White Matter Microstructural Damage Research Articles

Abstract 9: Pervasive White Matter Microstructure Dysintegrity Related To High Blood Pressure Among Asymptomatic Population

Background: Blood pressure is the strongest contributor to clinically evident cerebrovascular disease. We investigated the role of blood pressure on white matter (WM) microstructure among asymptomatic individuals without clinically evident cerebrovascular disease. Methods: We conducted a nested study within the UK Biobank, restricting our analysis to participants without cerebrovascular disease or dementia and with available brain diffusion tensor imaging (DTI). We tested for association between systolic blood pressure (SBP) and six different DTI metrics: fractional anisotropy (FA), mean diffusivity (MD), tensor mode (MO), intra-cellular volume fraction (ICVF), isotropic or free water volume fraction (ISOVF), and orientation dispersion index (OD) across 48 WM tracts using multivariable linear regression adjusted for potential confounders. We used Bonferroni-corrected p-values (0.05/48) for statistical significance. Results: We analyzed 33,440 participants. Mean age was 63.0 (SD 7.7), and 17,688 (53%) were female. Higher SBP is independently associated with pervasive decrease in FA and ICVF and increase in MD (Figure), after adjustment for vascular risk-factors. SBP was also associated with lower neurite OD (a more specific metric of axonal damage) in bilateral posterior corona radiata, external capsule, medial lemniscus, and corticospinal tracs. FA and OD of external capsule and posterior corona radiata had the largest drop per 10 mmHg increase of SBP (steepest slope). Conclusions: Higher SBP is associated with pervasive WM microstructure dysintegrity in asymptomatic individuals without evident cerebrovascular disease. DTI metrics of the posterior corona radiata and external capsule are most reflective of variations in SBP and may provide a potential biomarker to assess subtle WM microstructural damage in hypertensive patients or monitor treatment response in clinical trials.

Determining the OPTIMAL DTI analysis method for application in cerebral small vessel disease

BackgroundDTI is sensitive to white matter (WM) microstructural damage and has been suggested as a surrogate marker for phase 2 clinical trials in cerebral small vessel disease (SVD). The study’s objective is to establish the best way to analyse the diffusion-weighted imaging data in SVD for this purpose. The ideal method would be sensitive to change and predict dementia conversion, but also straightforward to implement and ideally automated. As part of the OPTIMAL collaboration, we evaluated five different DTI analysis strategies across six different cohorts with differing SVD severity. MethodsThose 5 strategies were: (1) conventional mean diffusivity WM histogram measure (MD median), (2) a principal component-derived measure based on conventional WM histogram measures (PC1), (3) peak width skeletonized mean diffusivity (PSMD), (4) diffusion tensor image segmentation θ (DSEG θ) and (5) a WM measure of global network efficiency (Geff). The association between each measure and cognitive function was tested using a linear regression model adjusted by clinical markers. Changes in the imaging measures over time were determined. In three cohort studies, repeated imaging data together with data on incident dementia were available. The association between the baseline measure, change measure and incident dementia conversion was examined using Cox proportional-hazard regression or logistic regression models. Sample size estimates for a hypothetical clinical trial were furthermore computed for each DTI analysis strategy. ResultsThere was a consistent cross-sectional association between the imaging measures and impaired cognitive function across all cohorts. All baseline measures predicted dementia conversion in severe SVD. In mild SVD, PC1, PSMD and Geff predicted dementia conversion. In MCI, all markers except Geff predicted dementia conversion. Baseline DTI was significantly different in patients converting to vascular dementia than to Alzheimer’ s disease. Significant change in all measures was associated with dementia conversion in severe but not in mild SVD. The automatic and semi-automatic measures PSMD and DSEG θ required the lowest minimum sample sizes for a hypothetical clinical trial in single-centre sporadic SVD cohorts. ConclusionDTI parameters obtained from all analysis methods predicted dementia, and there was no clear winner amongst the different analysis strategies. The fully automated analysis provided by PSMD offers advantages particularly for large datasets.

Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability.

Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.

