The fatty acid composition of cerebrosides and sulfatides in a case of adult metachromatic leukodystrophy

Summary The fatty acid composition of cerebrosides and sulfatides in the white matter of a brain from a patient with adult MLD was analysed by gas-liquid chromatography and compared to the results obtained from a normal control of the same age. In adult MLD a relative increase of short chain fatty acids affecting mainly the cerebrosides and also a diminution of unsaturated fatty acids affecting mainly the sulfatides were found. The whole composition of the sulfatides was altered to a larger extent than of the cerebrosides and this result was in contrast to results obtained in infantile MLD. These findings were discussed on the basis of a similar enzymatic defect in both adult and infantile cases and with regard to a chronic demyelinating process.Dedicated with gratitude and affection to Prof. H. J. Bauer on the occasion of his 60th birthday.     

Fatty acid composition of cerebrosides and cerebroside sulphatides in cerebral oedema

Summary The fatty acid composition of cerebrosides and sulphatides has been investigated in the oedematous areas of the white matter of three brains associated with cerebral tumour and compared with corresponding normal areas. There was a decrease in C24 non-hydroxy fatty acids of cerebrosides.The results have been correlated with previously reported lipid studies of cerebral oedema and fatty acid composition in various disease processes of the central nervous system.It would seem probable that these results are a reflection of early stages in secondary demyelination.

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Zusammenfassung Die Fettsäurezusammensetzung der Cerebroside und Sulfatide in ödematösen Gebieten des Marklagers von drei Gehirnen bei Hirngeschwülsten wurde untersucht und mit entsprechenden normalen Gebieten verglichen. Es bestand eine Verminderung der C 24-nicht-hydroxylierten Fettsäurereste der Cerebroside.Die Ergebnisse werden mit früheren Lipiduntersuchungen bei Hirnödem sowie der Fettsäurezusammensetzung bei verschiedenen Erkrankungen des ZNS verglichen.Es ist wahrscheinlich, daß diese Befunde den frühen Stadien sekundärer Entmarkung entsprechen.

     

Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination

Changes in fatty acid composition of complex lipids were analyzed in postmortem white matter from a patient with late onset adrenoleukodystrophy (ALD). The specimen showed three regions with progressive myelin breakdown: morphologically normal white matter; areas with active demyelination and perivascular lymphocyte and macrophage infiltration; and areas with marked gliosis. In the morphologically intact region, cholesterol esters were similar in amount and fatty acid composition to those in control tissue, although marked changes were observed in the actively demyelinating area. Galactolipids in these areas were also similar to those in controls. In contrast, glycerophospholipids were increased in amount and in very long chain fatty acids (VLCFA), which are the hallmark of ALD, at the active edge of the demyelinative lesion and even in the apparently intact sample. Further fractionation of the glycerophospolipids by high performance liquid chromatography showed a significant (up to 39-fold) accumulation of hexacosanoic acid (C26:0) in phosphatidylcholine, but not in other phosphatidyl derivatives. The consistent increases in phosphatidylcholine VLCFA in all samples from the ALD brain, which are postulated to represent progressive stages in the development of the disorder, suggest that phosphatidylcholine may be involved in antigen formation and may underlie an immunological basis for the pathogenesis of ALD.     

Free fatty acid patterns in normal and multiple sclerosis white matter

The relative compositions of free fatty acids (FFA) in white matter from six multiple sclerosis (MS) and seven control brains were determined by gas chromatography. The major components of all samples were oleic, stearic and palmitic acids, with lesser amounts of arachidonic acid, and a long chain fatty acid, identified as 24:4. MS samples had significantly less of the 24:4 fraction compared with controls, but no other differences were noted. The spectrum of FFA was similar in most respects to those reported for phosphatidylcholine and cholesterol esters. This supports current theories that a major pathway of lipid catabolism in the brain involves transfer of fatty acids from phosphatidylcholine to cholesterol.     

