Parietal Normal-appearing White Matter Research Articles

Extensive Brain Pathologic Alterations Detected with 7.0-T MR Spectroscopic Imaging Associated with Disability in Multiple Sclerosis.

Background MR spectroscopic imaging (MRSI) allows in vivo assessment of brain metabolism and is of special interest in multiple sclerosis (MS), where morphologic MRI cannot depict major parts of disease activity. Purpose To evaluate the ability of 7.0-T MRSI to depict and visualize pathologic alterations in the normal-appearing white matter (NAWM) and cortical gray matter (CGM) in participants with MS and to investigate their relation to disability. Materials and Methods Free-induction decay MRSI was performed at 7.0 T. Participants with MS and age- and sex-matched healthy controls were recruited prospectively between January 2016 and December 2017. Metabolic ratios were obtained in white matter lesions, NAWM, and CGM regions. Subgroup analysis for MS-related disability based on Expanded Disability Status Scale (EDSS) scores was performed using analysis of covariance. Partial correlations were applied to explore associations between metabolic ratios and disability. Results Sixty-five participants with MS (mean age ± standard deviation, 34 years ± 9; 34 women) and 20 age- and sex-matched healthy controls (mean age, 32 years ± 7; 11 women) were evaluated. Higher signal intensity of myo-inositol (mI) with and without reduced signal intensity of N-acetylaspartate (NAA) was visible on metabolic images in the NAWM of participants with MS. A higher ratio of mI to total creatine (tCr) was observed in the NAWM of the centrum semiovale of all MS subgroups, including participants without disability (marginal mean ± standard error, healthy controls: 0.78 ± 0.04; EDSS 0-1: 0.86 ± 0.03 [P = .02]; EDSS 1.5-3: 0.95 ± 0.04 [P < .001]; EDSS ≥3.5: 0.94 ± 0.04 [P = .001]). A lower ratio of NAA to tCr was found in MS subgroups with disabilities, both in their NAWM (marginal mean ± standard error, healthy controls: 1.46 ± 0.04; EDSS 1.5-3: 1.33 ± 0.03 [P = .03]; EDSS ≥3.5: 1.30 ± 0.04 [P = .01]) and CGM (marginal mean ± standard error, healthy controls: 1.42 ± 0.05; EDSS ≥3.5: 1.23 ± 0.05 [P = .006]). mI/NAA correlated with EDSS (NAWM of centrum semiovale: r = 0.47, P < .001; parietal NAWM: r = 0.43, P = .002; frontal NAWM: r = 0.34, P = .01; frontal CGM: r = 0.37, P = .004). Conclusion MR spectroscopic imaging at 7.0 T allowed in vivo visualization of multiple sclerosis pathologic findings not visible at T1- or T2-weighted MRI. Metabolic abnormalities in the normal-appearing white matter and cortical gray matter were associated with disability. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Barker in this issue.

Neurochemical Changes in the Brain and Neuropsychiatric Symptoms in Clinically Isolated Syndrome.

To assess cognitive impairment and affective symptoms and their association with damage to normal-appearing white matter (NAWM) in patients with clinically isolated syndrome (CIS), we compared neuropsychological test scores between patients with CIS and healthy controls and examined correlations between these and proton magnetic resonance spectroscopy (1H-MRS) outcomes in patients with CIS. Forty patients with CIS and 40 healthy participants were tested with a set of neuropsychological tests, which included the Beck Depression Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS). Single-voxel 1H-MRS was performed on frontal and parietal NAWM of patients with CIS to assess ratios of N-acetyl-aspartate (NAA) to creatine (Cr), myo-inositol (mI), and choline (Cho), as well as mI/Cr and Cho/Cr ratios. Patients with CIS had lower cognitive performance and higher scores for the BDI and anxiety subscale of HADS than healthy controls. There were significant correlations between the following neuropsychological tests and metabolic ratios in the frontal NAWM: Stroop Color-Word Test and Cho/Cr, Symbol Digit Modalities Test and mI/Cr, as well as NAA/mI, Go/no-go reaction time, and NAA/Cho, as well as NAA/mI, Californian Verbal Learning Test, and NAA/Cr. BDI scores were related to frontal NAA/mI and parietal NAA/Cr and Cho/Cr ratios, whereas HADS-depression scores were associated with frontal NAA/Cr and NAA/mI and parietal NAA/Cr and Cho/Cr ratios. HADS-anxiety correlated with parietal NAA/Cr ratio. This study suggests that neurochemical changes in the NAWM assessed with single-voxel 1H-MRS are associated with cognitive performance and affective symptoms in patients with CIS.