Accumulation of amyloid‐β alters white matter integrity in cognitively unimpaired middle‐aged females

AbstractBackgroundThe APOE‐ε4 allele is the strongest known genetic risk factor for Alzheimer’s disease (AD) and is associated with higher amyloid‐β (Aβ) deposition. White matter (WM) microstructural damages are known to occur early at the preclinical stage of AD. Although stable associations between APOE‐ε4 status and WM alternations have been reported in patients with AD and mild cognitive impairment, few studies have described WM differences in cognitively unimpaired (CU) subjects at risk of AD. We aim to investigate associations of APOE‐ε4 status and Aβ load with WM microstructural changes in mid‐age CU individuals.Method151 CU participants from the Prospective Imaging Study of Ageing (PISA) were included (aged 44‐66, 78% female, 77 APOE‐ε4 carriers (ε4+) and 74 non‐carriers (ε4‐)) and underwent Aβ PET and 3T MRI scans including multi‐shell diffusion‐weighted images. Aβ load was quantified in Centiloid (CL) on PET and Aβ+ was defined as CL ≥ 20. Tract based spatial statistics (TBSS) analysis was performed on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) to assess WM alternations associated with APOE‐ε4 status and/or Aβ load. All analyses were corrected for age and for multiple comparisons.ResultA significant effect of gender, but not APOE‐ε4 or Aβ status was observed on WM integrity in the full cohort. When considering females only, APOE‐ε4 carriers showed regional increased MD in several right WM tracts. However, these differences were no longer significant when correcting for Aβ status. In contrast, significant WM alternations associated with Aβ+ status were found when correcting for APOE‐ε4 status. In this female‐only subset, widespread WM microstructural damages were observed in Aβ+ε4+ subjects (N=10) compared to Aβ‐ε4+ (N=51) and Aβ‐ε4‐ (N=54) subjects. No significant differences were observed between Aβ‐ε4+ and Aβ‐ε4‐ subjects. Similar differences were also observed in the global diffusion metrics of WM tracts.ConclusionThese findings suggest that WM alternations associated with Aβ accumulation appear in mid‐life CU female subjects. Future studies in larger cohorts enriched for gender, APOE and Aβ status are required to clarify the relative contributions of APOE‐ε4 and Aβ status on WM microstructural damage.

Longitudinal White Matter Damage Evolution in Parkinson's Disease.

White matter hyperintensities (WMHs) have a role in cognitive impairment in normal brain aging, while the effect on Parkinson's disease (PD) progression is still controversial. To investigate the longitudinal evolution of micro- and macrostructural damage of cerebral white matter (WM) and its relationship with the clinical picture in PD. A total of 154 PD patients underwent clinical, cognitive, and magnetic resonance imaging (MRI) assessment once a year for up to 4 years. Sixty healthy controls underwent the same protocol at baseline. WMHs were identified and total WMH volume was measured. WMHs were also used as exclusion masks to define normal-appearing white matter (NAWM). Using tract-based spatial statistics, diffusion tensor (DT) MRI metrics of whole-brain WM and NAWM were obtained. Linear mixed-effects models defined the longitudinal evolution and association between variables. WM alterations were tested as risk factors of disease progression using linear regression and Cox proportional hazards models. At baseline, PD patients showed alterations of all DT MRI measures compared to controls. Longitudinally, DT MRI measures did not vary significantly and no association with clinical variables was found. WMH volume changed over time and was associated with impairment in global cognition, executive functions, and language. Baseline WMH volume was a moderate risk factor for progression to mild cognitive impairment. Our study suggests an association between WMHs and cognitive deterioration in PD, whereas WM microstructural damage is a negligible contributor to clinical deterioration. WMHs assessed by MRI can provide an important tool for monitoring the development of cognitive impairment in PD patients. © 2021 International Parkinson and Movement Disorder Society.

T1/T2 ratio: A quantitative sensitive marker of brain tissue integrity in multiple sclerosis.

