Integrity Of Normal-appearing White Matter Research Articles

Investigating Brain Network Characteristics Interrupted by Covert White Matter Injury in Patients with Moyamoya Disease: Insights from Graph Theoretical Analysis

Chronic ischemia in adult moyamoya disease (MMD) reduces the integrity of normal-appearing white matter (WM). We investigated whether covert WM impairment alters large-scale brain networks and specific neural circuits associated with neurocognitive dysfunction in MMD. Forty-six participants (control, n= 23; MMD, n= 23) were examined using diffusion tensor imaging and streamline tractography. Structural connectivity among 90 cortical and subcortical brain regions was evaluated using the mean fractional anisotropy along the fiber tracts. Graph theoretical analysis was used to measure network parameters and inter-regional connectivity. Global network parameters were reduced in patients with MMD, including cluster coefficient (controls vs. MMD: 3.62 ± 0.24 vs. 3.26 ± 0.36; P < 0.0001), characteristic path length (controls vs. MMD: 1.20 ± 0.02 vs. 1.17 ± 0.01; P < 0.001), and small-world property (controls vs. MMD: 3.07 ± 0.18 vs. 2.83 ± 0.27; P < 0.001). Reduced pairwise connectivity was found in prefrontal neural circuits within the middle/inferior frontal gyrus; supplementary motor area; and insular, inferior temporal, and dorsal cingulate cortices. Covert WM microstructural changes in patients with MMD alter large-scale brain networks, as well as lateral prefrontal neural circuits. Evaluation of structural connectivity may be useful to assess the severity of chronic ischemic injury from a network perspective.

Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant.

Grey matter atrophy is common in multiple sclerosis. However, in contrast with other neurodegenerative diseases, it is unclear whether grey matter atrophy in multiple sclerosis is a diffuse 'global' process or develops, instead, according to distinct anatomical patterns. Using source-based morphometry we searched for anatomical patterns of co-varying cortical thickness and assessed their relationships with white matter pathology, physical disability and cognitive functioning. Magnetic resonance imaging was performed at 3 T in 208 patients with long-standing multiple sclerosis (141 females; age = 53.7 ± 9.6 years; disease duration = 20.2 ± 7.1 years) and 60 age- and sex-matched healthy controls. Spatial independent component analysis was performed on cortical thickness maps derived from 3D T1-weighted images across all subjects to identify co-varying patterns. The loadings, which reflect the presence of each cortical thickness pattern in a subject, were compared between patients with multiple sclerosis and healthy controls with generalized linear models. Stepwise linear regression analyses were used to assess whether white matter pathology was associated with these loadings and to identify the cortical thickness patterns that predict measures of physical and cognitive dysfunction. Ten cortical thickness patterns were identified, of which six had significantly lower loadings in patients with multiple sclerosis than in controls: the largest loading differences corresponded to the pattern predominantly involving the bilateral temporal pole and entorhinal cortex, and the pattern involving the bilateral posterior cingulate cortex. In patients with multiple sclerosis, overall white matter lesion load was negatively associated with the loadings of these two patterns. The final model for physical dysfunction as measured with Expanded Disability Status Scale score (adjusted R(2) = 0.297; P < 0.001) included the predictors age, overall white matter lesion load, the loadings of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

Corticospinal tract integrity is related to primary motor cortex thinning in relapsing–remitting multiple sclerosis

Background: The relationship between white matter injury and cortical atrophy development in relapsing–remitting multiple sclerosis (RRMS) remains unclear. Objectives: To investigate the associations between corticospinal tract integrity and cortical morphology measures of the primary motor cortex in RRMS patients and healthy controls. Methods: 51 RRMS patients and 30 healthy controls underwent MRI examination for cortical reconstruction and assessment of corticospinal tract integrity. Partial correlation and multiple linear regression analyses were used to investigate the associations of focal and normal appearing white matter (NAWM) injury of the corticospinal tract with thickness and surface area measures of the primary motor cortex. Relationships between MRI measures and clinical disability as assessed by the Expanded Disability Status Scale and disease duration were also investigated. Results: In patients only, decreased cortical thickness was related to increased corticospinal tract NAWM mean, axial and radial diffusivities in addition to corticospinal tract lesion volume. The final multiple linear regression model for PMC thickness retained only NAWM axial diffusivity as a significant predictor (adjusted R2= 0.270, p= 0.001). Clinical measures were associated with NAWM corticospinal tract integrity measures. Conclusions: Primary motor cortex thinning in RRMS is related to alterations in connected white matter and is best explained by decreased NAWM integrity.

