Integrity Of Normal-appearing White Matter Research Articles

White Matter Correlates of Speech in Cerebrovascular Disease

AbstractBackgroundAnalyses of spoken discourse (speech beyond single words or sentences) can detect cognitive impairment in cerebrovascular disease (CVD) [Roberts, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and visible white matter damage detected using structural magnetic resonance imaging (MRI) and potential early‐stage damage in normal‐appearing white matter (NAWM) detected using diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered speech.MethodSpoken discourse and 3T MRI data were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n = 127). Spoken discourse analyses were completed previously [Roberts et al., 2021]. White matter hyperintensities (WMH) and the NAWM portions of the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculus (UNC) were segmented in each hemisphere (Figure 1). Mean values of fractional anisotropy (FA) and mean diffusivity (MD) within NAWM, and normalized WMH volume were calculated for each of the white matter tracts. Three canonical correlation analyses examined associations between 10 spoken discourse measures and the imaging metrics (WMH volume, FA, MD) in each tract.ResultCanonical correlations were significant for FA (rc = 0.51, p<0.05) and MD (rc = 0.56, p<0.05) but not WMH volume (rc = 0.42, p = 0.69). Among the white matter tracts, the strongest canonical loadings were seen for FA and MD in the left SLFp (FA: 0.80; MD: ‐0.61) and left SLFt (FA: 0.60; MD: ‐0.40) (Figure 2). Higher FA and lower MD in the left SLFp and left SLFt were associated with fluency, information content, and syntax performance.ConclusionSpoken discourse performance was associated with microstructural integrity of NAWM but not visible white matter damage. These results suggest that DTI metrics provide a more relevant assessment of white matter tract function in relation to speech than a volumetric measure of tract lesion load. Of the white matter tracts investigated in this study, spoken discourse performance in CVD was most strongly linked to white matter microstructure in the parietal and temporal endings of the left superior longitudinal fasciculus.

White Matter Correlates of Speech in Cerebrovascular Disease

AbstractBackgroundAnalyses of spoken discourse (speech beyond single words or sentences) can detect cognitive impairment in cerebrovascular disease (CVD) [Roberts, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and visible white matter damage detected using structural magnetic resonance imaging (MRI) and potential early‐stage damage in normal‐appearing white matter (NAWM) detected using diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered speech.MethodSpoken discourse and 3T MRI data were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n = 127). Spoken discourse analyses were completed previously [Roberts et al., 2021]. White matter hyperintensities (WMH) and the NAWM portions of the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculus (UNC) were segmented in each hemisphere (Figure 1). Mean values of fractional anisotropy (FA) and mean diffusivity (MD) within NAWM, and normalized WMH volume were calculated for each of the white matter tracts. Three canonical correlation analyses examined associations between 10 spoken discourse measures and the imaging metrics (WMH volume, FA, MD) in each tract.ResultCanonical correlations were significant for FA (rc = 0.51, p<0.05) and MD (rc = 0.56, p<0.05) but not WMH volume (rc = 0.42, p = 0.69). Among the white matter tracts, the strongest canonical loadings were seen for FA and MD in the left SLFp (FA: 0.80; MD: ‐0.61) and left SLFt (FA: 0.60; MD: ‐0.40) (Figure 2). Higher FA and lower MD in the left SLFp and left SLFt were associated with fluency, information content, and syntax performance.ConclusionSpoken discourse performance was associated with microstructural integrity of NAWM but not visible white matter damage. These results suggest that DTI metrics provide a more relevant assessment of white matter tract function in relation to speech than a volumetric measure of tract lesion load. Of the white matter tracts investigated in this study, spoken discourse performance in CVD was most strongly linked to white matter microstructure in the parietal and temporal endings of the left superior longitudinal fasciculus.

Diffusion Tensor Imaging in Parenchymal Neuro-Behçet's Disease.