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.

Dysregulation of energy metabolism in multiple sclerosis measured in vivo with diffusion-weighted spectroscopy

Objective: We employed diffusion-weighted magnetic resonance spectroscopy (DW-MRS), which allows to measure in vivo the diffusion properties of metabolites, to explore the functional neuro-axonal damage and the ongoing energetic dysregulation in multiple sclerosis (MS). Methods: Twenty-five patients with MS and 18 healthy controls (HC) underwent conventional magnetic resonance imaging (MRI) and DW-MRS. The apparent diffusion coefficient (ADC) of total N-acetyl-aspartate (tNAA) and creatine–phosphocreatine (tCr) were measured in the parietal normal-appearing white matter (NAWM) and in the thalamic grey matter (TGM). Multiple regressions were used to compare metabolite ADCs between groups and to explore clinical correlations. Results: In patients compared with HCs, we found a reduction in ADC(tNAA) in the TGM, reflecting functional and structural neuro-axonal damage, and in ADC(tCr) in both NAWM and TGM, possibly reflecting a reduction in energy supply in neurons and glial cells. Metabolite ADCs did not correlate with tissue atrophy, lesional volume or metabolite concentrations, while in TGM metabolite ADCs correlated with clinical scores. Conclusion: DW-MRS showed a reduction in tCr diffusivity in the normal-appearing brain of patients with MS, which might reflect a state of ongoing energy dysregulation affecting neurons and/or glial cells. Reversing this energy dysregulation before neuro-axonal degeneration arises may become a key objective in future neuroprotective strategies.

Metabolic changes in normal appearing white matter in multiple sclerosis patients using multivoxel magnetic resonance spectroscopy imaging.

Demyelination and axonal degeneration caused by multiple sclerosis (MS) exist in the white matter and not only in the lesion area. Magnetic resonance spectroscopy (MRS) could provide a unique insight into metabolic changes in the normal appearing white matter (NAWM). To evaluate the subtle axonal degeneration and delineate the spatial distribution of metabolite abnormalities in the NAWM in patients with MS. A total of 17 clinically definite relapsing-remitting MS (RRMS) patients and 21 healthy controls were enrolled in this study. 2D 1H magnetic resonance spectroscopic imaging (MRSI) performed at 3 Tesla was used to measure metabolite concentrations in the frontal-parietal-occipital NAWM. Ratios of N-acetyl-aspartate (NAA) and choline (Cho) to creatine (Cr) and Cho to NAA were calculated in each voxel. MS patients showed decreased NAA/Cr and increased Cho/NAA ratios in the NAWM compared to healthy controls. In the parietal NAWM, the extent of NAA/Cr decrease was significantly higher than that in the frontal and parietal-occipital NAWM. Decreased NAA in the NAWM would provide useful metabolic information for evaluation of disease progression in MS. The high extent of NAA decrease in the parietal NAWM helps improve the accuracy of the prediction.

Biexponential diffusion alterations in the normal‐appearing white matter of glioma patients might indicate the presence of global vasogenic edema

PurposeTo investigate normal‐appearing white matter (NAWM) microstructure of glioma patients with biexponential diffusion analysis in order to reveal the nature of diffusion abnormalities and to assess whether they are region‐specific or global.Materials and MethodsTwenty‐four newly diagnosed glioma patients (grade II–IV) and 24 matched control subjects underwent diffusion‐weighted imaging at 3T. Diffusion parameters were calculated using monoexponential and biexponential models. Apparent diffusion coefficient (ADC) values were measured in the entire NAWM of the hemisphere contralateral and ipsilateral to the tumor. In the contralateral NAWM, regional ADC values were assessed in the frontal, parietal, occipital, and temporal NAWM.ResultsADCmono and ADCfast were significantly higher than control values in all investigated regions except the temporal NAWM (P &lt; 0.04). ADCslow was significantly increased in the total contralateral, frontal, and parietal NAWM (P &lt; 0.03), while pslow was decreased in both total hemispheric NAWM and the parietal NAWM of glioma patients compared to controls (P &lt; 0.04). ADCmono, ADCfast, ADCslow, and pslow were significantly different among the NAWM of the four lobes of the contralateral hemisphere in both groups (P &lt; 0.0001), and these regional differences were similar in patients and controls (P &gt; 0.05). Hemispheric ADCmono and pslow differences were different between groups (P &lt; 0.05).ConclusionGlobally altered diffusion parameters suggest the presence of global vasogenic edema in the NAWM of glioma patients, which is further supported by the finding that regional differences in patients follow those found in controls. Alternatively, some tumor infiltration might contribute to diffusion abnormalities in the NAWM, especially in the tumor‐affected hemisphere. J. Magn. Reson. Imaging 2016;44:633–641.

