Age‐Associated White Matter Lesions: The MRC Cognitive Function and Ageing Study

Cerebral white matter lesions (WML) are common in the aging brain and are associated with dementia and depression. They are associated with vascular risk factors and small vessel disease, suggesting an ischemic origin, but recent pathology studies suggest a more complex pathogenesis. Studies using samples from the population‐representative Medical Research Council Cognitive Function and Ageing Study neuropathology cohort used post‐mortem magnetic resonance imaging to identify WML for further study. Expression of hypoxia‐related molecules and other injury and protective cellular pathways in candidate immunohistochemical and gene expression microarray studies support a role for hypoxia/ischemia. However, these approaches also suggest that immune activation, blood–brain barrier dysfunction, altered cell metabolic pathways and glial cell injury contribute to pathogenesis. These abnormalities are not confined to WML, but are also found in apparently normal white matter in brains with lesions, suggesting a field effect of white matter abnormality within which lesions arise. WML are an active pathology with a complex pathogenesis that may potentially offer a number of primary and secondary intervention targets.     

Enriched Environment and White Matter in Aging Brain

Normal aging is commonly associated with decreased cognitive functions, which could be conspicuously alleviated by enriched environment (EE) with physical, social, and sensory stimuli, suggesting that aging brain still has intriguing plasticity. Multiple researches have been carried out to explore the structural and the molecular changes in aging brain, which would be considered for evidences that EE regulated brain plasticity. Because there is no significant neuron loss in aging cerebral cortex and the white matter is crucial for cognitive functions, this review focused on the age‐related white matter changes and the effects of EE on aged white matter. Data from our stereology laboratory revealed that age‐related spatial memory declines had more to do with white matter alterations, which were due to marked demyelination and loss of oligodendrocytes in the white matter. We also demonstrated that EE recovered spatial memory impairment and increased white matter volume by promoting marked remyelination in aged brain. This review approached the issue that EE might contribute to normal aging and be beneficial for those suffering from demyelinated diseases. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

HFE H63D,C282Y and AGTR1 A1166C Polymorphisms and Brain White Matter Lesions in the Aging Brain

Abstract: Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens’ scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.     

White Matter Hypoperfusion and Damage in Dementia: Post‐Mortem Assessment

Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel‐associated proteins that allow rapid measurement of microvessel density, markers of blood–brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution.     

脑白质病变的研究进展

脑白质病变与临床上许多疾病密切相关,而且影响到了有关疾病的预后。本文就近年来脑白质病变的研究进展进行了综述,希望能为今后的研究提供新的思路。     

Contribution of 1425G/A Polymorphism in Protein Kinase C-Eta (PRKCH) Gene and Brain White Matter Lesions to the Risk of Sudden Sensorineural Hearing Loss in a Japanese Nested Case-Control Study

Abstract: Protein kinase C-eta (PRKCH) gene has been recently identified as a susceptible risk locus for cerebral infarction and hemorrhage in the Asian populations. The inner ear artery, a usual branch of anterior inferior cerebellar artery, is an end artery with minimal collaterals, therefore, the inner ear is particularly vulnerable to ischemia. The potential association between the development of stroke and sudden sensorineural hearing loss (SSNHL) has been implied. The authors hypothesized that the PRKCH polymorphism predisposing to stroke is associated with SSNHL risk, in view of brain magnetic resonance imaging (MRI) findings. The authors compared 33 cases of prevalent SSNHL with other cases among 2188 adults aged 40 to 79 years who participated in the Study of Aging, to assess the impact of PRKCH 1425G/A polymorphism in consideration of brain MRI findings. Multiple logistic regression was used to obtain odds ratios (ORs) for SSNHL, with adjustment for other possibly influential factors under additive model of minor allele. The per-allele OR for SSNHL risk was 1.770 (95% confidence interval: 1.024–3.060) after adjustments. The effect of the 1425A-allele varied by white matter lesion (WML) status. A significant impact of the A-allele on SSNHL risk increment was observed in higher-WML group, but not in no- or mild-WML group. The 1425A-allele of PRKCH has probably contributed to the susceptibility to SSNHL, despite the etiological heterogeneity of SSNHL, and the impact of the PRKCH 1425A variation observed in this study may imply underlying vascular pathogenesis of SSNHL.     