Parenchymal Neuro-Behçet's disease (p-NBD) usually presents with a characteristic lesion in the mesodiencephalic region. However, there is a lack of information regarding the axonal integrity of normal-appearing white matter in p-NBD. Diffusion tensor imaging (DTI) is based on the properties of diffusivity and anisotropy that indicate the integrity of axons. The primary objective of the study was to compare p-NBD patients to healthy controls using diffusion tensor magnetic resonance imaging (DTI-MRI). The study enrolled parenchymal p-NBD patients who maintained stable disease status for 12 months. Healthy controls were chosen from a population with a similar age and gender distribution. Axial DTI was acquired using single-shot echo-planar imaging. Group analyses were carried out using the track-based spatial statistics tool of FMRIB software library (FSL). Correlations between DTI parameters and clinical outcomes were analyzed in the patient group. We recruited 12 patients with p-NBD and 12 healthy individuals. We found significant fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) differences in the superior longitudinal fasciculus, superior corona radiata, anterior corona radiata, body and genu of the corpus callosum, external capsule, and anterior limb of the internal capsule, mainly in the frontal white matter. Patients with p-NBD exhibit significant DTI alterations in the otherwise normal-appearing frontal association tracts. This study may contribute to a better understanding of the neuropsychological impairment pattern in patients with p-NBD, which is often associated with frontal cognitive networks.

Diffusion Tensor Imaging Revealed Microstructural Changes in Normal-Appearing White Matter Regions in Relapsing-Remitting Multiple Sclerosis.

BackgroundAxons and myelin sheaths are the physical foundation for white matter (WM) to perform normal functions. Our previous study found the metabolite abnormalities in frontal, parietal, and occipital normal-appearing white matter (NAWM) regions in relapsing–remitting multiple sclerosis (RRMS) patients by applying a 2D 1H magnetic resonance spectroscopic imaging method. Since the metabolite changes may associate with the microstructure changes, we used the diffusion tensor imaging (DTI) method to assess the integrity of NAWM in this study.MethodDiffusion tensor imaging scan was performed on 17 clinically definite RRMS patients and 21 age-matched healthy controls on a 3.0-T scanner. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 19 predefined regions of interest (ROIs), which were generated by removing a mask of manually drawn probabilistic lesion map from the Johns Hopkins University white-matter atlas. The mean values of FA, MD, AD, and RD were compared between different groups in the same ROIs.ResultsA probabilistic lesion map was successfully generated, and the lesion regions were eliminated from the WM atlas. We found that the RRMS patients had significantly lower FA in the entire corpus callosum (CC), bilateral of anterior corona radiata, and right posterior thalamic radiation (PTR). At the same time, RRMS patients showed significantly higher MD in the bilateral anterior corona radiata and superior corona radiata. Moreover, all AD values increased, and the bilateral external capsule, PTR, and left tapetum NAWM show statistical significance. What is more, all NAWM tracts showed increasing RD values in RRMS patients, and the bilateral superior corona radiata, the anterior corona radiata, right PTR, and the genu CC reach statistical significance.ConclusionOur study revealed widespread microstructure changes in NAWM in RRMS patients through a ready-made WM atlas and probabilistic lesion map. These findings support the hypothesis of demyelination, accumulation of inflammatory cells, and axonal injury in NAWM for RRMS. The DTI-based metrics could be considered as potential non-invasive biomarkers of disease severity.

Normal-Appearing White Matter Deteriorates over the Year After an Ischemic Stroke and Is Associated with Global Cognition.

Normal-appearing white matter (NAWM) is a hub of plasticity, but data relating to its influence on post-ischemic stroke (IS) outcome remain scarce. The aim of this study was to evaluate the relationship between NAWM integrity and cognitive outcome after an IS. A longitudinal study was conducted including supra-tentorial IS patients. A 3-Tesla brain MRI was performed at baseline and 1year, allowing the analyses of mean fractional anisotropy (FA) and mean diffusivity (MD) in NAWM masks, along with the volume of white matter hyperintensities (WMH) and IS. A Montreal Cognitive Assessment (MoCA), an Isaacs set test, and a Zazzo's cancellation task were performed at baseline, 3months and 1year. Mixed models were built, followed by Tract-based Spatial Statistics (TBSS) analyses. Ninety-five patients were included in the analyses (38% women, median age 69 ± 20). FA significantly decreased, and MD significantly increased between baseline and 1year, while cognitive scores improved. Patients who decreased their NAWM FA more over the year had a slower cognitive improvement on MoCA (β = - 0.11, p = 0.05). The TBSS analyses showed that patients who presented the highest decrease of FA in various tracts of white matter less improved their MoCA performances, regardless of WMH and IS volumes, demographic confounders, and clinical severity. NAWM integrity deteriorates over the year after an IS, and is associated with a cognitive recovery slowdown. The diffusion changes recorded here in patients starting with an early preserved white matter structure could have long term impact on cognition.

