Normal-appearing White Matter Volume Research Articles

Unraveling the link: white matter damage, gray matter atrophy and memory impairment in patients with subcortical ischemic vascular disease.

Prior MRI studies have shown that patients with subcortical ischemic vascular disease (SIVD) exhibited white matter damage, gray matter atrophy and memory impairment, but the specific characteristics and interrelationships of these abnormal changes have not been fully elucidated. We collected the MRI data and memory scores from 29 SIVD patients with cognitive impairment (SIVD-CI), 29 SIVD patients with cognitive unimpaired (SIVD-CU) and 32 normal controls (NC). Subsequently, the thicknesses and volumes of the gray matter regions that are closely related to memory function were automatically assessed using FreeSurfer software. Then, the volume, fractional anisotropy (FA), mean diffusivity (MD), amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values of white matter hyperintensity (WMH) region and normal-appearing white matter (NAWM) were obtained using SPM, DPARSF, and FSL software. Finally, the analysis of covariance, spearman correlation and mediation analysis were used to analyze data. Compared with NC group, patients in SIVD-CI and SIVD-CU groups showed significantly abnormal volume, FA, MD, ALFF, and ReHo values of WMH region and NAWM, as well as significantly decreased volume and thickness values of gray matter regions, mainly including thalamus, middle temporal gyrus and hippocampal subfields such as cornu ammonis (CA) 1. These abnormal changes were significantly correlated with decreased visual, auditory and working memory scores. Compared with the SIVD-CU group, the significant reductions of the left CA2/3, right amygdala, right parasubiculum and NAWM volumes and the significant increases of the MD values in the WMH region and NAWM were found in the SIVD-CI group. And the increased MD values were significantly related to working memory scores. Moreover, the decreased CA1 and thalamus volumes mediated the correlations between the abnormal microstructure indicators in WMH region and the decreased memory scores in the SIVD-CI group. Patients with SIVD had structural and functional damages in both WMH and NAWM, along with specific gray matter atrophy, which were closely related to memory impairment, especially CA1 atrophy and thalamic atrophy. More importantly, the volumes of some temporomesial regions and the MD values of WMH regions and NAWM may be potentially helpful neuroimaging indicators for distinguishing between SIVD-CI and SIVD-CU patients.

42 White matter injury is driven by HIV duration, immune and vascular factors in virally suppressed people living with HIV: a longitudinal diffusion imaging study

Objective:The aim of the current longitudinal study was to use improved brain white matter integrity outcomes (better at resolving white matter complexity, hence with improved biological significance compared to traditional diffusion tensor imaging - DTI outcomes) while considering baseline age, cardiovascular diseases (CVD), and HIV disease markers impacts on the health of major white matter tracts in virally suppressed people Living with HIV infection (PLHIV) versus demographically, geographically, and life-style comparable HIVnegative controls. Furthermore, white-matter hyperintensity (WMH) and normal-appearing white matter (NAWM) volumes and microstructure were considered.Participants and Methods:At baseline 48 HIV-controls and 84 virally suppressed PLHIV (mean age 55), and at 24-month follow-up, 40 HIV-controls and 75 virally suppressed PLHIV underwent an MRI scan (3T Phillips) collecting a high-resolution anatomical MRI, FLAIR, and a 32-direction diffusion imaging. The diffusion data were processed using mrtrix and intra-cranial volume-corrected outcomes included fibre density (FD), fibre cross-section (log was used; logFC) and a composite fibre density and cross-section (FDC). The volumetric data was first processed in Freesurfer 6.0, and WMH were segmented using the “pgs” U-Net neural network. Using mixed models, we examine the longitudinal mrtrix outcomes across major white matter tracts by HIV status, and associations with CVD (sum of the scaled scores of total cholesterol, HDL, Systolic BP, current smoking, and diabetes) and HIV disease (HIV duration, historical AIDS, nadir CD4, baseline CD4) markers. Additionally, we assessed the volume, and FDC in the periventricular and deep WMH, as well as NAWM, and the associations with CVD and HIV disease markers. We used FDR control procedure (alpha = 0.05), and all p-values reported are FDR adjusted.Results:Relative to controls, PLHIV showed significant reductions (p<.05 - p<.01) of FC, and FDC to a lesser extent, in multiple long cortical association tracts, and within striatal- and thalamic-frontoparietal connections. A small HIV by age interaction was only detected for FC of inferior longitudinal fasciculus (Beta = -0.004, SE = 0.002 p<.04). However, HIV duration (corrected for baseline age) was associated with worse FDC across multiple tracts (p<03 -p<.001). Baseline CD4 counts associated with lower FD in frontal association tracts (p<.05 -p<.005). Furthermore, WMH increased in size with time, age, and higher CVD risk factors, but not HIV status. In PLHIV, deep WMH and NAWM microstructure were both associated with worse CVD but not HIV disease markers.Conclusions:The fine integrity of major white matter tracts is impacted by HIV status, HIV duration and baseline CD4, whereas WMH and NAWM volumes and microstructure are affected by CVD. Our study provides further evidence of the immuno-vascular underpinning of HIV neuropathogenesis in virally suppressed PLHIV. The convergence of these effects in aging PLHIV may lead to early neurodegeneration. Hence, improving CVD health and maintaining high CD4 is critical.