Regional differences in cerebral asymmetries of human cortical white matter

The form of the structural asymmetries across the cerebral hemispheres, that support well-established functional asymmetries, are not well understood. Although, many previous studies have investigated structural differences in areas associated with strong functional asymmetries, such as language processes, regions of the brain with less well established functional laterality have received less attention. The current study aims to address this by exploring global white matter asymmetries of the healthy human brain using diffusion tensor imaging (DTI) and tractography. DTI was conducted on twenty-nine healthy right-handed males, and pathways from the four major lobes were reconstructed using probabilistic tractography. Mean FA, parallel and perpendicular diffusion values were calculated and compared across hemispheres for each pathway generated. Significant asymmetries in the parietal (rightward asymmetry) and occipital (leftward asymmetry) pathways were found in FA measures. However, asymmetric patterns in parallel and/or perpendicular diffusion were observed in all four lobes, even in pathways with symmetrical FA. For instance, significant rightward asymmetry in parallel diffusion was found in the parietal and frontal lobes, whereas significant leftward asymmetry was found in the temporal and occipital lobes. We suggest that these different patterns of diffusion asymmetry reflect differences in microanatomy that support the known patterns of differential functional asymmetry. The different directions of anatomical asymmetry support the notion that there may be a number of different lateralising influences operating in the brain.     

Migration of xenogenic astrocytes in myelinated tracts: a novel probe for immune responses in white matter

Summary Experimental brain transplantation allows the study of the development of the immune response against brain antigens within the brain itself. This laboratory has developed a transplantation model in which rabbit embryo brain fragments are placed in the brains of newborn mice. The migration of xenogenic astrocytes is traced by a monoclonal antibody which combines with donor but not host glial fibrillary acidic protein. In the first 4 weeks after transplantation, the donor astrocytes successfully migrate, often within myelinated tracts. Following this period, T cells make their apperance and xenogenic astrocytes disappear by 10 weeks. The propensity for clearly identified foreign astrocytes to migrate in myelinated tracts coupled with a well-defined time course of host-vs-graft interaction suggested that the model could be used to study the immune response in white matter. The studies reported here provide sequential examples of the relationship between migration by foreign astrocytes in myelinated tracts and the development of the host immune response. Extensive migration in white matter tracts was first observed in the absence of any T cell response. Subsequently T cells were found at the transplantation site. Finally Ia was found to be expressed on blood vessels and microglia were strongly reactive in white matter that contained T cells but no foreign astrocytes. These observations support the suggestion that the model can be used to more precisely define cellular immune events that occur within white matter.Supported by the Veterans Administration (US), the Ministère de la Recherche et de la Technologie, and the Philippe Foundation (Paris and New York) (sabbatical support provided to J. Booss) INSERM, the Association pour la Recherche sur la Sclérose en Plaques (ARSEP) and the Myelin Project Foundation     

MRI evidence of white matter damage in a mouse model of Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of NBS1, Nbn, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. In this study we used MRI to study the brain morphology and organization of Nbn deleted mice. Using conventional T(2)-weighted magnetic resonance, we found that the brains of the mutant mice (Nbs1-CNS-del) were significantly smaller than those of the wild-type animals, with marked mal-development of the cerebellum. Region of interest analysis of the T(2) maps revealed significant T(2) increase in the areas of white matter (corpus callosum, internal capsule and midbrain), with minor changes, if any, in gray matter. Diffusion tensor imaging (DTI) data confirmed that fractional anisotropy values were significantly reduced in these areas, mainly due to increased radial diffusivity (water diffusion perpendicular to neuronal fibers). Biochemical analysis showed low and dispersed staining for MBP and GalC in Nbs1-CNS-del brains, indicating defects in myelin formation and oligodendrocyte development. Myelin index and protein levels were significantly reduced in these brains. Our results point to a novel function of Nbs1 in the development and organization of the white matter.     

Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part II)

The objective of this study was to investigate the relative impact of brain white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle metabolism (including serum folate, vitamin B12 and homocysteine levels) on the outcome of antidepressant treatment in non-elderly subjects with major depressive disorder (MDD). Fifty MDD subjects were administered brain magnetic resonance imaging (MRI) scans at 1.5 T to detect T2 WMHs. The severity of brain WMHs was classified with the Fazekas scale (range = 0–3). We assessed cardiovascular risk factors in all MDD subjects (age, gender, smoking, diabetes, family history, hypertension, cholesterol). MDD patients also had serum folate, vitamin B12 and homocysteine levels measured. All MDD subjects received treatment with fluoxetine 20 mg/day for 8 weeks. In a logistic regression, the severity of subcortical WMHs and the presence of hypofolatemia were independent predictors of lack of clinical response to antidepressant treatment. Separately, hypofolatemia also predicted lack of remission to antidepressant treatment. These associations were independent of the presence of smoking, diabetes, family history, hypercholesterolemia, hyperhomocysteinemia and low B12 levels. Although preliminary, the results of the present work suggest that subcortical brain WMHs and hypofolatemia may have an independent negative impact on the likelihood of responding to antidepressant treatment in non-geriatric subjects with MDD.     

Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part I)

The objective of the present work was to study the interrelationship between white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle including serum folate, vitamin B12, and homocysteine levels in a relatively young sample of outpatients with major depressive disorder (MDD), and to compare the severity of white matter hyperintensities in MDD patients and healthy volunteers. Fifty MDD outpatients (34% women, age 40.6 ± 10.3 years), free of psychotropic medications for at least 2 weeks before enrollment, underwent magnetic resonance imaging (MRI) scans of the brain to detect T2 WMHs and also had (1) serum folate, vitamin B12, homocysteine and cholesterol levels measured, and (2) cardiovascular risk factors assessed during the same study visit. Thirty-five healthy comparison subjects (40% women, age 39.2 ± 9.8 years) also underwent brain MRI scans. Hypofolatemia, hypertension and age independently predicted a greater severity of total brain WMHs. Separately, the same factors also predicted a greater severity of subcortical WMHs. Hypofolatemic and hypertensive patients had more severe WMHs than normal controls. In light of the adverse impact of WMHs on a number of health-related outcomes later in life, hypofolatemia and hypertension may represent modifiable risk factors to prevent the occurrence of such adverse outcomes.     

Migrating and myelinating potential of subventricular zone neural progenitor cells in white matter tracts of the adult rodent brain

Adult neural stem cells in the subventricular zone (SVZ) produce neuronal progenitors that migrate along the rostral migratory stream (RMS) and generate olfactory interneurons. Here, we evaluate the migratory potential of SVZ cells outside the RMS and their capacity to generate oligodendrocytes in the adult brain. We show that SVZ cells migrate long distances when grafted into white matter tracts such as the cingulum (Ci) and corpus callosum (CC). Furthermore, 22 days postinjection, most present morphologic and phenotypic characteristics of cells committed to the oligodendrocyte lineage. Cells grafted in shiverer CC and Ci become MBP-positive oligodendrocytes, abundantly myelinating these white matter tracts. Type A progenitors are involved in this myelinating process. Altogether, this study reveals the migrating and myelinating potential of SVZ cells in a new environmental context. Therefore, SVZ cells stand as interesting candidates for the development of novel therapeutic strategies for demyelinating diseases.     

精神分裂症早期的脑白质和灰质信号强度下降

目的分析精神分裂症早期阶段脑灰质和脑白质结构的变化。方法对25例早期阶段(病程小于6个月)的首发未用药的精神分裂症患者和28名正常对照的脑部进行磁共振T1加权成像,所得图像以统计参数图软件包进行预处理,再对两组脑灰质密度和白质信号强度进行t检验。结果患者组左侧岛叶区(x=34,y=18,z=-2,体素集合数=163)、左枕叶(x=14,y=-66,z=14,体素集合数=76)、右侧额叶(x=46,y=44,z=8,体素集合数=74)白质信号强度较正常对照组降低(t=-3.78,P=0.007;t=-3.36,P=0.02;t=3.26,P=0.03);右侧枕叶(x=10,y=-84,z=8,体素集合数=64)脑灰质信号强度比正常对照组降低(t=3.12,P=0.03)。结论精神分裂症早期阶段即存在脑实质结构异常,以白质为著。     

Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study

Activation of glial cells and white matter changes (rarefaction of the white matter) induced in the rat brain by permanent bilateral occlusion of the commom carotid arteries were immunohistochemically investigated up to 90 days. One day after ligation of the arteries, expression of the major histocompatibility complex (MHC) class I antigen in microglia increased in the white matter including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. After 3 days of occlusion, MHC class I antigen was still elevated and in addition MHC class II antigen and leukocyte common antigen were up-regulated in the microglia in these same regions. Astroglia, labeled with glial fibrillary acidic protein, increased in number in these regions after 7 days of occlusion. A few lymphocytes, labeled with CD4 or CD8 antibodies, were scattered in the neural parenchyma 1 h after occlusion. Activation of glial cells and infiltration of lymphocytes persisted after 90 days of occlusion in the white matter and the retinofugal pathway. However, cellular activation and infiltration in microinfarcts of the gray matter was less extensive and was substantially diminished 30 days after occlusion. The white matter changes were most intense in the optic nerve and optic tract, moderate in the medial part of the corpus callosum, internal capsule and anterior commissure, and slight in the fiber bundles of the caudoputamen. These results indicated that chronic cerebral hypoperfusion induced glial activation preferentially in the white matter. This activation seemed to be an early indicator of the subsequent changes in the white matter.     

Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice

Some lines of evidence have suggested that subcortical ischemic vascular dementia (SIVD) is a common form of vascular dementia (VaD), and that its pathological changes are the development of ischemic white matter (WM) lesions under chronic hypoperfusion and lacunes. Here, we have developed a novel mouse model of VaD with WM lesions, which was induced by right unilateral common carotid artery occlusion (rUCCAO). The mice subjected to rUCCAO exhibited chronic cerebral hypoperfusion in the cerebral hemisphere ipsilateral to rUCCAO monitored using a laser-Doppler flow meter (p<0.01), and significant WM damage in the corpus callosum (p<0.05) and deficits in object recognition test correlated with the damage of frontal-subcortical circuits (p<0.01). However, no differences in spontaneous alternation or spontaneous motor activity were observed. Furthermore, the levels of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), significantly increased (p<0.01), and those of anti-inflammatory cytokines, such as interleukin-4 (IL-4) and interleukin-10 (IL-10), significantly decreased in the ischemic brain (p<0.05). These results suggest that this model is a useful tool for investigating the associations among inflammatory reactions, cognitive impairment, and WM damage, which may help elucidating the pathomechanism of VaD, particularly SIVD.     

Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52–64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF- and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.     

急性腔隙性脑梗死伴脑白质病变对认知功能的变化影响

目的探讨急性腔隙性脑梗死（LI）伴脑白质病变（WML）患者的认知功能障碍特点。方法收集137例患者和正常对照组30例,根据头颅MRIT2加权像及FLAIR像,将病例组分为LI组、WML组和u合并WML组,应用蒙特利尔认知评估量表（MoCA）进行认知评估。结果与对照组相比,WML组的延迟回忆与语言评分明显下降（P〈0．01）;LI组患者注意计算、语言、执行功能评分显著降低（P〈0．01）;LI合并WML组患者延迟记忆、视空间与执行功能评分显著降低（P〈0．01）。与LI组和WML组相比,执行功能障碍在LI合并WML组更明显（P〈0．01）。结论LI合并WML可导致患者认知功能障碍,主要表现为延迟记忆、视空间与执行等认知功能的受损;MoCA在皮层下缺血性脑血管病引起的血管性认知障碍的评定中具有很大的优势。     