White matter hyperintensities and normal-appearing white matter integrity in the aging brain

White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.

PREVALENCE AND CORRELATES OF SUBJECTIVE MEMORY IMPAIRMENT IN A RURAL ITALIAN POPULATION OF SUBJECTS AGED 50 YEARS AND OVER: DATA FROM THE ZABUT AGING PROJECT

Background: Neuropathology related to dementia slowly accumulates over decades. Consequently, identifying persons at a higher risk of dementia could postpone or prevent dementia by timely targeting modifiable risk factors. In this light, mild cognitive impairment (MCI) has been identified as the transitional stage between normal aging and dementia. So far, the understanding of MCI in thegeneral population remains limited. Therefore,we investigated determinants, MRI-correlates, and prognosis of MCI within the populationbasedRotterdamStudy.Methods:A total of 4198 participants were included in this study. Firstly, we studied age, APOE4 carriership, waist circumference, hypertension, diabetes mellitus, total and HDL-cholesterol levels, smoking, and stroke as potential determinants of MCI. Determinants were assessed cross-sectionally at baseline (2002-2005) and up to 7 years prior to baseline (1997-2001). Secondly, in a subset of 682 participants, we compared volumetric, microstructural, and focal MRI-correlates in persons with and withoutMCI. Thirdly, we followed participants for incident dementia and mortality until 2012 and assessed associations between MCI and the risk of dementia, Alzheimer’s disease, and mortality. Results: 417 Participants had MCI, of whom 254 non-amnestic and 163 amnestic MCI. At baseline, older age (OR 1.20, 95%-CI 1.11;1.29), APOE -e4 carriership (OR 1.26, 95%-CI 1.00;1.59), lower total cholesterol levels (OR 0.87, 95%-CI 0.78;0.98), and stroke (OR 2.12, 95%-CI 1.40;3.19) were related to MCI. Additionally, lower HDL-cholesterol levels (OR 0.86, 95%-CI 0.75;0.98) and current smoking (OR 1.49, 95%-CI 1.06;2.09) were associated with MCI when assessed 7 years prior to baseline. Persons with MCI, particularly thosewith non-amnestic MCI, had larger white matter lesion volumes, worse microstructural integrity of normal-appearing white matter, and higher prevalence of lacunes, compared to cognitively healthy participants. MCI was associated with an increased risk of dementia (HR 3.98, 95%-CI 2.97;5.33), Alzheimer’s disease (HR 4.03, 95% CI 2.92;5.56), and mortality (HR 1.54, 95%-CI 1.28;1.85). Figure shows cumulative incidence curves of dementia, Alzheimer’s disease, and mortality of persons without MCI and those with non-amnestic and amnestic MCI. Conclusions: We found that several vascular risk factors and MRI-correlates of cerebrovascular disease related to MCI in the general population. Participants with MCI had an increased risk of dementia, including Alzheimer’s disease, and mortality.

What explains gray matter atrophy in long-standing multiple sclerosis?