Paranasal sinuses opacification on magnetic resonance imaging in relation to brain health in sporadic small vessel disease – Systematic review and pilot analysis

BackgroundThe paranasal sinus mucosal thickening, visible in magnetic resonance imaging (MRI), maybe a source of inflammation in microvessels, but its relationship with small vessel disease (SVD) is unclear. We reviewed the literature and analysed a sample of patients with sporadic SVD to identify any association between paranasal sinus opacification severity and SVD neuroimaging markers. MethodsWe systematically reviewed MEDLINE and EMBASE databases up to April 2020 for studies on paranasal sinus mucosal changes in patients with SVD, cerebrovascular disease (CVD), and age-related neurodegenerative diseases. We analysed clinical and MRI data from 100 participants in a prospective study, the Mild Stroke Study 3 (ISRCTN 12113543) at 1–3, 6 and 12 months following a minor stroke to test key outcomes from the literature review. We used multivariate linear regression to explore associations between modified Lund-Mackay (LM) scores and brain, white matter hyperintensities (WMH), enlarged perivascular spaces (PVS) volumes at each time point, adjusted for baseline age, sex, diabetes, hypercholesterolaemia, hypertension and smoking. ResultsThe literature review, after screening 3652 publications, yielded 11 primary studies, for qualitative synthesis with contradictory results, as positive associations/higher risk from 5/7 CVD studies were contradicted by the two studies with largest samples, and data from dementia studies was equally split in their outcome. From the pilot sample of patients analysed (female N = 33, mean age 67.42 (9.70) years), total LM scores had a borderline negative association with PVS in the centrum semiovale at baseline and 6 months (B = -0.25, SE = 0.14, p = 0.06) but were not associated with average brain tissue, WMH or normal-appearing white matter volumes. ConclusionThe inconclusive results from the literature review and empirical study justify larger studies between PVS volume and paranasal sinuses opacification in patients with sporadic SVD.

Sleep quality, perivascular spaces and brain health markers in ageing - A longitudinal study in the Lothian Birth Cohort 1936