Biexponential diffusion alterations in the normal‐appearing white matter of glioma patients might indicate the presence of global vasogenic edema

To investigate normal-appearing white matter (NAWM) microstructure of glioma patients with biexponential diffusion analysis in order to reveal the nature of diffusion abnormalities and to assess whether they are region-specific or global. Twenty-four newly diagnosed glioma patients (grade II-IV) and 24 matched control subjects underwent diffusion-weighted imaging at 3T. Diffusion parameters were calculated using monoexponential and biexponential models. Apparent diffusion coefficient (ADC) values were measured in the entire NAWM of the hemisphere contralateral and ipsilateral to the tumor. In the contralateral NAWM, regional ADC values were assessed in the frontal, parietal, occipital, and temporal NAWM. ADCmono and ADCfast were significantly higher than control values in all investigated regions except the temporal NAWM (P < 0.04). ADCslow was significantly increased in the total contralateral, frontal, and parietal NAWM (P < 0.03), while pslow was decreased in both total hemispheric NAWM and the parietal NAWM of glioma patients compared to controls (P < 0.04). ADCmono , ADCfast , ADCslow , and pslow were significantly different among the NAWM of the four lobes of the contralateral hemisphere in both groups (P < 0.0001), and these regional differences were similar in patients and controls (P > 0.05). Hemispheric ADCmono and pslow differences were different between groups (P < 0.05). Globally altered diffusion parameters suggest the presence of global vasogenic edema in the NAWM of glioma patients, which is further supported by the finding that regional differences in patients follow those found in controls. Alternatively, some tumor infiltration might contribute to diffusion abnormalities in the NAWM, especially in the tumor-affected hemisphere. J. Magn. Reson. Imaging 2016;44:633-641.

Reduced NAA-levels in the NAWM of patients with MS is a feature of progression. A study with quantitative magnetic resonance spectroscopy at 3 Tesla.

BackgroundReduced N-acetyl-aspartate (NAA) levels in magnetic resonance spectroscopy (MRS) may visualize axonal damage even in the normal appearing white matter (NAWM). Demyelination and axonal degeneration are a hallmark in multiple sclerosis (MS).ObjectiveTo define the extent of axonal degeneration in the NAWM in the remote from focal lesions in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS).Material and Methods37 patients with clinical definite MS (27 with RRMS, 10 with SPMS) and 8 controls were included. We used 2D 1H-MR-chemical shift imaging (TR = 1500ms, TE = 135ms, nominal resolution 1ccm) operating at 3Tesla to assess the metabolic pattern in the fronto–parietal NAWM. Ratios of NAA to creatine (Cr) and choline (Cho) and absolute concentrations of the metabolites in the NAWM were measured in each voxel matching exclusively white matter on the anatomical T2 weighted MR images.ResultsNo significant difference of absolute concentrations for NAA, Cr and Cho or metabolite ratios were found between RRMS and controls. In SPMS, the NAA/Cr ratio and absolute concentrations for NAA and Cr were significantly reduced compared to RRMS and to controls.ConclusionsIn our study SPMS patients, but not RRMS patients were characterized by low NAA levels. Reduced NAA-levels in the NAWM of patients with MS is a feature of progression.

3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis

MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin–spin relaxometry detected damage in NAWM of MS patients (n=13) vs. age-matched normal controls [(NL) (n=11)]. Baseline characteristics of the MS group were: age (mean±SD) 42.5±5.4 (range 33–51 years), disease duration 9.0±6.4 (range 1–22 years), Expanded Disability Status Scale score 2.5±1.7 (range 1–6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (=1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p=0.00047), frontal NAWM (p=0.00015), parietal NAWM (p=0.0069) and callosal genu (p=0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p=0.019). However, the normalized WM volume fractions were similar in both MS and NL (p>0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.

