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A statistical method for determining the proportions of gray matter, white matter, and CSF using computed tomography.

The brain may be considered as a collection of volume elements (voxels) containing unknown proportions of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). If one assumes that (1) the attenuation coefficients for voxels with the same proportions of GM, WM, and CSF follow a Gaussian distribution whose mean is a weighted average of the mean attenuation coefficients of pure GM, WM, and CSF and (2) the voxel-to-voxel variation in proportion follows a Dirichlet probability distribution, then the overall proportions of GM, WM, and CSF can be calculated by optimizing the parameters of a compound Dirichlet-Gaussian distribution. This approach permits a quantitative analysis of the compartmental composition of the brain and may be useful in the evaluation of patients with cerebral edema, hydrocephalus, and leukoencephalopathy.

Brain

Causal relationship between white matter structural connectivity and epilepsy.

White matter structural connectivity has recently been linked to epilepsy pathogenesis, yet its causal role remains unclear. This study used Mendelian randomization (MR) to investigate the causal relationship between white matter structural connectivity and epilepsy. GWAS summary statistics for white matter structural connectivity were sourced from the UK Biobank, while epilepsy data were obtained from FinnGen R10 and the International League Against Epilepsy (ILAE). Our MR analysis revealed significant causal links between white matter structural connectivity and epilepsy risk. Increased connectivity between the right hemisphere visual and salience/ventral attention networks (RH Vis to RH Sal/VentAttn WMSC) was associated with higher epilepsy risk in FinnGen_R10_FE_STRICT (OR&#xa0;=&#xa0;2.25, 95&#xa0;% CI&#xa0;=&#xa0;1.43-3.56, p&#xa0;<&#xa0;0.01, FDR P&#xa0;=&#xa0;0.019). Conversely, increased connectivity between left and right hemisphere salience/ventral attention networks (LH Sal/VentAttn to RH Sal/VentAttn WMSC) was linked to reduced epilepsy risk in FinnGen_R10_GE_STRICT (OR&#xa0;=&#xa0;0.17, 95&#xa0;% CI&#xa0;=&#xa0;0.07-0.46, p&#xa0;<&#xa0;0.01, FDR P&#xa0;=&#xa0;0.033). A total of 15 nominally significant associations were identified across datasets. These findings suggest a causal relationship between white matter structural connectivity and epilepsy, offering insights into disease mechanisms and potential therapeutic targets.

Humans

Natural abundance carbon-13 nuclear magnetic resonance studies of bovine white matter and myelin.

Whole bovine white matter yields a poorly resolved natural abundance 13C nuclear magnetic resonance (NMR) spectrum. The spectrum principally reflects carbon atoms of the constituent membrane lipids: several resonances could be specifically assigned but no resonances attributable to cholesterol are detectable. Except for the methyl group at the terminus of fatty acyl chains, lipid carbons giving rise to the 13C NMR spectrum have values of spin-lattice relaxation time between 140 and 500 ms, indicating significant restrictions on segmental and rotational mibolities but consistent with a generally fluid structural organization. The 13C NMR spectrum of myelin isolated from bovine white matter is similar to that for the whole white matter itself. In both white matter and isolated meylin, the integrated intensities for several carbon atoms are considerably less than those for the same carbon atoms in total lipid extracts. The data for white matter and myelin are consistent with a model in which observed line broadening is due to restrictions in the amplitude of chain flexing rather than to severe restrictions on chain segmental motion. Failure to detect resonances of cholesterol ring system carbon atoms may reflect marked anisotropy of rotational reorientation.

Animals

Distribution of anticonvulsant drugs in gray and white matter of human brain.

Gray and white matter were obtained during neurosurgical therapy of focal epilepsy from 17 patients. In 10 patients, receiving only phenobarbital, the drug was uniformly distributed between gray and white matter. Phenytoin concentrations averaged 1.4-fold greater in white matter than in gray matter when expressed per gram wet weight of tissue. The gray matter/plasma ratio of phenytoin was approximately 2-fold greater than that of phenobarbital. Carbamazepine levels were also slightly greater in white matter. The data revealed wide differences between drugs in the relative concentrations in gray and white matter, which must be taken into account in any quantitative studies of anticonvulsant drug levels in the brain.

Anticonvulsants

The cellular associates of late life changes in white matter microstructure.

The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain.

Aging

A spatially resolved genomic-molecular atlas of human white-matter microstructure.

Human white matter has been linked to inherited variation, circulating molecular state and brain disease, but these layers have rarely been mapped onto the same tract anatomy. Here we measured genetic effects along 6,090 atlas-aligned fiber pathways sampled at 609,000 locations in 72,185 UK Biobank participants, and integrated proteomic and metabolomic profiles within the same anatomical frame. Genetic effects were not whole-tract properties: each locus formed a spatial footprint along fiber trajectories, ranging from single locations to broad multi-tract patterns and reflecting regional polygenicity rather than tract heritability. This map identified 258, 186 and 298 previously unreported loci for fractional anisotropy, mean diffusivity and axial diffusivity; spatial patterns replicated in adults and 157 of 315 FA loci replicated in adolescence in ABCD. Mendelian randomization linked localized genetic effects to neurodegenerative and psychiatric traits, with Alzheimer's disease showing directional effects across 12 of 17 tracts. Multi-omic analyses identified 97 proteomic and 161 metabolomic associations, with the broadest signals from lipid metabolites including linoleic acid and phosphatidylcholines. The strongest lipid-metabolite and genetic signals converged in the corpus callosum, placing inherited variation, disease risk and systemic lipid metabolism on the same localized tract segments.

