% (ALIC) to −2.8% (PCT). A significant increase of RD was found in the CP (3.5%) and ALIC (2.1%). The average longitudinal change from the baseline was reduced at 12 months for most VOIs. However, the standard deviation increased, indicating that the temporal pattern varied individually. The follow‐up measurements at 3 and 12 months correlated for the CP, CST, PCT, and GCC (P &lt; 0.04).Conclusion:DTI data suggest early (3 months) effects of proton therapy on microstructures in the white matter. The subsequent follow‐up indicated individual variation of the changes, which was partly implied by the early effects.

Pre-Symptomatic Loss Of Cerebral White Matter Integrity In Those At Genetic Risk Of Amyotrophic Lateral Sclerosis (S26.004)

Pre-Symptomatic Loss Of Cerebral White Matter Integrity In Those At Genetic Risk Of Amyotrophic Lateral Sclerosis (S26.004)

Cerebral White Matter Integrity and Resting-State Functional Connectivity in Middle-aged Patients With Type 2 Diabetes

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.

Quantitative neuroimaging in mucolipidosis type IV

Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin-1 (TRPML1). Affected patients suffer from neurodevelopmental abnormalities and progressive retinal dystrophy. In a prospective natural history study we hypothesized the presence of an additional slow cerebral neurodegenerative process. We have recruited 5 patients, tested their neurodevelopmental status, and measured cerebral regional volumes and white matter integrity using MRI yearly. Over a period of up to 3years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland Scale and the FA values in the corticospinal tract (corr coef 0.39), and a negative correlation with the MD values (corr coef −0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. Therefore, our findings may be helpful for designing future clinical trials.

Cerebral white matter integrity in children with active versus remitted epilepsy 5 years after diagnosis

Diffusion tensor imaging (DTI) studies have reported white matter abnormalities in childhood-onset epilepsy, but the mechanisms and timing underlying these abnormalities, and their resolution, are not well understood. This study examined white matter integrity in children with active versus remitted epilepsy. Tract-based spatial statistics (TBSS) was used to examine whole-brain DTI indices of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in 20 children with epilepsy 5-6 years after diagnosis, compared to 29 healthy controls. To determine the status of white matter following cessation of seizures, participants with epilepsy were classified as active versus remitted and comparisons included: (1) controls versus all children with epilepsy, (2) controls versus children with remitted seizures, (3) controls versus children with active seizures, and (4) children with active versus remitted epilepsy. In the active compared to remitted epilepsy group, significantly higher FA and lower MD, AD and RD values were dispersed in the internal capsule, cingulum, body of the corpus callosum, superior corona radiata and superior fronto-occipital fasciculus. Similar differences were found between the active epilepsy and the control group. There were no significant differences between the remitted epilepsy and control groups. Children with active epilepsy differed in white matter integrity compared to children with remitted epilepsy and healthy controls. It remains to be determined whether these findings represent the outcomes of seizure remission versus an initial biomarker for those children who will ultimately have intractable epilepsy.

Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people

To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption. Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured. Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs -2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline. There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity.

Physical activity is related to the structural integrity of cerebral white matter

To investigate the relation between physical exercise and the microstructural integrity of cerebral white matter. Four hundred forty individuals with cerebral small-vessel disease, aged between 50 and 85 years, without dementia, were included and underwent MRI scanning. Physical exercise was assessed with a structured questionnaire. The cross-sectional relation between physical exercise and the microstructural integrity of the white matter was assessed by applying Tract-Based Spatial Statistics to diffusion tensor imaging parameters. Being more physically active was negatively related to the mean, axial, and radial diffusivity in numerous regions of the white matter, indicative of higher white matter integrity. These data indicate an association between physical activity and the integrity of the cerebral white matter's microstructure. Prospective studies are required to investigate a possible causal association between physical activity and cognitive decline.

