NAWM) And Grey Matter Research Articles

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.

The Impact of Covert Lacunar Infarcts and White Matter Hyperintensities on Cognitive and Motor Outcomes After Stroke

Background and AimsIn addition to overt stroke lesions, co-occurring covert lesions, including white matter hyperintensities (WMH) and covert lacunar infarcts (CLI), contribute to poststroke outcome. The purpose of this study was to examine the relationship between covert lesions, and motor and cognitive outcomes in individuals with chronic stroke. MethodsVolumetric quantification of clinically overt strokes, covert lesions (periventricular and deep: pWMH, dWMH, pCLI, dCLI), ventricular and sulcal CSF (vCSF, sCSF), and normal appearing white (NAWM) and gray matter (NAGM) was performed using structural magnetic resonance imaging. We assessed motor impairment and function, and global cognition, memory, and other cognitive domains. When correlation analysis identified more than one MR parameter relating to stroke outcomes, we used regression modeling to identify which factor had the strongest impact. ResultsNeuropsychological and brain imaging data were collected from 30 participants at least 6 months following a clinically diagnosed stroke. Memory performance related to vCSF (r = −0.52, P = .004). The strongest predictor of nonmemory domains was pCLI (r2 = 0.28, P = .004). Motor impairment and function were most strongly predicted by the volume of stroke and NAWM (r2 = 0.36; P = .001), and dWMH (r2 = 0.39; P = .001) respectively. ConclusionsCovert lesion type and location have important consequences for post-stroke cognitive and motor outcome. Limiting the progression of covert lesions in aging populations may enhance the degree of recovery post-stroke.

Increased Microglial Activation in the Brain of Secondary Progressive Multiple Sclerosis Patients Detected Using [11C]PK11195 PET (S21.003)

Objective: To investigate, whether microglial activation is increased in the brain of secondary progressive multiple sclerosis patients (SPMS) compared to healthy controls using [11C]PK11195 and positron emission tomography (PET). Background In SPMS, the widespread inflammation and neurodegeneration of the central nervous system leads to progressive disability. Neuropathological studies have shown that normal appearing white (NAWM) and gray matter (NAGM) are important loci of neuronal damage and microglial activation in progressive MS. However, these findings are poorly detectable using conventional imaging modalities (MRI). Importantly, in vivo imaging of activated microglia is possible using PET and translocator protein (TSPO) binding tracer [11C]PK11195. Design/Methods: Brain MRI and 60 minute dynamic [11C]PK11195 PET imaging were performed in 8 healthy controls (6 women, 2 men; mean age 49.8 years) and 9 SPMS patients (6 women, 3 men; mean age 49.6 years) without immunomodulatory treatment and with mean expanded disability status scale (EDSS) score 6.3. Anatomical regions of interests (ROI) were drawn onto the PET images co-registered with MRI. The ROI specific binding potential (BPnd) of [11C]PK11195 was calculated from the distribution volume ratio estimated using the Logan graphical analysis method with supervised cluster analysis (SVCA) approach. Results: The BPnd of [11C]PK11195 was significantly increased in the NAWM and thalami in SPMS patients compared to control group (p=0.008 and p=0.018, respectively). Also, a trend for increased BPnd in cortical gray matter of SPMS vs. control group was noted with a borderline significant difference in BP in the combined neocortex ROI (p=0.048). Conclusions: Evaluating microglial activation with a TSPO-binding PET-ligand provides a unique tool to assess diffuse brain inflammation in NAWM and NAGM areas in vivo. Our findings of increased [11C]PK11195 binding in NAWM and NAGM of SPMS patients underline the significance of diffuse microglial activation in progressive MS. Supported by: The Finnish Academy. Disclosure: Dr. Rissanen has received research support from Novartis. Dr. Tuisku has nothing to disclose. Dr. Virta has received research support from Orion-Pharma, GE Healthcare, and Bayer Schering. Dr. Paavilainen has nothing to disclose. Dr. Parkkola has nothing to disclose. Dr. Rinne has nothing to disclose. Dr. Airas has nothing to disclose.