High Mean Platelet Volume Is Associated with Cerebral White Matter Hyperintensities in Non-Stroke Individuals

PurposeThe mean platelet volume (MPV) is regarded as a marker for thrombosis, atherosclerosis, and inflammation in various vascular diseases. However, it still remains unclear whether plasma MPV is associated with cerebral white matter hyperintensities (WMH) and cerebral microvascular pathology in the elderly population.Materials and MethodsWe examined whether MPV level is associated with the presence of cerebral WMH on brain magnetic resonance imaging from 870 non-stroke outpatient subjects. The subjects were divided into three groups according to the consecutive level of MPV (low T1, middle T2, and high T3 MPV tertile groups). To determine the association of MPV levels with the WMH, logistic regression and receiver operating characteristic curve analyses were conducted.ResultsSubjects with higher MPV level were older and more likely to have hypertension, diabetes mellitus, and low renal function. Cerebral WMH were more prevalent in subjects with higher MPV level. After adjusting for confounding factors, moderate to severe cerebral WMH were significantly associated with high MPV tertile level. This association remained significant after adjusting for other cerebral vascular pathologies. T2 [odds ratio (OR): 1.49, 95% confidence interval (CI): 1.03–2.15] and T3 MPV tertile groups (OR: 1.51, 95%CI: 1.04–2.20) had more cerebral WMH lesions compared to T1 MPV tertile group. In addition, the subjects with higher Fazekas scores showed higher MPV level (p=0.020).ConclusionWe found that high MPV level is independently associated with cerebral WMH. This result suggests that platelet activation plays a role in the development of cerebral WMH.     

Cerebral Amyloid Angiopathy,Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA

Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.     

Age-Induced White Matter Changes in the Human Brain: A Stereological Investigation

In the present pilot study, age-related white matter changes were investigated by the use of design-based stereological methods. In the brains of elderly subjects, the total volume of the white matter and the total volume of the myelinated fibers therein were lower than in those of young subjects (15% and 17%, respectively), but the differences were not statistically significant. The total length of the myelinated fibers of the white matter in the elderly group of 86,000 km was, statistically, significantly decreased by 27% compared with 118,000 km in the young group. This loss of the total nerve fiber length was accompanied in particular by a decline of the myelinated fibers with a small diameter. The mean diameter of the myelinated fibers in the young group was significantly smaller than in the old group, but the relative size distributions of the myelinated fiber diameters between the young and old groups were similar. Our findings show that the atrophy of the human white matter during ageing is probably caused by a loss of myelinated fibers with a small diameter.     

Glial Scar Formation Occurs in the Human Brain after Ischemic Stroke

Reactive gliosis and glial scar formation have been evidenced in the animal model of ischemic stroke, but not in human ischemic brain. Here, we have found that GFAP, ED1 and chondroitin sulphate proteoglycans (CSPG) expression were significantly increased in the cortical peri-infarct regions after ischemic stroke, compared with adjacent normal tissues and control subjects. Double immunolabeling showed that GFAP-positive reactive astrocytes in the peri-infarct region expressed CSPG, but showed no overlap with ED1-positive activated microglia. Our findings suggest that reactive gliosis and glial scar formation as seen in animal models of stroke are reflective of what occurs in the human brain after an ischemic injury.     