To identify the measures of focal and diffuse white matter (WM) abnormalities that are related to whole-brain, deep, and cortical gray matter (GM) atrophy in long-standing multiple sclerosis (MS). The institutional review board approved the study; all subjects gave written informed consent. Magnetic resonance (MR) imaging was performed at 3 T in 208 patients with MS of long-standing duration (disease duration ≥ 10 years) and in 60 healthy control subjects. Normalized GM volume (NGMV), normalized WM volume (NWMV), normalized deep GM volume (NDGMV), cortical thickness, and normalized lesion volume (NLV) were quantified. Tissue integrity of normal-appearing WM (NAWM) and lesions was measured by using diffusion-tensor MR imaging. Multivariate associations between measures of GM atrophy and WM abnormalities were assessed in the patient group by using multiple linear regression. NGMV, NDGMV, and cortical thickness were reduced in patients with MS (all P < .001). The final model for NGMV consisted of NWMV, NLV, and patient age and sex (adjusted R(2) = 0.58, P < .001). NWMV, NLV, and patient sex were the explanatory variables for NDGMV (adjusted R(2) = 0.75, P < .001). The model for cortical thickness consisted of fractional anisotropy of NAWM, NLV, and patient age and sex (adjusted R(2) = 0.32, P < .001). The relationship between GM atrophy and WM abnormalities was weaker in primary and secondary progressive disease than in relapsing-remitting disease. Whole-brain and deep GM atrophy were particularly explained by WM atrophy and lesion volume, while cortical atrophy was associated with NAWM integrity loss. The weaker relationship between GM atrophy and WM abnormalities in patients with progressive disease might indicate a more independent neurodegenerative disease process in these patients.

The effects of cerebral small-vessel disease in normal-appearing white matter integrity in mild cognitive impairment: A diffusion tensor imaging study

The effects of cerebral small-vessel disease in normal-appearing white matter integrity in mild cognitive impairment: A diffusion tensor imaging study

Associations between T1 white matter lesion volume and regional white matter microstructure in aging

White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal-appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity.

Changes in Integrity of Normal-Appearing White Matter in Patients with Moyamoya Disease: A Diffusion Tensor Imaging Study

DTI is widely used for the evaluation of white matter integrity in various neurologic diseases. The purpose of this study was to investigate changes in white matter integrity by using DTI in NAWM of patients with MMD and to evaluate the correlation between diffusion and perfusion characteristics through an interhemispheric comparison. We retrospectively reviewed 20 primary MMD patients with asymmetric disease stage and 20 age-matched healthy controls. FA(CS) and ADC(CS) values of bilateral centrum semiovale were measured by using region of interest analysis. Mean FA(CS) and ADC(CS) were compared between patient and control groups by unpaired t test. Interhemispheric differences in FA(CS) and ADC(CS) were assessed and compared between the H-TTP(delayed) and the H-TTP(shorter) by using paired t test. AIs also were assessed to verify interhemispheric differences. The patient group showed a significantly lower mean FA(CS) and a higher mean ADC(CS) value than the control group. In the patient group, the H-TTP(delayed) had a significantly lower FA(CS) and higher ADC(CS) value than the H-TTP(shorter). Both AI(FA) and AI(ADC) were significantly higher in the patient compared with the control group. DTI can describe subtle changes in white matter integrity in NAWM of patients with primary MMD that are not detected by conventional MR imaging. In addition, diffusion characteristics are well correlated with perfusion characteristics. We believe that DTI is a useful ancillary tool to evaluate patients with MMD.

Diffusion Tensor Imaging and Gait in Elderly Persons With Cerebral Small Vessel Disease

Although cerebral small vessel disease, including white matter lesions (WML) and lacunar infarcts, is associated with gait disturbances, not all individuals with small vessel disease have these disturbances. Identical-appearing WML on MRI could reflect different degrees of microstructural integrity. Moreover, conventional MRI does not assess the integrity of normal-appearing white matter (NAWM). We therefore investigated the relation between white matter integrity assessed by diffusion tensor imaging in WML, NAWM, several regions of interest, and gait. A total of 484 nondemented elderly persons between 50 and 85 years old with cerebral small vessel disease were included in this analysis and underwent MRI and diffusion tensor imaging scanning. Mean diffusivity and fractional anisotropy within WML, NAWM, and regions of interest were related to quantitative and semiquantitative gait parameters. Mean diffusivity in the WML was inversely related with gait (velocity β=-0.15; P=0.002). For the fractional anisotropy, this relation was less evident. The same was found in the NAWM (velocity β=-0.21; P<0.001) and for some parameters also after additional adjustment for WML and lacunar infarcts. This study indicates that integrity of both WML and NAWM, beyond the detection limit of conventional MRI, is associated with gait disturbances.