Diffusion Tensor Imaging Abnormalities in Cognitively Impaired Multiple Sclerosis Patients

Cognitive impairment can add to the burden of disease in patients with multiple sclerosis (MS). The aim of this study was to assess the relative importance of diffusion tensor imaging (DTI) indices derived from normal appearing white matter (NAWM) and grey matter (NAGM) in determining cognitive dysfunction in MS patients. Sixty two MS patients [51 female, mean age = 41 (sd = 9.6) years, median expanded disability status scale (EDSS) = 2.5] meeting modified McDonald criteria for MS underwent neuropsychological testing using the Neuropsychological Screening Battery for MS (NSBMS) and magnetic resonance imaging (MRI, 1.5T GE) that included DTI sequences. Total T1 hypointense and T2 hyperintense lesion volumes were obtained using semi-automated software. Lesion volumes were subtracted from whole-brain parenchyma to obtain measures of NAWM and NAGM. Fractional anisotropy (FA) of NAWM and mean diffusivity (MD) of NAGM were obtained. Cognitive impairment was present in 11 patients (18%). These patients had higher EDSS scores, were less educated, and were more likely to have secondary progressive MS. They also had higher hypointense (p = 0.001) and hyperintense (p = 0.004) lesion volumes, greater NAWM atrophy (p = 0.007), lower FA of total NAWM (p = 0.003), and higher MD of total NAGM (p = 0.015). Using a logistic regression analysis, and after controlling for demographic and disease-related differences between groups, FA of NAWM emerged as a significant predictor of cognitive impairment adding to the variance derived from lesion and atrophy data. This study underlies the important role of normal-appearing brain tissue in the pathogenesis of MS-related cognitive impairment.

White matter hemodynamic abnormalities precede sub-cortical gray matter changes in multiple sclerosis

Background Hypoperfusion has been reported in lesions, normal-appearing white (NAWM) and gray matter (NAGM) of patients with clinically definite multiple sclerosis (MS) by using perfusion MRI. However, it is still unknown how early such changes in perfusion occur. The aim of our study was to assess the presence of hemodynamic changes in the NAWM and subcortical NAGM of patients with clinically isolated syndrome (CIS) in comparison to healthy controls and to patients with early relapsing-remitting (RR) MS. Methods Absolute cerebral blood flow (CBF), blood volume (CBV) and mean transit time (MTT) were measured in the periventricular and frontal NAWM, thalamus and putamen nuclei of 12 patients with CIS, 12 with early RR-MS and 12 healthy controls using dynamic susceptibility contrast enhanced (DSC) T2⁎-weighted MRI. Results Compared to controls, CBF was significantly decreased in the periventricular NAWM of CIS patients and in the periventricular NAWM and putamen of RR-MS patients. Compared to CIS, RR-MS patients showed a significant CBF decrease in the putamen. Conclusions CBF was decreased in the NAWM of both CIS and RR-MS patients and in the subcortical NAGM of RR-MS patients suggesting a continuum of tissue perfusion decreases beginning in white matter and spreading to gray matter, as the disease progresses.

Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI

The mechanisms underlying the progressive course of multiple sclerosis (MS) are not fully understood yet. Since diffusion tensor (DT) MRI can provide quantitative estimates of both MRI-visible and MRI-occult brain damage related to MS, the present study investigated the value of DT MRI-derived measures for the assessment of the short-term accumulation of white and gray matter (GM) pathology in patients with primary progressive (PP) and secondary progressive (SP) MS. Fifty-four patients with PPMS and 22 with SPMS were studied at baseline and after a mean follow-up of 15 months. Dual-echo, T1-weighted, and DT MRI scans of the brain were acquired on both occasions. Total lesion volumes (TLV) and percentage brain volume changes (PBVC) were computed. Mean diffusivity (MD) and fractional anisotropy (FA) maps of the normal-appearing white (NAWM) and gray matter (NAGM) were produced, and histogram analysis was performed. In both patient groups, a significant increase of average lesion MD ( P = 0.01) and of average NAGM MD ( P = 0.007) was found at follow-up. No significant differences between PPMS and SPMS patient groups were found for the on-study changes of any MRI-derived measure. No significant correlations were found between the percentage changes of DT MRI-derived measures and those of TLV and PBVC. No significant changes of DT MRI-derived measures were observed in age-matched healthy controls over the same study period. Over a 1-year period of follow-up, DT MRI can detect tissue changes beyond the resolution of conventional MRI in the NAGM of patients with progressive MS. The accumulation of DT MRI-detectable gray matter damage does not seem to merely depend upon the concomitant increase of T2-visible lesion load and the reduction of brain volume. These observations suggest that progressive NAGM damage might yet be an additional factor leading to the accumulation of disability in progressive MS.

Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis.

Magnetic resonance (MR) techniques are of value in following the pathological process of multiple sclerosis in vivo. They are widely applied to monitor the disease natural history and its modification by treatment. However, serial studies of lesion measures have yielded generally disappointing correlations with the development of clinical disability. A potential explanation for this is the presence of abnormalities, beyond the visible lesions, in the normal appearing white matter (NAWM) and grey matter (NAGM). Quantitative structural MR techniques, including measures of magnetisation transfer, diffusion, relaxation times and spectroscopic metabolite concentrations, reveal that there are abnormalities in NAWM and NAGM. These are present from clinical onset and become more pronounced with clinical progression, increasing disability and increasing lesion load. Furthermore, functional MRI (fMRI) studies of motor and visual paradigms has identified a range of responses suggesting that cortical plasticity exists; such modified responses are seen in the earliest stages of disease and in the absence of visible lesions, but are more pronounced with disease progression and increasing lesion load and abnormality in the NAWM. Limited reproducibility and sensitivity to change can pose methodological limitations for MR studies of NAWM and NAGM, especially when follow up intervals are relatively short. Whilst existing quantitative MR measures from normal appearing tissues provide valuable information to understand the natural history and monitor treatment effects in MS, none of them fully or even predominantly accounts for the patient's functional state nor can be relied on as a definitive surrogate measure of treatment effect. Better resolution of the abnormalities is needed especially in grey matter where pathological foci are known to be abundant. Studies correlating structural MR and fMRI parameters with measures of function in well defined anatomical pathways should further elucidate the pathogenic role of abnormality in the normal appearing tissues. In future, new imaging modalities are needed that provide a more specific measure of histopathological and cellular aspects of the disease process in vivo.

A functional magnetic resonance imaging study of patients with secondary progressive multiple sclerosis

Although several functional magnetic resonance imaging (fMRI) studies have shown adaptive cortical changes in patients with early multiple sclerosis (MS), the presence of brain plasticity and its role in limiting the functional consequences of brain tissue damage in patients with secondary progressive (SP) MS have not been fully investigated yet. In this study, we assessed the movement-associated brain pattern of cortical activations in patients with SPMS and investigated whether the extent of cortical brain activations is correlated with the extent of brain structural changes. From 13 right-handed SPMS patients and 15 sex- and age-matched healthy volunteers, we obtained: (a) brain dual-echo scans; (b) brain mean diffusivity and fractional anisotropy maps of the normal-appearing white (NAWM) and gray matter (NAGM); (c) fMRI during the performance of simple motor tasks [flexion–extension of the last four fingers of the right hand (task 1) and flexion–extension of the right foot (task 2)]. Compared to healthy volunteers, during task 1 performance, SPMS patients showed more significant activations of the ipsilateral inferior frontal gyrus, middle frontal gyrus, bilaterally, and contralateral intraparietal sulcus. During task 2 performance, SPMS patients had more significant activations of the contralateral primary sensorimotor cortex and thalamus and of the ipsilateral upper bank of sylvian fessure. For both tasks, strong correlations ( r values ranging from −0.83 to 0.88) were found between relative activations of cortical areas of the motor network and the severity of structural changes of the NAWM and NAGM. This study demonstrates that cortical plasticity does occur in patients with SPMS and that it might have a role in limiting the clinical impact of MS-related damage. It also suggests that, in these patients, functional abilities are sustained by increased recruitment of highly specialized cortical areas.

Magnetisation transfer ratio and mean diffusivity of normal appearing white and grey matter from patients with multiple sclerosis

OBJECTIVETo assess the feasibility of a new technique based on diffusion anisotropy to segment white and grey matter of the brain. To use this technique to measure the mean diffusivity...