White matter changes measured by multi-component MR Fingerprinting in multiple sclerosis

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

This thesis aimed to investigate the feasibility of two diffusion imaging techniques, Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), on detecting subtle physiological or pathological microstructural changes in normal-appearing neural tissues of human central nervous system. 
\n At first, ten patients with neuromyelitis optica (NMO) and twelve age- and gender-matched healthy subjects were recruited. DTI-derived indices including fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivities were quantified in the lateral and dorsal columns of cervical spinal cord. Based on the regions of interest (ROIs) measurement, NMO patients showed reduced FA, increased MD and radial diffusivity compared to control subjects, while axial diffusivity did not show any significant difference. The three former DTI metrics also showed significant correlations with disability scores, and especially FA was found to be sensitive to mild NMO. Our results show that DTI-derived indices can quantitatively assess the white matter (WM) abnormalities with seemingly normal appearance in conventional MRI, and are associated with the level of clinical disability, suggesting that DTI may have great potential as a useful diagnostic tool in the clinical setting.
\n DKI is an extension of conventional DTI to probe the non-Gaussian diffusion property in biological tissues. Besides the four conventional DTI-derived metrics, DKI also provide three additional kurtosis metrics (mean kurtosis (MK), axial and radial kurtosis). In the second study, ROI-based analysis was used to characterize age-related microstructural changes in WM, cortical and subcortical gray matter (GM) of 27 healthy adults (21~59 yrs). Though the volumes of GM and WM were still preserved, DTI-derived metrics can detect the subtle changes in WM and GM. Meanwhile, MK and radial kurtosis significantly increased in both caudate nucleus and putamen while Thalamus showed little aging effect in the diffusivity and kurtosis metrics but significantly decreased only in FA. Our results demonstrated that DKI is sensitive to detect the age-related alterations in neural microstructures at the stage of early aging.
\n In addition, DKI has been applied to detect the pathological changes in the normal-appearing neural tissues of 18 patients with multiple sclerosis (MS), compared to 22 healthy controls. Diffuse WM abnormalities have been observed extensively in the brain, revealed by DKI-derived metrics. Though the volumetric and voxel-wise analysis revealed no significant changes in the volume of cortical GM, decreased FA and kurtoses with increased diffusivities in MS group were sensitive to disclose the subtle alterations in global and regional cortical GM tissues. Significant correlations have been found between FA in the global, frontal and temporal cortical GM in relapsing-remitting MS patients and their disability scores, suggesting FA as an important biomarker to monitor the disease progress in cortical GM. Moreover, elevated kurtosis indices in MS patients did not correlate with diffusivities in caudate nucleus, putamen and thalamus, suggesting these metrics may be vulnerable to different pathologic aspects of the disease.
\n In conclusion, DKI is sensitive to neural alterations during normal aging and in MS pathologies, and can provide complementary information to conventional MRI and DTI.

Combined Use of Clinical, Lesion Topography, and Thalamic Volume Helps Differentiating Multiple Sclerosis from its Mimickers

In this cross-sectional study we used magnetic resonance imaging (MRI)-based voxel based morphometry (VBM) in a sample of HIV positive patients to detect structural gray and white matter changes. Forty-eight HIV positive subjects with (n = 28) or without (n = 20) cognitive deficits (mean age 48.5 ± 9.6 years) and 48 age- and sex-matched HIV negative controls underwent MRI for VBM analyses. Clinical testing in HIV patients included the HIV dementia scale (HDS), Unified Parkinson's Disease Rating Scale (UPDRS) and the grooved pegboard test. Comparing controls with HIV positive patients with cognitive dysfunction (n = 28) VBM showed gray matter decrease in the anterior cingulate and temporal cortices along with white matter reduction in the midbrain region. These changes were more prominent with increasing cognitive decline, when assigning HIV patients to three cognitive groups (not impaired, mildly impaired, overtly impaired) based on performance in the HIV dementia scale. Regression analysis including all HIV positive patients with available data revealed that prefrontal gray matter atrophy in HIV was associated with longer disease duration (n = 48), while motor dysfunction (n = 48) was associated with basal ganglia gray matter atrophy. Lower CD4 cell count (n = 47) correlated with decrease of occipital gray matter. Our results provide evidence for atrophy of nigro-striatal and fronto-striatal circuits in HIV. This pattern of atrophy is consistent with motor dysfunction and dysexecutive syndrome found in HIV patients with HIV-associated neurocognitive disorder.