Microstructural changes in normal-appearing white matter in male sleep apnea patients are reversible after treatment: A pilot study.

Visually appreciable white matter (WM) changes have been described in obstructive sleep apnea (OSA). However, few data exist on the involvement of silent WM abnormalities. This prospective study investigated the microstructural integrity of normal-appearing white matter (NAWM) in male OSA patients before and after continuous positive airway pressure (CPAP) treatment, using a neuroimaging approach. Magnetic resonance imaging (MRI) was acquired from 32 participants (16 severe never-treated OSA and 16 controls). Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the microstructural NAWM changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). In order to evaluate the efficacy of the therapy, OSA patients underwent MRI evaluations at baseline and after 3months of treatment (follow-up). CPAP treatment significantly increased the FA in NAWM of the brain stem, corpus callosum and bilateral internal capsule of OSA patients at follow-up compared to baseline (p<0.05, TFCE-corrected). OSA patients also showed increases in AD in the corpus callosum, superior corona radiata, and internal capsule of the right hemisphere (p<0.05, TFCE-corrected) after CPAP treatment. A significant negative correlation was found between the FA of the corona radiata, corpus callosum, internal capsule, limbic structures, and neuropsychological scores at follow-up evaluation. No significant differences were found in MD and RD of NAWM in our patients after treatment. Our results demonstrate that FA and AD of NAWM in major tracts such as the corpus callosum and the internal capsule increased significantly after CPAP treatment, as a potential beneficial effect of ventilatory therapy. The recovery of NAWM alterations might also be related to the improvement in the neurocognitive profile, suggesting that nonclearly visible WM alterations may contribute to the physiopathology of OSA-related cognitive impairment.

Longitudinal analysis of T1w/T2w ratio in patients with multiple sclerosis from first clinical presentation

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS). Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally. Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1–60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria. Results: At baseline, sT1w/T2w (p = 0.152) and cortical thickness (p = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal R2 = 0.061). The association was modulated by failing NEDA-3 (marginal R2 = 0.097). Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures.

Perilesional neurodegenerative injury in multiple sclerosis: Relation to focal lesions and impact on disability

BackgroundAxonal injury is the primary source of irreversible neurological decline in persons with multiple sclerosis (pwMS). Identifying and quantifying myelin and axonal loss in lesional and perilesional tissue in vivo is fundamental for a better understanding of multiple sclerosis (MS) outcomes and patient impairment. Using advanced magnetic resonance imaging (MRI) methods, consisting of selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment diffusion MRI with the spherical mean technique (SMT), we conducted a cross-sectional pilot study to assess myelin and axonal damage in the normal appearing white matter (NAWM) surrounding chronic black holes (cBHs) and how this pathology correlates with disability in vivo. We hypothesized that lesional axonal transection propagates tissue injury in the surrounding NAWM and that the degree of this injury is related to patient disability. MethodsEighteen pwMS underwent a 3.0 Tesla conventional clinical MRI, inclusive of T1 and T2 weighted protocols, as well as SIR-qMT and SMT. Regions of interests (ROIs) were manually delineated in cBHs, NAWM neighboring cBHs (perilesional NAWM), distant ipsilateral NAWM and contra-lateral distant NAWM. SIR-qMT-derived macromolecular-to-free pool size ratio (PSR) and SMT-derived apparent axonal volume fraction (Vax) were extracted to infer on myelin and axonal content, respectively. Group differences were assessed using mixed-effects regression models and correlation analyses were obtained by bootstrapping 95% confidence interval. ResultsIn comparison to perilesional NAWM, both PSR and Vax values were reduced in cBHs (p < 0.0001) and increased in distant contra-lateral NAWM ROIs (p < 0.001 for PSR and p < 0.0001 for Vax) but not ipsilateral NAWM (p = 0.176 for PSR and p = 0.549 for Vax). Vax values measured in cBHs correlated with those in perilesional NAWM (Pearson rho = 0.63, p < 0.001). No statistically relevant associations were seen between PSR/Vax values and clinical and/or MRI metrics of the disease with the exception of cBH PSR values, which correlated with the Expanded Disability Status Scale (Pearson rho = −0.63, p = 0.03). ConclusionsOur results show that myelin and axonal content, detected by PSR and Vax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This finding is indicative of an ongoing anterograde/retrograde degeneration and suggests that treatment prevention of cBH development is a key factor for preserving NAWM integrity in surrounding tissue. It also suggests that measuring changes in perilesional areas over time may be a useful measure of outcome for proof-of-concept clinical trials on neuroprotection and repair. PSR and Vax largely failed to capture associations with clinical and MRI characteristics, likely as a result of the small sample size and cross-sectional design, however, longitudinal assessment of a larger cohort may unravel the impact of this pathology on disease progression.