The aim of this study is to determine whether cerebral white matter (WM) microstructural damage, defined by decreased fractional anisotropy (FA) and increased axial (AD) and radial (RD) diffusivities, could be detected as accurately by measuring the T1/T2 ratio, in relapsing-remitting multiple sclerosis (RRMS) patients compared to healthy control (HC) subjects. Twenty-eight RRMS patients and 24 HC subjects were included in this study. Region-based analysis based on the ICBM-81 diffusion tensor imaging (DTI) atlas WM labels was performed to compare T1/T2 ratio to DTI values in normal-appearing WM (NAWM) regions of interest. Lesions segmentation was also performed and compared to the HC global WM. A significant 19.65% decrease of T1/T2 ratio values was observed in NAWM regions of RRMS patients compared to HC. A significant 6.30% decrease of FA, as well as significant 4.76% and 10.27% increases of AD and RD, respectively, were observed in RRMS compared to the HC group in various NAWM regions. Compared to the global WM HC mask, lesions have significantly decreased T1/T2 ratio and FA and increased AD and RD (p < . 001). Results showed significant differences between RRMS and HC in both DTI and T1/T2 ratio measurements. T1/T2 ratio even demonstrated extensive WM abnormalities when compared to DTI, thereby highlighting the ratio's sensitivity to subtle differences in cerebral WM structural integrity using only conventional MRI sequences.

ProspeCtive study to evaluate efficacy, safety and tOlerability of dietary supplemeNT of Curcumin (BCM95) in subjects with Active relapsing MultIple Sclerosis treated with subcutaNeous Interferon beta 1a 44 mcg TIW (CONTAIN): A randomized, controlled trial

Backgroundmultiple sclerosis (MS) is a complex disease sustained by several pathogenic mechanisms. As such, combination therapy strategies, targeting a range of disease mechanisms, might represent the ideal therapeutic approach. Here we investigated the efficacy of curcumin, a naturally occurring poly-phenolic phytochemical with potent anti-inflammatory and antioxidant properties, in subjects under treatment with IFN β-1a, to test the effects of this combination therapy on clinical and MRI parameters of inflammation and neurodegeneration in relapsing MS (RMS). Methodseighty active RMS were prospectively enrolled, randomized (1:1) to either the IFN-curcumin or the IFN-placebo group and followed up longitudinally with clinical and MRI assessments for 24 months. Primary endpoint was the efficacy of curcumin versus placebo as add-on therapy on new/enlarging T2 lesions in RMS subjects under treatment with subcutaneous IFN β-1a 44 mcg TIW. Efficacy on clinical parameters (relapses and disability progression), other MRI parameters of inflammation (T1 Gd-enhancing lesions, combined unique active-CUA lesions) and neurodegeneration (T1-hypointense lesions, grey matter loss and white matter microstructural damage) as well as safety and tolerability of curcumin were explored as secondary endpoints. Resultsten subjects dropped out from the study by month 12 (6 in the IFN-curcumin group and 4 in the IFN-placebo group), and 27 by month 24 (11 in the IFN-curcumin group and 16 in the IFN-placebo group). Although no between-group difference was present in terms of proportion of subjects free from new/enlarging T2 lesions, a lower proportion of patients with CUA lesions was noted at month 12 in the IFN-curcumin group in comparison with the IFN-placebo group (7.5% vs 17.5%, χ² test p= 0.0167). This result was not confirmed at month 24. The statistical analysis failed to reveal any difference between the two treatment groups – IFN-curcumin and IFN-placebo – in terms of relapses, disability progression, other MRI metrics of inflammation and MRI changes suggestive of ongoing neurodegeneration. No difference in the rate and nature of adverse events was observed between the two treatment groups. ConclusionAlthough the study drop-out rate was too high to allow definite conclusions, our findings suggest that curcumin might add to IFN β-1a efficacy on radiological signs of inflammation in MS, while it did not seem to exert any neuroprotective effect as assessed by clinical and MRI parameters. (NCT01514370)

White and Gray Matter Abnormalities in Australian Footballers With a History of Sports-Related Concussion: An MRI Study.

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.

Blood Pressure Determinants of Cerebral White Matter Hyperintensities and Microstructural Injury: UK Biobank Cohort Study.

[Figure: see text].