Journal Article

Electrophoretic and morphologic studies on normal human white matter obtained at surgery with special reference to its basic protein component.

Histologically confirmed normal pieces of human white matter removed during surgical approach to underlying pathology were studied by acrylamide disc gel electrophoresis and electron microscopy. A basic electrophoretic pattern of the white matter homogenates from three separate patients is described. Aliquots of white matter from two of these patients were incubated at 4 degrees C and 23 degrees C for intervals up to 18 hours, then homogenized and electrophoresed to detect any degradative changes in the basic protein band. Results of these studies indicated that the basic protein band of freshly obtained normal human white matter was unaffected by incubation at 23 degrees C for as long as 18 hours. Electron microscopic examination of white matter that was incubated for 2 hours at room temperature prior to fixation, showed sporadic areas of lamellar separation, a finding similar to but not as extensive as that described earlier in white matter obtained at autopsy that was performed 8 hours post-mortem. These findings 1) confirm earlier observations made on autopsy material, 2) are compatible with location of basic protein along the cytoplasmic surface of myelin lamellae, and 3) further emphasize the remarkable resistance of basic protein in situ to autolytic degradation.

Adult

Dose-dependent white matter changes associated with repetitive head impacts in former American football players.

Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45-74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45-74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen's d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen's d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P < 0.00001) and an earlier age of first exposure to tackle football (P < 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P < 0.04) and rotational force (P < 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

American football

The morphology of extrachoroidal ependyma overlying gray and white matter in the rabbit lateral ventricle.

A morphologic investigation of ependyma over gray matter (caudate nucleus) and over periventricular white matter (tapetum) of the rabbit lateral ventricle was undertaken prior to evaluation of morphological changes which occur with experimental hydrocephalus. Ependymal cells over the caudate nucleus are cuboidal and heavily ciliated. Numerous microvilli cover the cell surface. The lateral margins are straight and interdigitations between adjacent ependymal cells are absent. Ependymal cells over white matter are squamous. Nonciliated as well as ciliated cells contribute to the epithelial lining. Microvilli are present at the cell surface but tend to aggregate near the cellular borders. The lateral margins are convoluted and complex interdigitations are present between adjacent cells. Morphologic differences between ependymal cells over the caudate nucleus and those over periventricular white matter may help to explain the differential response to hydrocephalus observed in these two regions of the lateral ventricle.

Animals

A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis.

In a combined histological, biochemical and histochemical study of the macroscopically normal white matter in multipe sclerosis 72% of samples were histologically abnormal. The significance of this fact in the interpretation of previous biochemical studies and in the design of future studies is discussed. The present study showed a significant elevation of the lysosomal enzyme beta-glucosaminidase in the microscopically normal white matter in MS as compared with controls. Studies on lysosomes separated from microscopically normal or mild to moderately gliosed white matter in multiple sclerosis showed an increase in lysosomal fragility. Histochemical study of the microscopically normal white matter in multiple sclerosis revealed an increase in the number of acid phosphate-containing cells as compared with normal and neurological control material. The significance of these findings is discussed and it is suggested that irrespective of the primary or secondary nature of these abnormalities, the white matter may be rendered more susceptible to the pathogenetic process in this disease.

Acetylglucosaminidase

Vanishing White Matter Disease With EIF2B2 c.254 >A Variant: Mild Clinical and MRI Findings.

OBJECTIVES: Typical MRI findings of vanishing white matter disease (VWM) include diffuse white matter lesions with cystic degeneration. However, mild cases may lack these typical features, posing diagnostic challenges. METHODS: We describe 2 of 3 individuals carrying the homozygous c.254T >A variant in EIF2B2 identified at our hospital, excluding 1 previously reported case.1 Genetic analyses were performed using whole-genome sequence or whole-exome sequence analysis, and detected variants were confirmed by direct nucleotide sequence analysis. Brain MRI findings and clinical features were reviewed for the 2 individuals along with other cases in the literature with the same variant. RESULTS: A 69-year-old woman presented with recurrent transient dizziness and secondary amenorrhea. MRI of the brain revealed small T2-hyperintense lesions confined to the subcortical white matter with hyperintensities on diffusion-weighted images and mildly elevated apparent diffusion coefficient values. A 28-year-old woman presented with transient dizziness and secondary amenorrhea. MRI of the brain showed mild T2-hyperintense lesions in the cerebral white matter with frontal predominance. DISCUSSION: This report highlights the clinically mild cases of VWM with subtle abnormalities on brain MRI who had the homozygous c.254T >A in EIF2B2, further expanding the clinical spectrum of VWM and underscoring the importance of genetic assessments in the diagnosis of individuals with mild clinical and MRI findings.