Abstract TP75: Normal Appearing White Matter Integrity and Motor Impairment Severity in Acute Ischemic Stroke

Introduction: The effect of white matter hyperintensities (WMH) as measured by fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging on functional impairment and recovery after ischemic stroke has been investigated thoroughly. However, there has been growing interest to investigate normal-appearing white matter (NAWM) microstructural integrity following ischemic stroke onset with techniques such as diffusion tensor imaging (DTI). Methods: 52 patients with acute ischemic stroke and 36 without stroke were evaluated with a DTI and FLAIR imaging protocol and clinically assessed for severity of motor impairment using the Motricity Index within 72 hours of suspected symptom onset. Results: There were widespread decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) and radial diffusivity (RD) for the acute stroke group compared to the non-stroke group. As shown in the abstract figure with the blue voxels, there was a significant positive association between FA and motor function and a significant negative association between MD/RD and motor function. The NAWM regions of interest that were most sensitive to the Motricity Index were the anterior/posterior limb of the internal capsule in the infarcted hemisphere and the splenium of the corpus callosum, external capsule, posterior limb/retrolenticular part of the internal capsule, superior longitudinal fasciculus, and cingulum (hippocampus) of the intra-/contralateral hemisphere. Conclusion: The microstructural integrity of NAWM is a significant parameter to identify neural differences not only between those individuals with and without acute ischemic stroke, but also correlated with severity of acute motor impairment.

Normal-Appearing White Matter Integrity Is a Predictor of Outcome After Ischemic Stroke.

Background and Purpose- The aim of the present study was to evaluate the relationship between normal-appearing white matter (NAWM) integrity and postischemic stroke recovery in 4 main domains including cognition, mood, gait, and dependency. Methods- A prospective study was conducted, including patients diagnosed for an ischemic supratentorial stroke on a 3T brain MRI performed 24 to 72 hours after symptom onset. Clinical assessment 1 year after stroke included a Montreal Cognitive Assessment, an Isaacs set test, a Zazzo cancelation task, a Hospital Anxiety and Depression scale, a 10-meter walking test, and a modified Rankin Scale (mRS). Diffusion tensor imaging parameters in the NAWM were computed using FMRIB (Functional Magnetic Resonance Imaging of the Brain) Diffusion Toolbox. The relationships between mean NAWM diffusion tensor imaging parameters and the clinical scores were assessed using linear and ordinal regression analyses, including the volumes of white matter hyperintensities, gray matter, and ischemic stroke as radiological covariates. Results- Two hundred seven subjects were included (66±13 years old; 67% men; median National Institutes of Health Stroke Scale score, 3; interquartile range, 2-6). In the models including only radiological variables, NAWM fractional anisotropy was associated with the mRS and the cognitive scores. After adjusting for demographic confounders, NAWM fractional anisotropy remained a significant predictor of mRS (β=-0.24; P=0.04). Additional path analysis showed that NAWM fractional anisotropy had a direct effect on mRS (β=-0.241; P=0.001) and a less important indirect effect mediating white matter hyperintensity burden. Similar results were found with mean diffusivity, axial diffusivity, and radial diffusivity. In further subgroup analyses, a relationship between NAWM integrity in widespread white matter tracts, mRS, and Isaacs set test was found in right hemispheric strokes. Conclusions- NAWM diffusion tensor imaging parameters measured early after an ischemic stroke are independent predictors of functional outcome and may be additional markers to include in studies evaluating poststroke recovery.