Diffusion tensor imaging measures of normal appearing white matter in patients who are aging, or have amnestic mild cognitive impairment, or Alzheimer’s disease

To evaluate whether cerebral white matter integrity is related to cognitive function, and whether diffusion tensor imaging (DTI) could differentiate amnestic mild cognitive impairment (aMCI) from Alzheimer’s disease (AD), 12 patients with AD, 12 with aMCI, and 12 controls were recruited for this study. Cognitive functions of all subjects were assessed using the Mini-Mental State Examination (MMSE) and AD Assessment Scale – Cognitive Subscale (ADAS-Cog). DTI studies were acquired, and fractional anisotropy (FA) and mean diffusivity (MD) values of normal-appearing white matter (NAWM) in multiple brain regions were obtained. Results showed that MMSE and ADAS-Cog subscores were significantly associated with white matter integrity of the temporal-parietal lobes. A decrease in FA values and an increase in MD values in multiple cortical regions were confirmed in patients with AD compared to controls. MD values in the posterior region of the corpus callosum in aMCI differed from those of early AD. Significant reductions of FA values in the NAWM of the parietal lobe was observed in aMCI compared to controls. Our data indicate that the microstructural white matter integrity in the temporal-parietal lobes is gradually impaired in the progressive process of AD, and that splenium MD values could be used as a biomarker differentiating aMCI from AD.

Age-related Changes of White Matter in the Elderly Population Measured by Diffusion Tensor Imaging

Background: A decline in cerebral White Matter (WM) integrity occurs across the adult lifespan, with more rapid degradation later in life. Diffusion Tensor Imaging (DTI) is a non-invasive method to evaluate the microscopic changes of WM in vivo. Linear regression models have been applied to depict the relationship between diffusion properties, such as Fractional Anisotropy (FA) and Mean Diffusivity (MD), derived from DTI and age. However, the fit of these linear regression models is unsatisfactory. Objectives: The purpose of our study was to investigate the age-related changes of WM in an elderly population. Methods: We performed statistical parametric mapping with DTI to evaluate the patterns of age-related microscopic WM changes with voxel-based analysis in the elderly population (>55 years old). A linear regression model was used to examine the associations between DTI parameters and age. Results: The fit of the linear regression model depicting the association between mean global FA, MD values (FA, MD derived from global WM), and age was better than that reported in prior studies using DTI (R2=0.4252, p<0.001 for global FA and age; R2=0.5309, p<0.001 for global MD and age). Moreover, comparable to previous studies, the mean global FA showed a significant negative correlation with mean global MD, indicating a true age-related phenomenon of increased interstitial or intracellular fluid accumulation in cerebral WM. The mean frontal FA value was significantly lower than the mean global FA value. However, there was no significant difference between the mean frontal MD value and the mean global MD value. Conclusions: Focusing on the elderly population, we can improve the fit of linear regression models to investigate the age-related changes of WM by DTI. These results suggest that age-related microscopic changes of WM might be occurring more consistently in later life.

Cerebral white matter integrity and executive function in adult survivors of childhood medulloblastoma.

Survivors of pediatric medulloblastoma are at risk for neurocognitive dysfunction. Reduced white matter integrity has been correlated with lower intelligence in child survivors, yet associations between specific cognitive processes and white matter have not been examined in long-term adult survivors. Twenty adult survivors of medulloblastoma were randomly recruited from a larger institutional cohort of adult survivors of childhood cancer. Survivors underwent comprehensive neurocognitive evaluations and MRI. Data on brain volume and cortical thickness and diffusion tensor imaging were acquired, including measures of fractional anisotropy, apparent diffusion coefficient, and axial and radial diffusivity. Observed neurocognitive scores were compared with population norms and correlated to MRI indices. Survivors were, on average, 29 years of age and 18 years postdiagnosis. Mean full-scale intelligence quotient was nearly 1 SD below the normative mean (86.3 vs 100, P = .004). Seventy-five percent of survivors were impaired on at least one measure of executive function. Radial diffusivity in the frontal lobe of both hemispheres was correlated with shifting attention (left: r(s) = -0.67, P = .001; right: r(s) = -0.64, P = .002) and cognitive flexibility (left: r(s) = -0.56, P = .01; right: r(s) = -0.54, P = .01). Volume and cortical thickness were not correlated with neurocognitive function. Neurocognitive impairment was common and involved many domains. Reduced white matter integrity in multiple brain regions correlated with poorer performance on tasks of executive function. Future research integrating diffusion tensor imaging should be a priority to more rigorously evaluate long-term consequences of cancer treatment and to inform cognitive intervention trials in this high-risk population.

The influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: Results of a one‐year exercise intervention

Cerebral white matter (WM) degeneration occurs with increasing age and is associated with declining cognitive function. Research has shown that cardiorespiratory fitness and exercise are effective as protective, even restorative, agents against cognitive and neurobiological impairments in older adults. In this study, we investigated whether the beneficial impact of aerobic fitness would extend to WM integrity in the context of a one-year exercise intervention. Further, we examined the pattern of diffusivity changes to better understand the underlying biological mechanisms. Finally, we assessed whether training-induced changes in WM integrity would be associated with improvements in cognitive performance independent of aerobic fitness gains. Results showed that aerobic fitness training did not affect group-level change in WM integrity, executive function, or short-term memory, but that greater aerobic fitness derived from the walking program was associated with greater change in WM integrity in the frontal and temporal lobes, and greater improvement in short-term memory. Increases in WM integrity, however, were not associated with short-term memory improvement, independent of fitness improvements. Therefore, while not all findings are consistent with previous research, we provide novel evidence for correlated change in training-induced aerobic fitness, WM integrity, and cognition among healthy older adults.

Quantitative High-Field Diffusion Tensor Imaging of Cerebral White Matter in Asymptomatic High-Grade Internal Carotid Artery Stenosis

Background: Recently, several studies using diffusion-sensitized MRI reported changes in patients with high-grade internal carotid artery stenosis (ICAS) suggestive of subtle brain tissue damage. We used diffusion tensor imaging (DTI) to investigate the microstructural cerebral white matter integrity in asymptomatic patients with high-grade ICAS. Methods: In 15 asymptomatic patients with unilateral high grade (>70%) ICAS, we used 3T MRI including DTI. We used a region-of-interest approach comparing quantitative DTI metrics between both hemispheres including the so-called border zones. MR images were also assessed for periventricular white matter lesions (PWML) as well as collaterals via the circle of Willis. Results: There was no significant intraindividual difference of fractional anisotropy or mean diffusivity values between the hemispheres for any region. PWML was graded 0° in 6 patients, I° in 9 and II° in 2. Conclusions: In clinically asymptomatic patients with high-grade unilateral ICAS, there was no difference between the DTI parameters of the affected and the unaffected hemisphere. These findings contrast with other studies in asymptomatic high-grade ICAS, which is likely due to patient selection. These findings argue against concomitant chronic tissue integrity changes and implicate the benignity of asymptomatic carotid artery disease in individual patients.

Longitudinal Assessment of Chemotherapy-Induced Structural Changes in Cerebral White Matter and Its Correlation With Impaired Cognitive Functioning

To uncover the neural substrate of cognitive impairment related to adjuvant chemotherapy, we studied cerebral white matter (WM) integrity before and after chemotherapy by using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment. Thirty-four young premenopausal women with early-stage breast cancer who were exposed to chemotherapy underwent neuropsychologic testing and DTI before the start of chemotherapy (t1) and 3 to 4 months after treatment (t2). Sixteen patients not exposed to chemotherapy and 19 age-matched healthy controls underwent the same assessment at matched intervals. In all groups, we used paired t tests to study changes in neuropsychologic test scores and whole-brain voxel-based paired t tests to study changes in WM fractional anisotropy (FA; a DTI measure that reflects WM tissue organization), with depression scores and intelligence quotient as included covariates. We correlated changes of neuropsychologic test scores with the mean change of FA for regions that survived the paired t tests in patients treated with chemotherapy. In contrast to controls, the chemotherapy-treated group performed significantly worse on attention tests, psychomotor speed, and memory at t2 compared with t1 (P < .05). In the chemotherapy-treated group, we found significant decreases of FA in frontal, parietal, and occipital WM tracts after treatment (familywise error P < .05), whereas for both control groups, FA values were the same between t1 and t2. Furthermore, performance changes in attention and verbal memory correlated with mean regional FA changes in chemotherapy-treated patients (P < .05). We report evidence of longitudinal changes in cognitive functioning and cerebral WM integrity after chemotherapy as well as an association between both.