BackgroundSleep is thought to play a major role in brain health and general wellbeing. However, few longitudinal studies have explored the relationship between sleep habits and imaging markers of brain health, particularly markers of brain waste clearance such as perivascular spaces (PVS), of neurodegeneration such as brain atrophy, and of vascular disease, such as white matter hyperintensities (WMH). We explore these associations using data collected over 6 years from a birth cohort of older community-dwelling adults in their 70s. MethodWe analysed brain MRI data from ages 73, 76 and 79 years, and self-reported sleep duration, sleep quality and vascular risk factors from community-dwelling participants in the Lothian Birth Cohort 1936 (LBC1936) study. We calculated sleep efficiency (at age 76), quantified PVS burden (at age 73), and WMH and brain volumes (age 73 to 79), calculated the white matter damage metric, and used structural equation modelling (SEM) to explore associations and potential causative pathways between indicators related to brain waste cleaning (i.e., sleep and PVS burden), brain and WMH volume changes during the 8th decade of life. ResultsLower sleep efficiency was associated with a reduction in normal-appearing white matter (NAWM) volume (β = 0.204, P = 0.009) from ages 73 to 79, but not concurrent volume (i.e. age 76). Increased daytime sleep correlated with less night-time sleep (r = −0.20, P < 0.001), and with increasing white matter damage metric (β = −0.122, P = 0.018) and faster WMH growth (β = 0.116, P = 0.026). Shorter night-time sleep duration was associated with steeper 6-year reduction of NAWM volumes (β = 0.160, P = 0.011). High burden of PVS at age 73 (volume, count, and visual scores), was associated with faster deterioration in white matter: reduction of NAWM volume (β = −0.16, P = 0.012) and increasing white matter damage metric (β = 0.37, P < 0.001) between ages 73 and 79. On SEM, centrum semiovale PVS burden mediated 5% of the associations between sleep parameters and brain changes. ConclusionSleep impairments, and higher PVS burden, a marker of impaired waste clearance, were associated with faster loss of healthy white matter and increasing WMH in the 8th decade of life. A small percentage of the effect of sleep in white matter health was mediated by the burden of PVS consistent with the proposed role for sleep in brain waste clearance.

Quantitative susceptibility mapping of the normal-appearing white matter as a potential new marker of disability progression in multiple sclerosis.

To investigate the normal-appearing white matter (NAWM) susceptibility in a cohort of newly diagnosed multiple sclerosis (MS) patients and to evaluate possible correlations between NAWM susceptibility and disability progression. Fifty-nine patients with a diagnosis of MS (n = 53) or clinically isolated syndrome (CIS) (n = 6) were recruited and followed up. All participants underwent neurological examination, blood sampling for serum neurofilament light chain (sNfL) level assessment, lumbar puncture for the quantification of cerebrospinal fluid (CSF) β-amyloid1-42 (Aβ) levels, and brain MRI. T2-weighted scans were used to quantify white matter (WM) lesion loads. For each scan, we derived the NAWM volume fraction and the WM lesion volume fraction. Quantitative susceptibility mapping (QSM) of the NAWM was calculated using the susceptibility tensor imaging (STI) suite. Susceptibility maps were computed with the STAR algorithm. Primary progressive patients (n = 9) showed a higher mean susceptibility value in the NAWM than relapsing-remitting (n = 44) and CIS (n = 6) (p = 0.01 and p = 0.02). Patients with a higher susceptibility in the NAWM showed increased sNfL concentration (ρ = 0.38, p = 0.004) and lower CSF Aβ levels (ρ = -0.34, p = 0.009). Mean NAWM susceptibility turned out to be a predictor of the expanded disability status scale (EDSS) worsening at follow-up (β = 0.41, t = 2.66, p = 0.01) and of the MS severity scale (MSSS) (β = 0.38, t = 2.43, p = 0.019). QSM in the NAWM seems to predict the EDSS increment over time. This finding might provide evidence on the role of QSM in identifying patients with an increased risk of early disability progression. • NAWM-QSM is higher in PPMS patients than in RRMS. • NAWM-QSM seems to be a predictor of EDSS worsening over time. • Patients with higher NAWM-QSM show increased sNfL concentration and lower CSF Aβ levels.