Diffusion Properties of Normal-Appearing White Matter Microstructure and Severity of Motor Impairment in Acute Ischemic Stroke.

The effect of white matter hyperintensities as measured by FLAIR MR imaging on functional impairment and recovery after ischemic stroke has been investigated thoroughly. However, there has been growing interest in investigating normal-appearing white matter microstructural integrity following ischemic stroke onset with techniques such as DTI. Fifty-two patients with acute ischemic stroke and 36 without stroke were evaluated with a DTI and FLAIR imaging protocol and clinically assessed for the severity of motor impairment using the Motricity Index within 72 hours of suspected symptom onset. There were widespread decreases in fractional anisotropy and increases in mean diffusivity and radial diffusivity for the acute stroke group compared with the nonstroke group. There was a significant positive association between fractional anisotropy and motor function and a significant negative association between mean diffusivity/radial diffusivity and motor function. The normal-appearing white matter ROIs that were most sensitive to the Motricity Index were the anterior/posterior limb of the internal capsule in the infarcted hemisphere and the splenium of the corpus callosum, external capsule, posterior limb/retrolenticular part of the internal capsule, superior longitudinal fasciculus, and cingulum (hippocampus) of the intrahemisphere/contralateral hemisphere. The microstructural integrity of normal-appearing white matter is a significant parameter to identify neural differences not only between those individuals with and without acute ischemic stroke but also correlated with the severity of acute motor impairment.

Reduced Myelin Signal in Normal-appearing White Matter in Neuromyelitis Optica Measured by 7T Magnetic Resonance Imaging

Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p = 0.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength.

Diffusion Tensor Imaging Reveals Microstructural Heterogeneity of Normal-Appearing White Matter and Related Cognitive Dysfunction in Glioma Patients.

Immunohistochemical data based on isocitrate–dehydrogenase (IDH) mutation status have redefined glioma as a whole-brain disease, while occult tumor cell invasion along white matter fibers is inapparent in conventional magnetic resonance imaging (MRI). The functional and prognostic impact of focal glioma may however relate to the extent of white matter involvement. We used diffusion tensor imaging (DTI) to investigate microstructural characteristics of whole-brain normal-appearing white matter (NAWM) in relation to cognitive functions as potential surrogates for occult white matter involvement in glioma. Twenty patients (12 IDH-mutated) and 20 individually matched controls were preoperatively examined using DTI combined with a standardized neuropsychological examination. Tumor lesions including perifocal edema were masked, and fractional anisotropy (FA) as well as mean, radial, and axial diffusivity (MD, RD, and AD, respectively) of the remaining whole-brain NAWM were determined by using Tract-Based Spatial Statistics and histogram analyses. The relationship between extratumoral white matter integrity and cognitive performance was examined using partial correlation analyses controlling for age, education, and lesion volumes. In patients, mean FA and AD were decreased as compared to controls, which agrees with the notion of microstructural impairment of NAWM in glioma patients. Patients performed worse in all cognitive domains tested, and higher anisotropy and lower MD and RD values of NAWM were associated with better cognitive performance. In additional analyses, IDH-mutated and IDH-wildtype patients were compared. Patients with IDH-mutation showed higher FA, but lower MD, AD, and RD values as compared to IDH-wildtype patients, suggesting a better preserved microstructural integrity of NAWM, which may relate to a less infiltrative nature of IDH-mutated gliomas. Diffusion-based phenotyping and monitoring microstructural integrity of extratumoral whole-brain NAWM may aid in estimating occult white matter involvement and should be considered as a complementary biomarker in glioma.