High field MR imaging and 1H-MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis

To prospectively investigate metabolic changes in the normal-appearing white matter (NAWM) of patients presenting with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to correlate these changes to conventional MR imaging findings in terms of MR imaging criteria. Multisequence MR imaging of the brain and (1)H-MR spectroscopy of the parietal NAWM were performed in 31 patients presenting with CIS and in 20 controls using a 3. 0 T MR system. MR imaging criteria and International Panel criteria were assessed based on imaging, clinical and paraclinical results. Metabolite ratios and absolute concentrations of N-acetyl-aspartate (tNAA), myoinositol (Ins), choline (Cho), and total creatine (tCr) were determined. The metabolite concentrations were correlated with the fulfilled MR imaging criteria. In comparison to the control group, the CIS group showed significantly decreased mean tNAA concentrations (-8. 1%, p = 0. 012). Significant changes could not be detected regarding Ins, tCr and Cho. No significant correlations between absolute metabolite concentrations and MR imaging criteria were observed. Patients with and without a lesion dissemination in space showed no significant differences of their metabolite concentrations. As assessed by (1)H-MRS a significant axonal damage already occurs during the first demyelinating episode in patients with CIS. Conventional MR imaging in terms of diagnostic imaging criteria does not significantly reflect NAWM disease activity in terms of metabolic alterations detected by (1)H-MR spectroscopy.

Prognostic value of high-field proton magnetic resonance spectroscopy in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis

The aim of this study was to determine the prognostic value of metabolic alterations in the normal-appearing white matter (NAWM) of patients presenting with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) with special regard to the prediction of conversion to definite MS. Using a 3T whole-body MR system, a multisequence conventional MRI protocol and single-voxel proton MR spectroscopy (PRESS, repetition time 2000 ms, echo times 38 ms and 140 ms) of the parietal NAWM were performed in 25 patients presenting with CIS at baseline and in 20 controls. Absolute concentrations of N-acetyl-aspartate (tNAA), myo-inositol (Ins), choline (Cho) and creatine (tCr) as well as metabolite ratios were determined. Follow-up including neurological assessment and conventional MRI was performed 3-4 and 6-7 months after the initial event. Nine patients converted to definite MS during the follow-up period. Compared to controls, those patients who converted to MS also showed significantly lower tNAA concentrations in the NAWM (-13.4%, P = 0.002) whereas nonconverters (-6.5%, P = 0.052) did not. The Ins concentration was 20.2% higher in the converter group and 1.9% higher in the nonconverter group, but these differences did not reach significance. No significant differences could be observed for tCr and Cho in either patient group. Axonal damage at baseline in patients presenting with CIS was more prominent in those who subsequently converted to definite MS in the short term follow-up, indicating that tNAA might be a sufficient prognostic marker for patients with a higher risk of conversion to early definite MS.

Diffusion Tensor Imaging of Normal-Appearing White Matter in Mild Cognitive Impairment and Early Alzheimer Disease: Preliminary Evidence of Axonal Degeneration in the Temporal Lobe

Diffusion tensor imaging (DTI) is a sensitive technique for studying cerebral white matter. We used DTI to characterize microstructural white matter changes and their associations with cognitive dysfunction in Alzheimer disease (AD) and mild cognitive impairment (MCI). We studied elderly subjects with mild AD (n = 6), MCI (n = 11), or normal cognition (n = 8). A standardized clinical and neuropsychological evaluation was conducted on each subject. DTI images were acquired, and fractional anisotropy (FA), axial diffusivity (DA), and radial diffusivity (DR) of normal-appearing white matter (NAWM) in frontal, temporal, parietal, and occipital lobes were determined. These diffusion measurements were compared across the 3 groups, and significant differences were further examined for correlations with tests of cognitive function. Compared with normal controls, AD subjects demonstrated decreased FA and increased DR in the temporal, parietal, and frontal NAWM and decreased DA in temporal NAWM. MCI subjects also showed decreased FA and decreased DA in temporal NAWM, with decreased FA and increased DR in parietal NAWM. Diffusion measurements showed no differences in occipital NAWM. Across all subjects, temporal lobe FA and DR correlated with episodic memory, frontal FA and DR correlated with executive function, and parietal DR significantly correlated with visuospatial ability. We found evidence for functionally relevant microstructural changes in the NAWM of patients with AD and MCI. These changes were present in brain regions serving higher cortical functions, but not in regions serving primary functions, and are consistent with a hypothesized loss of axonal processes in the temporal lobe.