Periventricular gradient of T1 tissue alterations in multiple sclerosis

ObjectivePathology in multiple sclerosis is not homogenously distributed. Recently, it has been shown that structures adjacent to CSF are more severely affected. A gradient of brain tissue involvement was shown with more severe pathology in periventricular areas and in proximity to brain surfaces such as the subarachnoid spaces and ependyma, and hence termed the “surface–in” gradient. Here, we study whether (i) the surface-in gradient of periventricular tissue alteration measured by T1 relaxometry is already present in early multiple sclerosis patients, (ii) how it differs between early and progressive multiple sclerosis patients, and (iii) whether the gradient-derived metrics in normal-appearing white matter and lesions correlate better with physical disability than conventional MRI-based metrics. MethodsForty-seven patients with early multiple sclerosis, 52 with progressive multiple sclerosis, and 92 healthy controls were included in the study. Isotropic 3D T1 relaxometry maps were obtained using the Magnetization-Prepared 2 Rapid Acquisition Gradient Echoes sequence at 3 T. After spatially normalizing the T1 maps into a study-specific common space, T1 inter-subject variability within the healthy cohort was modelled voxel-wise, yielding a normative T1 atlas. Individual comparisons of each multiple sclerosis patient against the atlas were performed by computing z-scores. Equidistant bands of voxels were defined around the ventricles in the supratentorial white matter; the z-scores in these bands were analysed and compared between the early and progressive multiple sclerosis cohorts. Correlations between both conventional and z-score-gradient-derived MRI metrics and the Expanded Disability Status Scale were assessed. ResultsPatients with early and progressive multiple sclerosis demonstrated a periventricular gradient of T1 relaxation time z-scores. In progressive multiple sclerosis, z-score-derived metrics reflecting the gradient of tissue abnormality in normal-appearing white matter were more strongly correlated with disability (maximal rho = 0.374) than the conventional lesion volume and count (maximal rho = 0.189 and 0.21 respectively). In early multiple sclerosis, the gradient of normal-appearing white matter volume with z-scores > 2 at baseline correlated with clinical disability assessed at two years follow-up. ConclusionOur results suggest that the surface-in white matter gradient of tissue alteration is detectable with T1 relaxometry and is already present at clinical disease onset. The periventricular gradients correlate with clinical disability. The periventricular gradient in normal-appearing white matter may thus qualify as a promising biomarker for monitoring of disease activity from an early stage in all phenotypes of multiple sclerosis.

Inversion Recovery Ultrashort TE MR Imaging of Myelin is Significantly Correlated with Disability in Patients with Multiple Sclerosis.

MR imaging has been widely used for the noninvasive evaluation of MS. Although clinical MR imaging sequences are highly effective in showing focal macroscopic tissue abnormalities in the brains of patients with MS, they are not specific to myelin and correlate poorly with disability. We investigated direct imaging of myelin using a 2D adiabatic inversion recovery ultrashort TE sequence to determine its value in assessing disability in MS. The 2D inversion recovery ultrashort TE sequence was evaluated in 14 healthy volunteers and 31 patients with MS. MPRAGE and T2-FLAIR images were acquired for comparison. Advanced Normalization Tools were used to correlate inversion recovery ultrashort TE, MPRAGE, and T2-FLAIR images with disability assessed by the Expanded Disability Status Scale. Weak correlations were observed between normal-appearing white matter volume (R = -0.03, P = .88), lesion load (R = 0.22, P = .24), and age (R = 0.14, P = .44), and disability. The MPRAGE signal in normal-appearing white matter showed a weak correlation with age (R = -0.10, P = .49) and disability (R = -0.19, P = .31). The T2-FLAIR signal in normal-appearing white matter showed a weak correlation with age (R = 0.01, P = .93) and disability (R = 0.13, P = .49). The inversion recovery ultrashort TE signal was significantly negatively correlated with age (R = -0.38, P = .009) and disability (R = -0.44; P = .01). Direct imaging of myelin correlates with disability in patients with MS better than indirect imaging of long-T2 water in WM using conventional clinical sequences.

Associations of subclinical cerebral small vessel disease and processing speed in non-demented subjects: A 7-year study

Markers of cerebral small vessel disease (CSVD) have previously been associated with age-related cognitive decline. Using longitudinal data of cognitively healthy, older adults (N = 216, mean age at baseline = 70.9 years), we investigated baseline status and change in white matter hyperintensities (WMH) (total, periventricular, deep), normal appearing white matter (NAWM), brain parenchyma volume (BPV) and processing speed over seven years as well as the impact of different covariates by applying latent growth curve (LGC) models. Generally, we revealed a complex pattern of associations between the different CSVD markers. More specifically, we observed that changes of deep WMH (dWMH), as compared to periventricular WMH (pWMH), were more strongly related to the changes of other CSVD markers and also to baseline processing speed performance. Further, the number of lacunes rather than their volume reflected the severity of CSVD. With respect to the studied covariates, we revealed that higher education had a protective effect on subsequent total WMH, pWMH, lacunar number, NAWM volume, and processing speed performance. The indication of antihypertensive drugs was associated with lower lacunar number and volume at baseline and the indication of antihypercholesterolemic drugs came along with higher processing speed performance at baseline. In summary, our results confirm previous findings, and extend them by providing information on true within-person changes, relationships between the different CSVD markers and brain-behavior associations. The moderate to strong associations between changes of the different CSVD markers indicate a common pathological relationship and, thus, support multidimensional treatment strategies.