Clinical contributors to cerebral white matter integrity in HIV-infected individuals

HIV-infected people frequently exhibit brain dysfunction characterized by preferential damage to the cerebral white matter. Despite suppressed viral load and reconstituted immune function afforded by combination antiretroviral therapy (CART), brain dysfunction continues to be observed even in medically stable individuals. To provide insight into the etiology of HIV-associated brain dysfunction in the CART era, we examined the effects of HIV disease markers, antiretroviral treatment, hepatitis C (HCV) coinfection, and age on DTI measures of white matter integrity in a cohort of 85 individuals aged 23 to 65 years with chronic HIV infection. Fractional anisotropy and mean diffusivity were derived from 29 cerebral white matter regions, which were segmented on each individual brain using a high-resolution T1-weighted image and registered to diffusion images. Significant effects of clinical variables were found on white matter abnormalities in nearly all brain regions examined. Most notably, HCV coinfection and older age were associated with decreased anisotropy or increased diffusivity in the majority of brain regions. Individuals with higher current CD4 levels exhibited higher anisotropy in parietal lobe regions, while those undergoing antiretroviral treatment exhibited higher anisotropy in temporal lobe regions. The observed diffuse pattern of white matter injury suggests that future neuroimaging studies should employ methodologies that are not limited to circumscribed regions of interest. The current findings underline the multifactorial nature of HIV-associated brain dysfunction in the CART era, and the importance of examining the effects of HIV disease in the context of other comorbidities, in particular HCV coinfection and aging.

Cardiorespiratory fitness is positively correlated with cerebral white matter integrity in healthy seniors

High cardiorespiratory fitness (CRF) is an important protective factor reducing the risk of cardiac-related disability and mortality. Recent research suggests that high CRF also has protective effects on the brain's macrostructure and functional response. However, little is known about the potential relationship between CRF and the brain's white matter (WM) microstructure. This study explored the relationship between a comprehensive measure of CRF (VO(2) peak, total time on treadmill, and 1-minute heart rate recovery) and multiple diffusion tensor imaging measures of WM integrity. Participants were 26 healthy community dwelling seniors between the ages of 60 and 69 (mean=64.79 years, SD=2.8). Results indicated a positive correlation between comprehensive CRF and fractional anisotropy (FA) in a large portion of the corpus callosum. Both VO(2) peak and total time on treadmill contributed significantly to explaining the variance in mean FA in this region. The CRF-FA relationship observed in the corpus callosum was primarily characterized by a negative correlation between CRF and radial diffusivity in the absence of CRF correlations with either axial diffusivity or mean diffusivity. Tractography results demonstrated that portions of the corpus callosum associated with CRF primarily involved those interconnecting frontal regions associated with high-level motor planning. These results suggest that high CRF may attenuate age-related myelin declines in portions of the corpus callosum that interconnect homologous premotor cortex regions involved in motor planning.

Diffusion tensor imaging in temporal lobe epilepsy

Although mesial temporal sclerosis (MTS) has long been recognized in association with temporal lobe epilepsy (TLE), there is a growing body of literature suggesting structural abnormalities extending beyond the temporal lobe in patients with TLE. Diffusion tensor imaging (DTI) is a novel imaging technique that provides insight into the structural integrity of cerebral white matter. DTI studies have demonstrated extensive bilateral white matter abnormalities in TLE that extend far beyond the temporal lobe, even in patients with unilateral MTS. The relationship between white matter abnormalities, seizures, and comorbidity in TLE remains unclear.