HIV-Associated Alterations in Normal-Appearing White Matter

There are conflicting reports of adverse HIV-associated alterations in white matter integrity as measured by diffusion tensor imaging (DTI). We sought to address these conflicting reports by assessing, on a voxel-by-voxel basis, HIV-associated regional changes in radiologically defined normal-appearing white matter (NAWM) integrity using high-resolution DTI. 30 HIV-seropositive (SP) and 30 HIV-seronegative (SN) nondemented, community-dwelling participants underwent DTI to derive whole-brain measures of white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD]). For each participant, the white matter T2 volume was thresholded to remove regions of abnormal signal, resulting in a NAWM mask, which was then applied to the FA and MD volumes to extract voxel-wise NAWM measures of white matter integrity. Voxel-wise group comparisons of FA and MD were conducted (P < 0.005, extent threshold 5 voxels) while controlling for age and substance-abuse history. There were no significant differences between the groups for demographic or cognitive performance variables. Summary whole-brain measures of FA and MD were equivalent between the SP and SN samples. Among the SP sample, history of substance abuse was associated with significantly increased whole-brain NAWM MD, and coinfection with hepatitis C virus (HCV) was associated with a trend for increased MD. Correlations between whole-brain NAWM FA and MD with cognitive performance measures were not significant. Regional analyses of DTI measures revealed variable differences in NAWM FA in the SP sample, with findings of both decreased and increased FA. Differences in NAWM MD were more consistent, with widespread increases noted in the SP sample compared to the SN sample. Eight of the 10 regions displaying significantly increased FA in the SP sample were also found to have significantly increased MD compared to the SN sample. Decreased white matter integrity is present even in radiologically defined NAWM in nondemented, community-dwelling patients with HIV. The decrease in NAWM integrity is best seen in increases in MD, a measure of generalized tissue breakdown. Indications of NAWM axonal integrity (FA) present a more complicated picture, with both decreased FA and increased FA in the SP sample. Our findings of variable HIV-associated FA changes in NAWM may account for previous conflicting reports of changes in DTI parameters in this population. The results of our study suggest that HIV infection contributes to variable changes in DTI values, reflecting both direct loss of axonal integrity and a loss of complexity to the underlying axonal matrix.

Quantitative morphologic evaluation of white matter in survivors of childhood medulloblastoma

In survivors of pediatric brain tumors, cranial radiation therapy can cause a debilitating cognitive decline associated with decreased volume in normal-appearing white matter (NAWM). We applied fractal geometry to quantify white matter (WM) integrity in the brain of medulloblastoma survivors. Fractal features of WM were evaluated by indices of fractal dimensions (FDs) of WM intensity and boundary on T1-weighted magnetic resonance images. The FD index of WM intensity was calculated by using a fractional Brownian motion model, and the FD index of WM boundary was calculated by using a box-counting method. Fractal features of WM on 116 magnetic resonance images of 58 patients with medulloblastoma were investigated at the start of therapy (Start TX) and approximately 2 years later (After TX). Patients were assigned to one of two groups based on change in NAWM volumes. Fractal features in patients with decreased NAWM volume were significantly greater After TX, whereas those in patients with increased NAWM volumes were not. Multiple linear regression analysis showed that fractal features were strongly correlated with NAWM volumes After TX in patients with decreased NAWM volume. These results demonstrated significant deficit in NAWM integrity and WM density changes in children treated for medulloblastoma. Multiple regression analysis illustrated that deficits in NAWM integrity in these children may partly explain the decrease in NAWM volume. We conclude that fractal geometry can be used to monitor the morphologic effects of neurotoxicity in brain tumor survivors.