Diffuse Tract Damage Correlates With Global Cognitive Impairment in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Tract-Based Spatial Statistics Study.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial arteriopathy characterized by recurrent lacunar stroke, migraine, and depression. The mechanism of cognitive dysfunction in CADASIL is still uncertain. The aim of this study was to use tract-based spatial statistics (TBSS) to map voxelwise the spatial distribution of brain microstructural change revealed by DTI-derived indices in patients with CADASIL to further study the underlying neuropsychopathological mechanism of CADASIL. Twelve patients with CADASIL and 11 age-, sex-matched healthy controls underwent magnetic resonance imaging at 3 T. Then we evaluated DTI-derived indices (fractional anisotropy [FA], mode of anisotropy [MO], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) of brain white matter (WM) between CADASIL patients and healthy subjects through TBSS. Compared with healthy controls, patients with CADASIL showed extensive decreased FA, MO and increased RD, AD, and MD throughout the entire brain (mainly the WM of the temporal poles, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, uncinate fasciculus, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and Scheltens scores. Decreased FA values and MO values were positively correlated with Montreal Cognitive Assessment scores in CADASIL patients. Increased AD, RD, and MD values were significantly negatively correlated with Montreal Cognitive Assessment scores. Widespread WM abnormalities were clearly shown in CADASIL by using TBSS. Severity of microstructural changes correlates significantly with extension of T2 hyperintensity. Moreover, WM microstructural damage and cognitive impairment were significantly correlated. This study indicated that WM tract damage plays an important role in cognitive impairment in CADASIL.

Abstract P349: Neuroprotective Effects of L-Carnitine on Vascular Dementia in Hemodialysis Patients

Background and purpose: L-carnitine alleviated oxidative stress and white matter lesions in an experimental study. Cognitive decline is not uncommon in hemodialysis patients, the pathogenesis of which has not been elucidated. Methods: Using novel diffusion magnetic resonance imaging techniques, white matter microstructural changes and cognitive decline in hemodialysis patients, and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent diffusion tensor imaging, diffusion kurtosis imaging, neurite orientation dispersion and density imaging, and laboratory and neuropsychological tests, which were compared between two groups based on the duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment; and (2) long-term l-carnitine treatment. Ten age and sex-matched controls were enrolled. Results: On neuropsychological testing, the majority of hemodialysis patients were categorized as having mild cognitive impairment. Seven patients were classified into the no or short-term l-carnitine treatment and long-term l-carnitine treatment groups. Compared to controls, microstructural disorders of white matter were widely detected in no or short-term l-carnitine treatment on diffusion magnetic resonance imaging. An autopsy study from the no or short-term l-carnitine treatment group showed rarefaction of myelinated fibers in white matter. In long-term l-carnitine treatment, microstructural damage on diffusion magnetic resonance imaging was alleviated along with lower levels of high-sensitivity C-reactive protein ( P &lt;0.001) and substantial increases of carnitine levels ( P &lt;0.001). The long-term l-carnitine treatment group showed better achievement in Trail Making Test-A ( P =0.017), which was correlated with amelioration of disorders in bilateral anterior thalamic radiations, the left cingulum in the cingulate gyrus, the right superior longitudinal fasciculus, and the forceps major ( P &lt;0.05). Conclusion: Novel diffusion magnetic resonance imaging tractography detected abnormalities of white matter tracts in hemodialysis patients. Long-term treatment with l-carnitine alleviated white matter microstructural damage and cognitive impairment.

White matter network damage mediates association between cerebrovascular disease and cognition

To determine whether white matter network disruption mediates the association between MRI markers of cerebrovascular disease (CeVD) and cognitive impairment. Participants (n = 253, aged ≥60 years) from the Epidemiology of Dementia in Singapore study underwent neuropsychological assessments and MRI. CeVD markers were defined as lacunes, white matter hyperintensities (WMH), microbleeds, cortical microinfarcts, cortical infarcts and intracranial stenosis (ICS). White matter microstructure damage was measured as fractional anisotropy and mean diffusivity by tract based spatial statistics from diffusion tensor imaging. Cognitive function was summarized as domain-specific Z-scores. Lacunar counts, WMH volume and ICS were associated with worse performance in executive function, attention, language, verbal and visual memory. These three CeVD markers were also associated with white matter microstructural damage in the projection, commissural, association, and limbic fibers. Path analyses showed that lacunar counts, higher WMH volume and ICS were associated with executive and verbal memory impairment via white matter disruption in commissural fibers whereas impairment in the attention, visual memory and language were mediated through projection fibers. Our study shows that the abnormalities in white matter connectivity may underlie the relationship between CeVD and cognition. Further longitudinal studies are needed to understand the cause-effect relationship between CeVD, white matter damage and cognition.