新型脑白质病变动物模型及其脑小血管的病理学研究

目的建立一个新型的具有高血压及脑小血管病理改变的脑白质病变(white matter lesions,WMLs)动物模型。方法 13只雄性Sprague-Dawley大鼠,随机分为假手术组(n=6)与易卒中型肾血管性高血压-改良的2VO组(stroke-prone renovascular hypertensive rat-modified 2 vessel occlusion RHRSP/Modified 2VO)(n=7),RHRSP/Modified 2VO组先行双肾双夹术制作RHRSP模型,12周后间隔1周先后夹闭双侧颈总动脉。双肾双夹术后20周对大鼠进行水迷宫试验观察大鼠是否存在空间记忆功能的受损,组织病理学检测观察是否存在脑白质病变及相应的脑小血管病理学改变。结果双肾双夹术后12周,RHRSP/Modified 2VO组7只大鼠收缩压均大于180 mm Hg;水迷宫实验:RHRSP/Modified 2VO组的逃避潜伏期较假手术组明显升高(P0.05),穿越平台次数及原平台象限停留时间比较假手术组明显降低[(2.5±1.05 vs.5±1.67);(28.04%±14.13%vs.49.69%±13.12%)],差异具有统计学意义(P0.05);RHRSP/Modified 2VO组脑白质病变的分级明显高于假手术组(2.17±0.75 vs.0.33±0.52),差异具有统计学意义(P0.05),且RHRSP/Modified 2VO大鼠存在脑小血管的病理改变(小动脉管壁增厚、血脑屏障破坏及静脉胶原沉积)。结论 RHRSP/Modified 2VO是适用的WMLs动物模型,可用于探究WMLs的发病机制及治疗靶点。     

FK506 ameliorates the discrimination learning impairment due to preventing the rarefaction of white matter induced by chronic cerebral hypoperfusion in rats

We examined the effects of the immunosuppressant tacrolimus (FK506) on the discrimination learning impairment induced by chronic cerebral hypoperfusion in rats. Chronic cerebral hypoperfusion was prepared by permanent ligation of bilateral common carotid arteries for male Wistar rats aged 9 weeks. FK506 (0.05 mg/kg, s.c.) recovered the learning impairment and also prevented the rarefaction of white matter and striatal neuronal cell damage. Our findings suggest that FK506 ameliorates the learning impairment mainly due to preventing neuropathological alterations.     

长时血压变异性与脑白质病变的相关性研究

目的探讨长时血压变异性(blood pressure variability,BPV)与脑白质病变(white matter lesions,WML)发病及严重程度的关系。方法选取符合条件的136例住院患者作为研究对象,每(20±10)d随诊间测量血压,随访12 m,采用改良Scheltens量表评定WML严重程度;分析两组患者的长时血压变异性指标(平均收缩压、平均舒张压、收缩压变异系数、舒张压变异系数、收缩压标准差、舒张压标准差等)。结果 (1)WML组患者平均收缩压、平均舒张压、收缩压变异系数、舒张压变异系数、收缩压标准差、舒张压标准差分别为(135.71±19.84)mmHg、(79.22±15.36)mm Hg、9.08±2.10、11.86±1.49、13.81±3.52、10.12±2.53,高于对照组的(124.88±17.96)mm Hg、(74.33±7.68)mm Hg、7.06±1.85、10.47±1.29、11.17±2.13、9.80±2.45,差异均有统计学意义(P<0.05);(2)WML组改良Scheltens量表评分,不同程度患者之间比较,收缩压水平、收缩压变异系数、收缩压标准差差异有统计学意义(P<0.05)。结论年龄、高血压、BPV增大是WML的危险因素,长时BPV对WML的发生及进展有一定的预测作用。     

MRI white matter hyperintensity in neuroleptic malignant syndrome (NMS)—a clue to pathogenesis?

Summary The case of a young female patient with neuroleptic malignant syndrome (NMS) and extended MRI white matter hyperintensity in the left parietal and both occipital lobes is reported. MRI lesions resembled findings in hypertensive encephalopathy, they were not readily compatible with CNS vasculitis. Venous sinus thrombosis could be ruled out. Vascular encephalopathy with transient white matter edema and a small residual left parietal lesion is suggested. Neurochemical implications are discussed with particular reference to a possible involvement of excitatory amino acids in NMS pathogenesis.