Axonal Damage But No Increased Glial Cell Activity in the Normal-Appearing White Matter of Patients with Clinically Isolated Syndromes Suggestive of Multiple Sclerosis Using High-Field Magnetic Resonance Spectroscopy

Proton MR spectroscopy ((1)H-MR spectroscopy) is a well-established method for the in vivo investigation of the normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS). Metabolic changes in NAWM are of special interest in patients with clinically isolated syndromes (CIS) suggestive of MS regarding further prognostic classifications. The purpose of this study was to investigate metabolic alterations in NAWM in patients with CIS with use of high-field (1)H-MR spectroscopy and to compare the results to those in patients with an early course of MS. With use of a 3T whole-body MR imaging system, single-voxel (1)H-MR spectroscopy (PRESS; TR: 2000 ms; TE: 38 ms and 140 ms) of the parietal NAWM was performed in 20 control subjects, 36 patients with CIS, and 12 patients with MS. Metabolite ratios and concentrations of N-acetylaspartate (tNAA), myo-inositol (mIns), choline, and total creatine (tCr) were determined. Compared with the control group, mean NAWM mIns concentrations were significantly elevated in the MS group (4.56 mmol/L versus 3.75 mmol/L, P = .02) but not in the CIS group (4.04 mmol/L, P = .44). The higher concentration of mIns in the MS group was also reflected in the increased Ins/tCr ratio (P = .02). The mean NAWM tNAA was significantly decreased in both patient groups compared with the control group (CIS, 13.42 mmol/L, P = .02; MS, 12.77 mmol/L versus 14.51 mmol/L, P = .008). A significant increase of the activity of the glial cells can only be observed in patients with an established diagnosis of MS but not in patients with CIS. Axonal damage occurs already during the first demyelinating episode in patients with CIS as well as in patients with definite MS.

IC-P-068: Diffusion tensor imaging of normal appearing white matter in MCI and AD

Structural magnetic resonance imaging (MRI) studies on mild cognitive impairment (MCI) and Alzheimer's disease (AD) have largely focused on the brain's cortical gray matter. However, cellular degeneration in cortical structures is usually accompanied by concomitant degeneration of axonal processes from these dying neurons. Pathoanatomical and imaging studies have confirmed both macroscopic and microscopic white matter changes in patients with AD. We propose that microstructural changes in subcortical brain regions should also be detectable in MCI. To examine the microstructural integrity of subcortical white mater in subjects with amnestic MCI and mild AD using diffusion tensor imaging (DTI). Elderly subjects with normal cognition (n=5), MCI (n=6) and mild AD (n=4) were recruited from our Alzheimer's Disease Research Center. Petersen criteria were used to diagnose amnestic MCI, and NINCDS–ADRDA criteria to diagnose AD. Normal appearing white matter (NAWM) was defined by normal signal intensity on standard T1–weighted, T2–weighted and FLAIR images. DTI images were acquired using a single shot, pulsed gradient, echo planar imaging protocol with twelve non–collinear gradient directions. Fractional anisotropy (FA), axial diffusivity (DA) and radial diffusivity (DR) of NAWM regions in the frontal, temporal, parietal and occipital lobes were measured and compared across the three groups using ANOVA with post–hoc Scheffe tests. Both AD and MCI subjects demonstrated significantly lower FA in frontal and temporal NAWM compared with normal control subjects (AD/MCI/normal = 0.28/0.28/0.35 in frontal NAWM, F=6.61, df =2, p<0.01; AD/MCI/normal = 0.41/0.44/0.52 in temporal NAWM, F=14.2, df =2, p<0.001). Radial diffusivity (DR) was significantly greater in AD and MCI subjects compared to normal controls in parietal NAWM (AD/MCI/normal = 0.62/0.60/0.56, F=11.9, df=2, p<0.001). Even in NAWM, we found evidence for microstructural changes in AD and MCI. These changes were present in brain regions serving higher cortical functions (frontal, temporal and parietal lobes), but not in regions serving primary functions (occipital lobe), and are consistent with a hypothesized loss of axonal processes in affected regions.