BackgroundWe previously developed an optimized q-space diffusional MRI technique (normalized leptokurtic diffusion [NLD] map) to delineate the demyelinated lesions of multiple sclerosis (MS) patients. Herein, we evaluated the utility of NLD maps to discern the white matter abnormalities in normal-appearing white matter (NAWM) and the abnormalities' possible associations with physical and cognitive disabilities in MS. MethodsWe conducted a retrospective observational study of MS patients treated at our hospital (Jan. 2012 to Dec. 2022). Clinical and MRI data were collected; Processing Speed Test (PST) data were obtained when possible. For a quantitative analysis of the NLD maps, we calculated the NLD index as GVROI/GVREF, where GV is a mean grayscale value in the regions of interest (ROIs) and the reference area (REF; cerebrospinal fluid). ResultsOne hundred-one individuals with MS were included. The lower corpus callosum and non-lesional WM NLD index were associated with worse Expanded Disability Status Scale (EDSS) and PST scores. The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly reduced in progressive MS compared to relapsing-remitting MS. We categorized MS severity as moderate/severe (EDSS score ≥ 4 points) and mild (EDSS score < 4 points). The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly lower in the moderate/severe MS group compared to the mild MS group. ConclusionThe NLD map revealed abnormalities in the non-lesional white matter, providing valuable insights for evaluating manifestations in MS patients.

Microbleeds (MBs) detected by gradient-echo T2*-weighted MRI (GRE-T2*),white matter changes and lacunar infarcts may be regarded as manifestations of microangiopathy. The establishment of a quantitative relationship among them would further strengthen this hypothesis. We aimed to investigate the frequency and the number of MBs in patients hospitalized with lacunar infarcts and their quantitative relationship with the severity of white matter changes (WMC) and the number of old lacunar infarcts. We performed a hospital-based survey of patients with acute lacunar infarct. Eighty-two consecutive Chinese patients with acute lacunar infarcts on diffusion-weighted imaging were recruited in 2002. The number of MBs, number of old lacunar infarcts on T2-weighted imaging and the severity of WMC on MRI on admission were recorded. MBs were detected in 22 (27%) patients. The number of MBs ranged from 1 to 42 (mean 6.59, median 3). Advancing age and previous transient ischemic attacks or cerebrovascular accidents (TIA/CVA) were more common in patients with MBs than those without. There were significant correlations among the number of MBs, extent of WMC and number of lacunar infarcts: lacunar infarcts and MBs (r = 0.297, p = 0.007); lacunar infarct and WMC (r = 0.331, p = 0.002); WMC and MBs (r = 0.522, p < 0.0001). In conclusion, linear associations exist among MBs, WMC and lacunar infarcts. Our results suggest that all three may have a shared pathogenesis such as advanced microangiopathy.

Background In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. Objective We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. Methods Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T2-weighted lesion load. Results Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1–8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (r s = −0.49; P = 0.001) and multiple sclerosis functional score (r s = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. Conclusion Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis.

While cerebrovascular disease can be observed in vivo using MRI, the multiplicity and heterogeneity in the mechanisms of cerebrovascular damage impede accounting for these measures in ageing and dementia studies. Our primary goal was to investigate the key sources of variability across MRI markers of cerebrovascular disease and evaluate their impact in comparison to amyloidosis on cognitive decline in a population-based sample. Our secondary goal was to evaluate the prognostic utility of a cerebrovascular summary measure from all markers. We included both visible lesions seen on MRI (white matter hyperintensities, cortical and subcortical infarctions, lobar and deep microbleeds) and early white matter damage due to systemic vascular health using diffusion changes in the genu of the corpus callosum. We identified 1089 individuals aged ≥60 years with concurrent amyloid-PET and MRI scans from the population-based Mayo Clinic Study of Aging. We divided these into discovery and validation datasets. Using the discovery dataset, we conducted principal component analyses and ascertained the main sources of variability in cerebrovascular disease markers. Using linear regression and mixed effect models, we evaluated the utility of these principal components and combinations of these components for the prediction of cognitive performance along with amyloidosis. Our main findings were (i) there were three primary sources of variability among the CVD measures—white matter changes are driven by white matter hyperintensities and diffusion changes; number of microbleeds (lobar and deep); and number of infarctions (cortical and subcortical); (ii) Components of white matter changes and microbleeds but not infarctions significantly predicted cognition trajectories in all domains with greater contributions from white matter; and (iii) The summary vascular score explained 3–5% of variability in baseline global cognition in comparison to 3–6% variability explained by amyloidosis. Across all cognitive domains, the vascular summary score had the least impact on memory performance (∼1%). Though there is mechanistic heterogeneity in the cerebrovascular disease markers measured on MRI, these changes can be grouped into three components and together explain variability in cognitive performance equivalent to the impact of amyloidosis on cognition. White matter changes represent dynamic ongoing damage, predicts future cognitive decline across all domains and diffusion measurements help capture white matter damage due to systemic vascular changes. Therefore, measuring and accounting for white matter changes using diffusion MRI and white matter hyperintensities along with microbleeds will allow us to capture vascular contributions to cognitive impairment and dementia.