Journal Article

Electron-microscopic identification of Marchi-positive bodies and argyrophilic granules in the spinal cord white matter of the guinea pig.

Sections from spinal cord white matter of normal and rhizotomized guinea pigs fixed by glutaraldehyde perfusion were stained with Marchi fluid or according to a suppressive silver technique. With the aid of the section-embedding method thin sections, cut from light-microscopically identified areas containing Marchi-positive bodies or argyrophilic granules, were examined in the electron microscope. The results show that the Marchi-positive bodies and argyrophilic granules, which are present in normal white matter, represent different histochemical expressions of the same entity--the myelinoid body. In view of the similarities between myelinoid bodies and myelin fragments formed during Wallerian degeneration it is suggested that this type of so called artifact staining of normal white matter inherent to both methods should instead be considered as an expression of a specificity of the two methods for degenerating nervous elements.

Animals

Laminar scars in cerebral white matter: a perinatal injury due to edema.

Branched plate-like demyelinated lesions were present in the gyral and central white matter of two individuals, 3 and 54 years of age. The degenerated areas contained very few axons and were densely gliotic, and in the older case, contained connective tissue fibers and were continuous with a large parenchymal cyst. The lesions were covered on both sides by normally myelinated white matter, often representing only the subcortical arcuate white matter, occasionally being considerably broader. In some of the latter zones, there was a central area of less severe degeneration which, however, spared the arcuate zone which remained normal. It is suggested that these lesions represent the effects of edema induced by birth injury, under circumstances which permitted the continued formation and maturation of white matter after the edema had subsided. The edema is thought due for the most part to diffuse hypoxia and acidosis, but other mechanisms, such as infection, venous stasis and trauma, may have contributed to the pathogenesis of the edema, and to the lesions directly.

Birth Injuries

Sex and APOE &#x3b5;4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized. METHODS: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age&#xa0;=&#xa0;73.06&#xa0;&#xb1;&#xa0;9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE &#x3b5;4 carrier status. RESULTS: Sex differences in FAFWcorr in projection tracts and APOE &#x3b5;4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex and APOE &#x3b5;4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HIGHLIGHTS: Sex and apolipoprotein E (APOE) &#x3b5;4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE &#x3b5;4 carriers tended to have higher free water than non-carriers.

Humans

Experimental spongy degeneration of the white matter induced by 6-aminonicotinamide intoxication.

Spongy state and degeneration of the white matter in the 6-aminonicotinamide intoxicated rats were studied neuropathologically and electromicroscopically. Young albino rats, four weeks of age, received 0.1% of 6-aminonicotinamide solution intraperitoneally as a single dose of 10 mg/Kg of body weight. Four hours after the administration, paralysis of the hind limbs occurred in the rats. Neuropathological investigations revealed a characteristic spongy and degenerative change of white matter as well as gray matter of the central nervous system. Corpus callosum, cerebellar cortex, and optic nerves showed edematous and spongy degeneration in the early stage of the experiment. Ultrastructural changes of myelin sheath were initially seen in the vicinity of severely damaged oligodendrocytes. The vacuoles in the myelin, i.e. intramyelinic vacuoles, were formed by splitting between the innermost myelin lamellae and axon. Axons remained usually unchanged in the early stage. The pathogenesis of ultrastructural changes of the white matter in the 6-aminonicotinamide intoxication was discussed.

6-Aminonicotinamide

[Soluble cerebral metalloproteins. II. Superoxide dismutases of cerebral gray and white matter].

Superoxide dismutases (SOD) of high purity have been obtained from grey and white matter of bovine brain cerebral hemispheres. The SOD obtained have been shown to have three isoenzymes (a, b, c). A study of the catalytic and macromolecular properties of the SOD obtained from grey and white matter of cerebral hemispheres as well as their optical and electron paramagnetic resonance spectra indicates that both proteins possess similar properties. The possible function of SOD in grey and white matter of brain is discussed.

Animals

Computerized cranial tomography in cerebral diseases of white matter.

Computerized tomographic scans were performed on 31 patients with primary diseases of the white matter. Among 18 patients with multiple sclerosis, acute lesions were visualized in five, all with symptomatic cerebral hemisphere disease. Characteristic white matter lesions were also demonstrated in adrenoleukodystrophy, spongiform encephalopathy, progressive multifocal leukoencephalopathy, disseminated necrotizing leukoencephalopathy, and an undiagnosed leukoencephalopathy associated with malignancy. Besides identifying white matter abnormalities, the CT scan patterns were often specific enough to help distinguish among the various etiologic possibilities for the abnormalities. Useful diagnostic characteristics included the anatomic distribution of lesions, mass effect, atrophic changes, and enhancement after contrast infusion.

Adrenal Insufficiency