Birth weight is associated with brain tissue volumes seven decades later but not with MRI markers of brain ageing

Birth weight, an indicator of fetal growth, is associated with cognitive outcomes in early life (which are predictive of cognitive ability in later life) and risk of metabolic and cardiovascular disease across the life course. Brain health in older age, indexed by MRI features, is associated with cognitive performance, but little is known about how variation in normal birth weight impacts on brain structure in later life. In a community dwelling cohort of participants in their early seventies we tested the hypothesis that birth weight is associated with the following MRI features: total brain (TB), grey matter (GM) and normal appearing white matter (NAWM) volumes; whiter matter hyperintensity (WMH) volume; a general factor of fractional anisotropy (gFA) and peak width skeletonised mean diffusivity (PSMD) across the white matter skeleton. We also investigated the associations of birth weight with cortical surface area, volume and thickness. Birth weight was positively associated with TB, GM and NAWM volumes in later life (β ≥ 0.194), and with regional cortical surface area but not gFA, PSMD, WMH volume, or cortical volume or thickness. These positive relationships appear to be explained by larger intracranial volume, rather than by age-related tissue atrophy, and are independent of body height and weight in adulthood. This suggests that larger birth weight is linked to more brain tissue reserve in older life, rather than age-related brain structural features, such as tissue atrophy or WMH volume.

Dual-Task Gait Cost and Frontal Lobe Integrity in Poststroke: Results From ONDRI

Dual-task gait performance is a marker of motor-cognitive interactions modulated by the frontal lobes. After a stroke, gait disturbances are more evident, particularly when concurrently completing a mental task and walking, an effect called high dual-task cost (DTC). Following a stroke, the potential association of high-DTC, integrity of the frontal lobes and cognitive functioning is unclear. This study screened 161 participants with stroke history from the Ontario Neurodegenerative Disease Research Initiative (ONDRI)-cerebrovascular disease cohort (69.2±7.41 years of age; 31.7% women). Individuals scoring zero in the National Institute of Health Stroke Scale were analyzed (n=102). DTC was the percentage change in gait speed from the single to dual-task condition. Standardized normal-appearing white matter (NAWM) and grey matter (NAGM) volumes from superior, middle and inferior frontal lobe were compared between DTC quartiles (adjusted for age, sex, and education) using a multivariate model (MANOVA), with total frontal lobe volume as a covariate. Another model compared group performance across 5 adjusted cognitive domains (attention, memory, language, visuospatial performance, and executive functioning). Univariate tests revealed that NAWM volume in the superior frontal lobe (F=4.50; p=0.005; partial eta-squared=0.122) was significantly different across DTC quartiles. Contrast tests suggested that the first quartile had larger NAWM than the second and fourth. DTC quartiles also showed differences in attention (F=2.93; p=0.03; partial eta-squared=0.083) and contrast tests indicated that the first quartile performed significantly better than second and fourth. DTC poststroke may be a proxy for structural integrity of superior frontal lobe regions and attention.

Reduced Global Efficiency and Random Network Features in Patients with Relapsing-Remitting Multiple Sclerosis with Cognitive Impairment.