White Matter Changes on Magnetic Resonance Imaging: A Risk Factor for Stroke in an African Population?

Cerebral small vessel diseases (SVDs) are a leading cause of age and hypertension-related stroke and dementia. The salient features of SVDs visible on conventional brain magnetic resonance images include white matter hyperintensities (WMHs) on T2-weighted images, small infarcts, macrohemorrhages, dilated perivascular spaces, microbleeds and brain atrophy. Among these, WMHs are the most common and often the earliest brain tissue changes. Moreover, over the past two decades, large population- and patient-based studies have established the clinical importance of WMHs, notably with respect to cognitive and motor disturbances. Here, we seek to provide a new and critical look at the pathogenesis of SVD-associated white matter (WM) changes. We first review our current knowledge of WM biology in the healthy brain, and then consider the main clinical and pathological features of WM changes in SVDs. The most widely held view is that SVD-associated WM lesions are caused by chronic hypoperfusion, impaired cerebrovascular reactivity (CVR) or blood-brain barrier (BBB) leakage. Here, we assess the arguments for and against each of these mechanisms based on population, patient and experimental model studies, and further discuss other potential mechanisms. Specifically, building on two recent seminal studies that have uncovered an anatomical and functional relationship between oligodendrocyte progenitor cells and blood vessels, we elaborate on how small vessel changes might compromise myelin remodelling and cause WM degeneration. Finally, we propose new directions for future studies on this hot research topic.

Longitudinal changes in gray and white matter microstructure during epileptogenesis in pilocarpine-induced epileptic rats

MULTIPLE SCLEROSIS AFTER COVID-19: A SIGN OF THINGS TO COME?

<h3>Background:</h3> White matter hyperintensities in MRI scans are age related but appear to be more prevalent in depressed patients. They may be more pronounced in late onset depression. This finding,...