Microstructural changes of normal-appearing white matter in Vascular Parkinsonism

ObjectiveSeveral evidences demonstrated the role of white matter (WM) lesions in the pathogenesis of Vascular Parkinsonism (VP), a clinical entity characterized by parkinsonism, postural instability, marked gait difficulty and poor response to levodopa. However, the involvement of normal appearing white matter (NAWM) in VP still remains unknown. This study aimed to investigate the microstructural integrity of NAWM in VP compared to Parkinson's disease (PD) and controls using neuroimaging approach. MethodsMagnetic resonance imaging data were acquired from 50 participants (15 VP, 20 PD and 15 controls). Diffusion tensor imaging (DTI) and Tract-based spatial statistics (TBSS) were performed to assess microstructural NAWM changes. In order to evaluate the relationship between specific fiber tract involvement and clinical picture, diffusion alterations were correlated with clinical features. ResultsCompared to PD patients and controls, significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in NAWM of corpus callosum, internal and external capsule, and corona radiata were present in VP. By contrast, DTI metrics were normal in NAWM-PD and controls. A significant correlation was found between FA and MD of anterior third of corpus callosum and clinical variables (postural instability, freezing-of-gait and symmetry of parkinsonism). ConclusionsThis study improves the knowledge on WM pathology in VP, as our results demonstrate that NAWM damage occurs in VP, but not in PD nor in controls. NAWM damage might relate to clinical picture and suggest that non-clearly-visible WM alterations may contribute to the physiopathology of this vascular disease.

White matter integrity and processing speed in sickle cell anemia.

ObjectiveThe purpose of this retrospective cross-sectional study was to investigate whether changes in white matter integrity are related to slower processing speed in sickle cell anemia.MethodsThirty-seven patients with silent cerebral infarction, 46 patients with normal MRI, and 32 sibling controls (age range 8–37 years) underwent cognitive assessment using the Wechsler scales and 3-tesla MRI. Tract-based spatial statistics analyses of diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) parameters were performed.ResultsProcessing speed index (PSI) was lower in patients than controls by 9.34 points (95% confidence interval: 4.635–14.855, p = 0.0003). Full Scale IQ was lower by 4.14 scaled points (95% confidence interval: −1.066 to 9.551, p = 0.1), but this difference was abolished when PSI was included as a covariate (p = 0.18). There were no differences in cognition between patients with and without silent cerebral infarction, and both groups had lower PSI than controls (both p < 0.001). In patients, arterial oxygen content, socioeconomic status, age, and male sex were identified as predictors of PSI, and correlations were found between PSI and DTI scalars (fractional anisotropy r = 0.614, p < 0.00001; r = −0.457, p < 0.00001; mean diffusivity r = −0.341, p = 0.0016; radial diffusivity r = −0.457, p < 0.00001) and NODDI parameters (intracellular volume fraction r = 0.364, p = 0.0007) in widespread regions.ConclusionOur results extend previous reports of impairment that is independent of presence of infarction and may worsen with age. We identify processing speed as a vulnerable domain, with deficits potentially mediating difficulties across other domains, and provide evidence that reduced processing speed is related to the integrity of normal-appearing white matter using microstructure parameters from DTI and NODDI.

Abstract TP50: Blood Brain Barrier Leakage Rates and Ischemic Tissue Outcomes in Patients With Advanced White Matter Disease

Background: The structural integrity of normal appearing white matter (NAWM) predicts outcomes after acute ischemic stroke (AIS); however, the underlying mechanisms are unclear. We evaluated blood-brain barrier (BBB) permeability and microstructural NAWM integrity in association with ischemic tissue outcomes. Methods: In a prospective observational study of patients with moderate to severe white matter hyperintensity (WMH) burden, 43 AIS patients had brain MRIs with dynamic susceptibilty contrast (DSC) perfusion performed within 12 hours and at 3-5 days after stroke onset. Acute infarct volume on diffusion-weighted imaging (DWIv) and final infarct volume (FIV) on follow-up FLAIR sequences were determined using a validated semi-automated method. Infarct growth (IG) was calculated from the acute DWIv subtracted from FIV. Median diffusivity metrics and BBB leakage rates (K2 coefficient) were measured in contralesional NAWM. Pearson correlation and linear regression were used for statistical analysis. Results: The K2 coefficient correlated with acute DWIv (ρ=0.30; p=0.046) and, marginally, with FIV (ρ=0.28; p=0.073). In univariate analysis, history of atrial fibrillation (β=23.8; p=0.009), and acute DWIv (β=1.2; p&lt;0.0001) were predictive of IG. Contralesional NAWM diffusivity metrics and K2 coefficient were not predictive of infarct growth. In the multivariable model, only acute DWIv independently predicted IG. Conclusion: In a prospective study of AIS patients with moderate to severe WMH burden, BBB leakage rates correlate with acute infarct volume. These findings suggest that NAWM microvascular integrity contribute to the severity of ischemic tissue outcomes.

Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke.

To characterize the effect of white matter microstructural integrity on cerebral tissue and long-term functional outcomes after acute ischemic stroke (AIS). Consecutive AIS patients with brain MRI acquired within 48 hours of symptom onset and 90-day modified Rankin Scale (mRS) score were included. Acute infarct volume on diffusion-weighted imaging (DWIv) and white matter hyperintensity volume (WMHv) on T2 fluid-attenuated inversion recovery MRI were measured. Median fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity values were calculated within normal-appearing white matter (NAWM) in the hemisphere contralateral to the acute lesion. Regression models were used to assess the association between diffusivity metrics and acute cerebral tissue and long-term functional outcomes in AIS. Level of significance was set at p < 0.05 for all analyses. Among 305 AIS patients with DWIv and mRS score, mean age was 64.4 ± 15.9 years, and 183 participants (60%) were male. Median NIH Stroke Scale (NIHSS) score was 3 (interquartile range [IQR] 1-8), and median normalized WMHv was 6.19 cm3 (IQR 3.0-12.6 cm3). Admission stroke severity (β = 0.16, p < 0.0001) and small vessel stroke subtype (β = -1.53, p < 0.0001), but not diffusivity metrics, were independently associated with DWIv. However, median FA in contralesional NAWM was independently associated with mRS score (β = -9.74, p = 0.02), along with age, female sex, NIHSS score, and DWIv. FA decrease in NAWM contralateral to the acute infarct is associated with worse mRS category at 90 days after stroke. These data suggest that white matter integrity may contribute to functional recovery after stroke.

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities (P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age (P < 0.001), all biomarkers varied with white matter hyperintensities burden (P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage.

Multimodal imaging findings in normal-appearing white matter of leucoaraiosis: a review

Leucoaraiosis (LA), also referred to as white matter hyperintensities (WMHs), are usually seen as patchy or confluent hyperintense areas on T2-weighted or fluid-attenuated inversion recovery MRI in the elderly. It...

Cerebral White Matter and Slow Gait: Contribution of Hyperintensities and Normal-appearing Parenchyma.

White matter hyperintensities (WMH), a common marker of cerebral small vessel disease, and lower microstructural integrity of normal-appearing white matter are associated with slower gait. How these cerebral measures interact in relation to slower gait is unknown. We assessed whether microstructural integrity of normal-appearing white matter, measured by fractional anisotropy (FA), moderates the association of higher WMH with slower gait. WMH, FA, and gait speed were acquired for 265 community-dwelling older adults (average age = 82.9 years). The inverse association between WMH and gait was robust to adjustment for age, gender, muscle strength, obesity, stroke, and hypertension (fully adjusted model: βs = -0.19, p = .001). The interaction between WMH and FA was significant; analyses stratified by FA showed that the inverse association between WMH and gait speed was significant only for those with low FA (FA < median, fully adjusted model: βs = -0.28, p = .001). Voxel-based results were similar for participants with FA less than median, there was an inverse association between gait speed and WMH which extended throughout the white matter (genu and body of corpus callosum, anterior limb of internal capsule, corona radiata, and superior longitudinal and fronto-occipital fasciculus). In contrast, for participants with FA ≥ median, the association was limited to the genu of corpus callosum, the cingulum, and the inferior longitudinal fasciculus. Microstructural integrity is a moderating factor in the association between WMH and gait. Future studies should examine whether higher microstructural integrity represents a source of compensation in those with greater WMH burden to maintain function in late life.