Graph theory uses structural similarity to analyze cortical structural connectivity. We used a voxel-based definition of cortical covariance networks to quantify and assess the relationship of network characteristics to cognition in a cohort of patients with relapsing-remitting MS with and without cognitive impairment. We compared subject-specific structural gray matter network properties of 18 healthy controls, 25 patients with MS with cognitive impairment, and 55 patients with MS without cognitive impairment. Network parameters were compared, and predictive value for cognition was assessed, adjusting for confounders (sex, education, gray matter volume, network size and degree, and T1 and T2 lesion load). Backward stepwise multivariable regression quantified predictive factors for 5 neurocognitive domain test scores. Greater path length (r = -0.28, P < .0057) and lower normalized path length (r = 0.36, P < .0004) demonstrated a correlation with average cognition when comparing healthy controls with patients with MS. Similarly, MS with cognitive impairment demonstrated a correlation between lower normalized path length (r = 0.40, P < .001) and reduced average cognition. Increased normalized path length was associated with better performance for processing (P < .001), learning (P < .001), and executive domain function (P = .0235), while reduced path length was associated with better executive (P = .0031) and visual domains. Normalized path length improved prediction for processing (R 2 = 43.6%, G2 = 20.9; P < .0001) and learning (R 2 = 40.4%, G2 = 26.1; P < .0001) over a null model comprising confounders. Similarly, higher normalized path length improved prediction of average z scores (G2 = 21.3; P < .0001) and, combined with WM volume, explained 52% of average cognition variance. Patients with MS and cognitive impairment demonstrate more random network features and reduced global efficiency, impacting multiple cognitive domains. A model of normalized path length with normal-appearing white matter volume improved average cognitive z score prediction, explaining 52% of variance.

Amyloid PET findings in multiple sclerosis are associated with cognitive decline at 18 months

ObjectiveTo study the clinical, cognitive, and radiological progression of a cohort of patients with MS, taking into account the amyloid PET with 18F-florbetaben analyses. MethodsTwenty-nine patients with MS were assessed with longitudinal structural MRI and a clinical and comprehensive neuropsychological protocol, with a mean interval between assessments of 18 ± 3.31 months. 18F-florbetaben PET was performed at baseline. Uptake was analysed in demyelinating plaques (DWM) and normal-appearing white matter (NAWM). Results were correlated with clinical, cognitive and MRI data. ResultsPatients with cognitive decline over the follow-up period showed a lower standardised uptake value ratio in NAWM and lower thalamic volume and a higher lesion load in the baseline MRI. Myelin status was correlated with EDSS and cognitive tests mainly evaluating visuospatial function and working memory. Lower uptake in NAWM at baseline was also associated with a growth in white matter lesion volume over time. ConclusionsLower white matter uptake in amyloid PET is associated with cognitive decline and an increase in white matter lesion volume during the follow-up. Our study suggests that 18F-florbetaben may be a useful biomarker in assessing myelin status in MS, understanding MS pathophysiology, and predicting cognitive outcomes.

Weak correlations between body height and several brain metrics in healthy elderly subjects.

The question whether body height is related to different brain size measures has recently gained renewed interest as some studies have reported that body height correlates with intelligence and several brain size measures. In this study, we re-evaluated this question by examining the relationship between body height and different brain size measures including intracranial volume, total brain volume, total cortical surface area, total cortical volume, volume of normal-appearing white matter, white matter hyperintensity, cortical surface area, cortical thickness, subcortical grey matter volume, cerebellar cortex and cerebellar white matter in a relatively large sample (n=216) of physically and cognitively healthy elderly subjects (mean age 71years, age range 65-85years). We identified small correlations (r=.11-.19) between body height and seven out of 10 brain metrics (total brain volume, cortical surface area, cortical volume, subcortical volume, normal-appearing white matter volume and cerebellar grey as well as white matter volumes) when controlling for sex and age. Based on these small relationships between body height and various brain size measures, we discuss the possible reasons and theoretical problems for these small relationships.

Normal-Appearing Cerebellar Damage in Neuromyelitis Optica Spectrum Disorder.

The cerebellum plays an important role in motor and cognitive functions. However, whether and how the normal-appearing cerebellum is impaired in patients with neuromyelitis optica spectrum disorders remain unknown. We aimed to identify the occult structural damage of the cerebellum in neuromyelitis optica spectrum disorder and its possible causes at the level of substructures. Normal-appearing gray matter volume of the cerebellar lobules and nuclei and normal-appearing white matter volume of the cerebellar peduncles were compared between patients with neuromyelitis optica spectrum disorder and healthy controls. The cerebellar damage of patients with neuromyelitis optica spectrum disorder in the hemispheric lobule VI, vermis lobule VI, and all cerebellar nuclei and peduncles was related only to spinal lesions; and cerebellar damage in the hemispheric lobules VIII and X was related only to the aquaporin-4 antibody. The mixed cerebellar damage in the hemispheric lobules V and IX and vermis lobule Crus I was related mainly to spinal lesions; and mixed cerebellar damage in the hemispheric lobule VIIb was related mainly to the aquaporin-4 antibody. Other cerebellar substructures showed no significant cerebellar damage. We have shown that the damage in cerebellar normal-appearing white matter and normal-appearing gray matter is associated with aquaporin-4-mediated primary damage or axonal degeneration secondary to spinal lesions or both. The etiologic classifications of substructure-specific occult cerebellar damage may facilitate developing neuroimaging markers for assessing the severity and the results of therapy of neuromyelitis optica spectrum disorder occult cerebellar damage.