Pain intensity and pain affect in relation to white matter changes

Despite the many neuroimaging studies that suggest gray matter volume reductions in schizophrenia, there is no compelling postmortem evidence to suggest neuronal loss, nor is there a distinctive or specific signature of gray matter abnormalities in schizophrenia. Instead, there appears to be no observed focal lesion that characterizes gray matter pathology in schizophrenia. This state of affairs has led to a movement away from conceptualizing schizophrenia as resulting from a single lesion, to conceptualizing schizophrenia as arising from abnormal communication between brain regions. Abnormal connectivity between brain regions is not a new concept, as Bleuler (1911) postulated such abnormalities. What is new, however, is an appreciation that brain regions that are not spatially proximal may be connected functionally into neural networks and that to understand altered neural connectivity we need to have a better understanding of the connections between brain regions which are made possible by white matter, the main infrastructure in the brain that makes possible long distance communication among neurons. Accordingly, a focus on white matter connections in the brain has become increasingly of interest in schizophrenia, particularly in the areas of imaging studies, postmortem studies, and new animal models of schizophrenia. This special issue focuses on schizophrenia and oligodendrocytes, the latter a class of neuroglia that give rise to myelin. The primary aim of this special issue is to understand and to clarify further white matter pathology in schizophrenia and how it may contribute to disconnectivity among brain regions, which results in the observed cognitive, behavioral, and clinical symptoms in this disorder. The first paper begins with a description of the theory that schizophrenia reflects a disorder of connectivity. The proposition put forth is that schizophrenia is, at least in part, the result of abnormal communication between brain regions that may be spatially distant but nonetheless functionally connected. As white matter is the main infrastructure for brain connectivity, this paper focuses on the use of a magnetic resonance imaging (MRI) technique called diffusion tensor imaging (DTI) to gain insight into the role of white matter abnormalities in schizophrenia. This paper also focuses on the functional implications of white matter abnormalities, particularly with regard to the possible role of myelin in modulating the transmission velocity of neural discharges. The paper ends with a speculative hypothesis about the relationship between gray matter and white matter abnormalities in schizophrenia. The second paper also focuses on altered neuronal connectivity. Here, however, the focus is on altered connectivity and impaired myelination in a postmortem study of schizophrenia and normal controls, where electron microscopy is used to study myelinated fibers and oligodendrocytes. This morphometric study examines myelinated fibers in the prefrontal cortex in both gray and white matter. Six types of abnormal fibers and ultrastructural alterations are described in the schizophrenia sample. The study reveals increased pathological fibers in gray matter in both young and elderly patients that are associated with positive symptoms, while in elderly patients, the frequency of pathological fibers in white matter is increased and these changes are associated with more negative symptoms. The key implication here is that altered myelinated fibers in white matter in schizophrenia likely follow alterations of myelinated fibers in gray matter that occur earlier in the course of illness. The third paper is a postmortem study on age-related changes in the number of oligodendrocytes in prefrontal cortex in schizophrenia, bipolar disorder and major depression. The study reveals an age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA9 and 10 that is seen only in normal controls and not in schizophrenia or in mood disorders. The absence of the normal age-related increase in oligodendrocytes in patients suggests that this aspect of normal brain development is dysregulated in schizophrenia and in mood disorders, and confirms postmortem and imaging data, further highlighting the fact that the absence of a normal age-related increase in oligodendrocytes is a key shared feature in these psychiatric populations. The fourth paper reviews white matter abnormalities in schizophrenia, including imaging and postmortem findings on the disconnectivity theory of schizophrenia, a major theme that underlies the three previous papers in this special issue. This paper then reviews some of the white matter diseases that commonly lead to psychotic symptoms and then reviews transgenic and mutant mouse models of schizophrenia. More specifically, genetic mouse models such as Plp1 transgenic mice and mutant mice heterogeneous for either NRG1 or its receptor erbB4, as well as Nogo-A- deficient mice are reviewed. This is followed by a focus on the myelin toxicity model of mice fed cuprizone. In the early stage (the second and third week) of the cuprizone feeding, mice show higher dopamine levels and lower norepinephrine levels in their prefrontal cortex, along with behavioral changes indicative of increased CNS activity. In the late stage (weeks 4–6), when demyelination and oligodendrocyte loss are obvious, mice display cognitive deficits as well as deficits in social interactions that are reminiscent of social withdrawal seen in patients with schizophrenia. Importantly, this cuprizone-feeding mouse may be used as an in vivo platform for psychopharmacological studies testing the effects of antipsychotic drugs on white matter alterations and associated behavioral changes, in addition to providing a new animal model of schizophrenia. The fifth and final paper of this special issue focuses on abnormal behavior and microstructural changes in juvenile mice that are repeatedly exposed to nonneurotoxic levels of amphetamine. These mice are compared with nonamphetamine treated mice. Oligodendrocyte numbers and three proteins expressed in mature oligodendrocytes are investigated in these young male mice at sacrifice. Treated mice showed higher locomotion and impaired spatial working memory, along with lowered Noga-A and GST-pi proteins, and lower MBP proteins, in frontal cortex and hippocampus and fewer mature oligodendrocytes in frontal cortex and corpus callosum, as well as lower MBP staining in frontal cortex, corpus callosum, and hippocampus, than untreated mice. These differences suggest that in wild-type mice late developing white matter is vulnerable to amphetamine and may lead to compromised white matter with increased dopamine in specific brain regions. Not only do these findings explain well the increased locomotion and impaired spatial working memory observed in amphetamine-treated mice, but also may serve as a principle for the amphetamine-treated mouse being used as a novel animal model of schizophrenia. To summarize, compared to the focus on gray matter and neurons, research on white matter and myelin/glial has been sparse in schizophrenia. In this special issue, neuroimaging findings are presented that suggest that myelin abnormalities in schizophrenia may underlie the white matter abnormalities observed using diffusion tensor imaging techniques. Data from postmortem studies also confirm the presence of oligodendrocyte and myelin abnormalities in schizophrenia as well as mood disorders. Oligodendrocytes provide protection and improve communication between brain regions and the oligodendroglia-producing myelin is approaching maturity in the same time frame as the onset of symptoms. Further, normal age-related white matter increases and related gray matter changes that likely predate the white matter changes are dysregulated in schizophrenia and may contribute to the clinical symptomatology of the disease. Finally, the recently developed animal models are not only of help in understanding connectivity abnormalities in schizophrenia but also provide novel platforms to test novel therapeutic approaches for schizophrenic patients. Treatments specifically targeting white matter, for example, may improve on the efficacy of those treatments currently in use. Martha E. Shenton Haiyun Xu Vahram Haroutunian George Bartzokis