Increased serum glial fibrillary acidic protein associates with microstructural white matter damage in multiple sclerosis: GFAP and DTI

BackgroundAstrocytes and microglial cells are now recognized as active players in contributing to the diffuse neuroaxonal damage associated with disease progression of multiple sclerosis (MS). The serum level of glial fibrillary acidic protein (GFAP), a biomarker for astrocytic activation, is increased in MS and associates with disease progression and disability. Similarly, diffusion tensor imaging (DTI) parameters for microstructural changes in brain, including demyelination and axonal loss, associate with disability. The association between brain DTI parameters and serum GFAP has not been previously explored in MS. The objective of the study was to get insights into DTI-measurable pathological correlates of elevated serum GFAP in the normal appearing white matter (NAWM) of MS. MethodsA total of 62 MS patients with median age of 49.2 years were included in the study. Study patients underwent DTI-MRI and blood sampling for GFAP determination by single molecule array (Simoa). Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the entire NAWM and six segmented NAWM regions. The associations between the DTI parameters and GFAP levels were analysed using Spearman correlation analysis and multiple regression model with sex and disease modifying treatment (no, 1st line or 2nd line) as adjustments. ResultsElevated serum GFAP levels correlated significantly with decreased FA values within the entire (ρ = -0.39, p = 0.03), frontal (ρ = -0.42, p = 0.02), temporal (ρ = -0.37; p = 0.04) and cingulate (ρ = -0.38, p = 0.034) NAWM, and increased MD and RD within the frontal NAWM (ρ = 0.36, p = 0.046 for both). Similarly, higher GFAP associated with lower FA in frontal and cingulate NAWM in the multiple regression model corrected for confounding variables (standardised regression coefficient β = -0.29, p = 0.045 and β = -0.33, p = 0.025). ConclusionsOur results give evidence that increased serum GFAP levels associate with DTI-measurable micro-damage in the NAWM in MS. Our work supports the use of serum GFAP as a biomarker for MS pathology-related astrocytopathy and related diffuse white matter damage.

White matter microstructural damage as an early sign of subjective cognitive decline

AbstractBackgroundSubjective cognitive decline (SCD) is considered a preclinical state of Alzheimer's disease (AD) and may represent a more advanced preclinical status than amnestic mild cognitive impairment (aMCI). Our aim was to explore changes in the white matter (WM) microstructure and their correlation with cognitive function in these AD‐spectrum patients.MethodDiffusion tensor images from 43 individuals with normal cognition (NC), 38 SCD patients and 36 aMCI patients were compared using an atlas‐based segmentation strategy. The correlation between diffusion parameters and cognitive function was further analysed.ResultThe anatomical pattern of WM impairment was generally similar between SCD and aMCI patients. However, aMCI patients showed significantly lower fractional anisotropy (FA) values in corpus callosum (forceps major (Fma) and forceps minor (Fmi)), as well as significantly increased mean diffusivity (MD) in the bilateral anterior thalamic radiation (ATR), left corticospinal tract (CST. L), Fmi, left Cingulum (cingulate gyrus) (CgC. L), left cingulum (hippocampus) (CgH. L), and left inferior fronto‐occipital fasciculus (IFO. L), than those of SCD subjects, indicating a disruption in WM microstructural integrity in the aMCI. Individuals with microstructural disruption in Fmi, CgC. L and CgH. L tracts performed worse in general cognition and memory function tests, as indicated by line regression analysis.ConclusionSCD individuals had extensive WM microstructural damage in a pattern similar to that seen in aMCI, although presenting a cognitive performance comparable to cognitively healthy individuals. Our results suggest that WM integrity might precede objectively measurable memory decline and may be a potential early biomarker for AD.

Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments

BackgroundPerinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts.MethodsDTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter.Results38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5.ConclusionEven directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study.

Cerebral white matter microstructural changes in isolated maxillofacial trauma and associated neuropsychological outcomes

Isolated traumatic maxillofacial injury without concomitant brain injury may cause delayed post-concussive symptoms. Early identification allows optimal diagnosis, prognostication, and therapeutic intervention. The aim of this prospective observational study was to investigate longitudinal microstructural changes of the white matter (WM) tracts based on diffusion tensor imaging (DTI) indices in patients with isolated maxillofacial injuries, immediately and 6 months post-trauma, and to correlate these DTI indices with neuropsychological changes observed. Twenty-one patients with isolated maxillofacial injuries and 21 age-matched controls were recruited. DTI was performed and indices were calculated for 50 WM tracts. The neuropsychological evaluation was done using the screening module of the Neuropsychological Assessment Battery. Patients were subjected to repeat DTI and neuropsychological evaluation at 6 months post-trauma. Reduced fractional anisotropy (FA) and increased median (MD) and radial diffusivity (RD) in the acute phase were seen in major association, projection, and commissural fibre bundles, indicative of vasogenic oedema. These changes correlated with attention and executive function deficits in the acute phase, as well as improvement in memory and visuospatial function in the chronic phase. Isolated maxillofacial trauma patients develop WM microstructural damage, which may impair cognitive performance acutely and over time. DTI indices can serve as predictive imaging biomarkers for long-term cognitive deficits in isolated maxillofacial injuries.

Examining Microstructural White Matter Differences between Children with Typical and Those with Delayed Recovery Two Weeks Post-Concussion

Delayed recovery from concussion can dramatically affect a child's social, emotional, and educational development, yet little is known about what causes some children to recover faster than others. The contribution of white matter disruption in children with delayed recovery has been hypothesized, but findings are limited by methodological issues such as: small heterogeneous samples, bias toward children with delayed recovery, and inconsistencies in timing of brain imaging, both within and between studies. The aim of the present study was to assess diffusion neuroimaging correlates of delayed recovery post-concussion in children. A prospective, longitudinal, observational cohort study was conducted at a statewide tertiary pediatric hospital. Forty-three children who presented to the emergency department (ED) with concussion (defined according to the Zurich/Berlin Consensus Statement on Concussion in Sport) underwent magnetic resonance imaging (MRI) at a 2 weeks post-injury and were classified as either normally recovering (n = 26) or delayed recovering (n = 17). Diffusion imaging comparison using voxelwise tract-based spatial statistics (TBSS) analysis found no difference between the groups in fractional anisotropy, axial diffusion, radial diffusion, or mean diffusivity metrics (p > 0.05 threshold-free cluster enhancement [TFCE] corrected). Post-hoc tract-based Bayesian analysis found evidence for the null in 11 unique white matter tracts (Bayes factor >3). These findings indicate that delayed recovery from post-concussive symptoms in children is unlikely to be caused by white matter microstructural damage.

Resting-State Functional Correlates of Social Cognition in Multiple Sclerosis: An Explorative Study.