Amyloid PET as a marker of normal-appearing white matter early damage in multiple sclerosis: correlation with CSF β-amyloid levels and brain volumes.

The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with β-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) β-amyloid1-42 (Aβ) levels, amyloid tracer uptake, and brain volumes. Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18F-florbetapir PET. Aβ levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted. We found a lower SUV in DWM compared to NAWM (p< 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p< 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aβ concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01). The correlation between CSF Aβ levels and NAWM-SUV suggests that the predictive role of β-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.

Executive Functions in Healthy Older Adults Are Differentially Related to Macro- and Microstructural White Matter Characteristics of the Cerebral Lobes.

Aging is associated with microstructural white matter (WM) changes. WM microstructural characteristics, measured with diffusion tensor imaging (DTI), are different in normal appearing white matter (NAWM) and WM hyperintensities (WMH). It is largely unknown how the microstructural properties of WMH are associated with cognition and if there are regional effects for specific cognitive domains. We therefore examined within 200 healthy older participants (a) differences in microstructural characteristics of NAWM and WMH per cerebral lobe; and (b) the association of macrostructural (WMH volume) and microstructural characteristics (within NAWM and WMH separately) of each lobe with measures of executive function and processing speed. Multi-modal imaging (i.e., T1, DTI, and FLAIR) was used to assess WM properties. The Stroop and the Trail Making Test were used to measure inhibition, task-switching (both components of executive function), and processing speed. We observed that age was associated with deterioration of white matter microstructure of the NAWM, most notably in the frontal lobe. Older participants had larger WMH volumes and lowest fractional anisotropy values within WMH were found in the frontal lobe. Task-switching was associated with cerebral NAWM volume and NAWM volume of all lobes. Processing speed was associated with total NAWM volume, and microstructural properties of parietal NAWM, the parietal WMH, and the temporal NAWM. Task-switching was related to microstructural properties of WMH of the frontal lobe and WMH volume of the parietal lobe. Our results confirm that executive functioning and processing speed are uniquely associated with macro- and microstructural properties of NAWM and WMH. We further demonstrate for the first time that these relationships differ by lobar region. This warrants the consideration of these distinct WM indices when investigating cognitive function.

11C-PBR28 and 18F-PBR111 Detect White Matter Inflammatory Heterogeneity in Multiple Sclerosis.

The objective of this study was to assess microglial activation in lesions and in normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients using PET. Methods: Thirty-four MS patients (7 with secondary progressive MS [SPMS], 27 with relapsing remitting MS [RRMS]) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO) binding status, underwent PET scanning with TSPO radioligands (11C-PBR28 or 18F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudoreference region). White matter lesions (WMLs) were classified as "active" (DVR highest in the lesion), "peripherally active" (perilesional DVR highest), "inactive" (DVR highest in surrounding NAWM), or "undifferentiated" (similar DVR across lesion, perilesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4 × 10-11). A higher proportion of lesions were inactive in patients with SPMS (35%) than RRMS (23%), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in the brains of MS patients relative to healthy controls with 2 TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

The relationship between working memory and cerebral white matter volume in survivors of childhood brain tumors treated with conformal radiation therapy.