Social cognition includes mental operations essential for functional social interactions, and several studies revealed an impairment of social cognition abilities in patients with Multiple Sclerosis (MS). These deficits have been related to global and focal gray matter atrophy as well as microstructural white matter damage. Although some studies reveal a correlation between social cognition and task-based functional magnetic resonance imaging (MRI), no studies to date have explored the association between brain resting-state functional connectivity (RS-FC) abnormalities and several measures of social cognition in MS. The aim of this explorative study was to assess the contribution of RS-FC abnormalities of major brain networks to social cognition in MS patients. Clinical, neuropsychological, and MRI data were collected from 41 non-depressed and cognitively preserved relapsing-remitting MS patients (mean disease duration = 8.8 ± 8.2 years; median Expanded Disability Status Scale = 1.5, range 0–6.5) and 25 matched healthy controls (HCs). The ToM Pictures Sequencing Task (TMPS) and the Reading the Mind in the Eyes Task were employed to evaluate social cognition. All participants underwent a structural MRI and RS functional MRI 3T protocol. Regional gray matter atrophy was measured, and FCs of the default mode (DMN), right and left fronto-parietal, executive (EN), salience, cerebellar, and limbic (LN) networks were evaluated by independent component analysis (ICA). Differences on TMPS were found between MS patients and HC (MS < HC). In the MS group, associations were found between right middle temporal gyrus FC (in the DMN) and reciprocity subscale of TMPS, posterior cingulate cortex (PCC) FC (in the DMN) and first-order false-belief subscale of TMPS, cingulate gyrus FC (in the EN) and TMPS as well as reciprocity subscale of TMPS, and right superior temporal gyrus (in the LN) and reciprocity subscale of TMPS. All detected RS-FC changes did not co-localize with regional gray matter atrophy. The results suggest an association between social cognition and RS-FC changes of DMN, EN, and LN in MS. Future studies should further explore the possible adaptive or maladaptive mechanisms of these FC abnormalities in MS.

White Matter Microstructural Damage as an Early Sign of Subjective Cognitive Decline

Background and Objective: Subjective cognitive decline (SCD) is considered a preclinical state of Alzheimer’s disease (AD) and may represent a more advanced preclinical status than amnestic mild cognitive impairment (aMCI). Our aim was to explore changes in the white matter (WM) microstructure and their correlation with cognitive function in these AD-spectrum patients.Methods: Diffusion tensor images from 43 individuals with normal cognition (NC), 38 SCD patients, and 36 aMCI patients were compared using an atlas-based segmentation strategy. The correlation between diffusion parameters and cognitive function was further analyzed.Results: The anatomical pattern of WM impairment was generally similar between SCD and aMCI patients. However, aMCI patients showed significantly lower fractional anisotropy (i.e., corpus callosum forceps major and forceps minor) and increased mean diffusivity [i.e., bilateral anterior thalamic radiation (ATR), left corticospinal tract (CST), forceps minor, left cingulum (cingulate gyrus), left cingulum hippocampus, and left inferior fronto-occipital fasciculus (IFO)] in some tracts than did SCD subjects, indicating a disruption in WM microstructural integrity in the aMCI. Individuals with microstructural disruption in forceps minor, left cingulum (cingulate gyrus), and left cingulum hippocampus tracts performed worse in general cognition and memory function tests, as indicated by line regression analysis.Conclusion: SCD individuals had extensive WM microstructural damage in a pattern similar to that seen in aMCI, although presenting a cognitive performance comparable with that of cognitively healthy individuals. Our results suggest that WM integrity might precede objectively measurable memory decline and may be a potential early biomarker for AD.

Gray matter atrophy cannot be fully explained by white matter damage in patients with MS

Background: Source-based morphometry (SBM) was recently used for non-random “patterns” of gray matter (GM) atrophy or white matter (WM) microstructural damage. Objective: To assess whether and to what extent such patterns may be inter-related in MS. Methods: SBM was applied to images of GM concentration and fractional anisotropy (FA) in MS patients (n = 41, median EDSS = 1) and normal controls (NC, n = 28). The same procedure was repeated on an independent and similar data set (39 MS patients and 13 NC). Results: We found in MS patterns of GM atrophy and reduced FA (p < 0.05, corrected). Deep GM atrophy was mostly (70%) explained by lesion load in projection tracts and lower FA in posterior corona radiata and thalamic radiation. By contrast, sensorimotor and posterior cortex atrophy was less (50%) dependent from WM damage. All patterns correlated with EDSS (r from −0.33 to −0.56, p < 0.03) while the only cognition-related correlation was between posterior GM atrophy pattern and processing speed (r = 0.45, p = 0.014). Reliability analysis showed similar results. Conclusion: In relatively early MS, we found a close link between deep GM atrophy pattern and WM damage while sensorimotor and posterior cortex patterns were partially independent from WM damage and perhaps related to primary mechanisms. Patterns were clinically relevant.