Survivors of childhood brain tumors (BTs) treated with CNS-directed therapy show changes in cerebral white matter that are related to neurocognitive late effects. We examined the association between white matter volume and working memory ability in survivors treated with conformal radiation therapy (CRT). Fifty survivors (25 males, age at assessment = 13.14 ± 2.88, age at CRT = 7.41 ± 3.41 years) completed Digit Span from the Wechsler Intelligence Scales for Children, 4th Edition and experimental Self-Ordered Search (SOS) tasks as measures of working memory. Caregiver ratings were obtained using the Behavior Rating Inventory of Executive Function. MRI exams were acquired on a 1.5 T scanner. Volumes of normal appearing white matter (NAWM) were quantified using a well-validated automated segmentation and classification program. Correlational analyses demonstrated that NAWM volumes were significantly larger in males and participants with tumors located in the infratentorial space. Correlations between NAWM volume and Digit Span Backward were distributed across anterior and posterior regions, with evidence for greater right hemisphere involvement (r = .32-.34, p ≤ .05). Correlations between NAWM volume with Digit Span Backward (r = .44-.52; p ≤ .05) and NAWM volume with SOS-Object Total (r = .45-.52, p ≤ .05) were of greater magnitude in females. No relationship was found between NAWM volume and caregiver report. Working memory performance in survivors of pediatric BTs treated with CRT are related to regionally specific NAWM volume. Developmental differences in cerebral myelination may explain findings of greater risk for neurocognitive late effects in female survivors. Future studies are needed to better isolate vulnerable white matter pathways, thus facilitating the development of neuroprotective interventions.

A randomized controlled phase II trial of riluzole in early multiple sclerosis.

ObjectivesWe evaluated the effect of riluzole versus placebo added to weekly IM interferon beta-1a in early multiple sclerosis (MS).MethodsThis is a randomized (1:1), double-blind, placebo-controlled trial of riluzole 50 mg twice daily in subjects with MS onset less than 1 year prior. Trial participation was up to 3 years. The primary endpoint was change in percent brain volume change. Secondary endpoints included changes in normalized gray and normal-appearing white matter volumes, retinal nerve fiber layer thickness (RNFL), MS Functional Composite and Symbol Digit Modalities Test scores. Mixed model regression analysis was used to compare the changes over time between groups.ResultsForty-three subjects were randomized to study drug (22 riluzole, 21 placebo). Baseline characteristics were overall similar between groups except for older age (P = 0.042), higher normalized cerebrospinal fluid volume (P = 0.050), lower normalized gray matter volume (P = 0.14), and thinner RNFL (P = 0.043) in the riluzole group. In the primary analysis, percent brain volume change in the placebo group decreased at a rate of 0.49% per year whereas the riluzole group decreased by 0.86% per year (0.37% more per year; 95% CI −0.78, 0.024; P = 0.065). Although age did not influence the rate of brain volume decline, the difference between groups was attenuated after adjustment for baseline normalized gray matter and lesion volume (0.26% more per year in riluzole group; 95% CI −0.057, 0.014; P = 0.22). Analyses of secondary outcomes showed no differences between groups.InterpretationThis trial provides class 1 evidence that riluzole treatment does not meaningfully reduce brain atrophy progression in early MS.

Neuroprotective lifestyles and the aging brain

Increased participation in leisure and physical activities may be cognitively protective. Whether activity might protect the integrity of the brain's white matter, or reduce atrophy and white matter lesion (WML) load, was examined in the Lothian Birth Cohort 1936 (n = 691), a longitudinal study of aging. Associations are presented between self-reported leisure and physical activity at age 70 years and structural brain biomarkers at 73 years. For white matter integrity, principal components analysis of 12 major tracts produced general factors for fractional anisotropy (FA) and mean diffusivity. Atrophy, gray and normal-appearing white matter (NAWM) volumes, and WML load were assessed using computational image processing methods; atrophy and WML were also assessed visually. A higher level of physical activity was associated with higher FA, larger gray and NAWM volumes, less atrophy, and lower WML load. The physical activity associations with atrophy, gray matter, and WML remained significant after adjustment for covariates, including age, social class, and health status. For example, physical activity (standardized β = -0.09, nonstandardized β = -0.09, p = 0.029) and stroke (standardized β = 0.18, nonstandardized β = 0.69, p = 0.003) each had an independent effect on rated WML load. Leisure activity was associated with NAWM volume, but was nonsignificant after including covariates. In this large, narrow-age sample of adults in their 70s, physical activity was associated with less atrophy and WML. Its role as a potential neuroprotective factor is supported; however, the direction of causation is unclear from this observational study.