Anatomy and White Matter Connections of the Superior Frontal Gyrus

The superior frontal gyrus (SFG) is an important region implicated in a variety of tasks including motor movement, working memory, resting-state, and cognitive control. A detailed understanding of the subcortical white matter of the SFG could improve postoperative morbidity related to surgery around this gyrus. Through DSI-based fiber tractography validated by gross anatomical dissection, we characterized the fiber tracts of the SFG based on their relationships to other well-known neuroanatomic structures. Diffusion imaging from the Human Connectome Project from 10 healthy adult subjects was used for fiber tractography. We evaluated the SFG as a whole based on its connectivity with other regions. All tracts were mapped in both hemispheres, and a lateralization index was calculated based on resultant tract volumes. Ten cadaveric dissections were then performed using a modified Klingler technique to delineate the location of major tracts integrated within the SFG. We identified four major SFG connections: the frontal aslant tract connecting to the inferior frontal gyrus; the inferior fronto-occipital fasciculus connecting to the cuneus, lingual gyrus, and superior parietal lobule; the cingulum connecting to the precuneus and parahippocampal gyrus/uncus; and a callosal fiber bundle connecting the SFG bilaterally. The functional networks of the SFG involve a complex series of white matter tracts integrated within the gyrus, including the FAT, IFOF, cingulum, and callosal fibers. Postsurgical outcomes related to this region may be better understood in the context of the fiber-bundle anatomy highlighted in this study. Clin. Anat. 33:823–832, 2020. © 2019 Wiley Periodicals, Inc.     

Heterogeneity of cellular inflammatory responses in ageing white matter and relationship to Alzheimer’s and small vessel disease pathologies

White matter lesions (WML) are common in the ageing brain, often arising in a field effect of diffuse white matter abnormality. Although WML are associated with cerebral small vessel disease (SVD) and Alzheimer’s disease (AD), their cause and pathogenesis remain unclear. The current study tested the hypothesis that different patterns of neuroinflammation are associated with SVD compared to AD neuropathology by assessing the immunoreactive profile of the microglial (CD68, IBA1 and MHC‐II) and astrocyte (GFAP) markers in ageing parietal white matter (PARWM) obtained from the Cognitive Function and Ageing Study (CFAS), an ageing population‐representative neuropathology cohort. Glial responses varied extensively across the PARWM with microglial markers significantly higher in the subventricular region compared to either the middle‐zone (CD68 p = 0.028, IBA1 p < 0.001, MHC‐II p < 0.001) or subcortical region (CD68 p = 0.002, IBA1 p < 0.001, MHC‐II p < 0.001). Clasmatodendritic (CD) GFAP⁺ astrocytes significantly increased from the subcortical to the subventricular region (p < 0.001), whilst GFAP⁺ stellate astrocytes significantly decreased (p < 0.001). Cellular reactions could be grouped into two distinct patterns: an immune response associated with MHC‐II/IBA1 expression and CD astrocytes; and a more innate response characterised by CD68 expression associated with WML. White matter neuroinflammation showed weak relationships to the measures of SVD, but not to the measures of AD neuropathology. In conclusion, glial responses vary extensively across the PARWM with diverse patterns of white matter neuroinflammation. Although these findings support a role for vascular factors in the pathogenesis of age‐related white matter neuroinflammation, additional factors other than SVD and AD pathology may drive this. Understanding the heterogeneity in white matter neuroinflammation will be important for the therapeutic targeting of age‐associated white matter damage.     

White matter changes in dementia of Alzheimer''s type: the difference in vulnerability between cell compartments

Structural white matter changes were found to be common in dementia of Alzheimer's type. A neuropathological investigation was undertaken in order to characterize and quantify these white matter changes. The tissue changes were compared with those in white matter in normal control cases and in complete white matter infarcts. Our results support the hypothesis that the white matter lesion seen in dementia of Alzheimer's type is due to incomplete infarction involving both axons and myelin and is a result of mild ischaemia. In mild ischaemia, the myelin compartment appears to be the most vulnerable. We have termed the lesion selective incomplete white matter infarction.     

晚发型抑郁症伴轻度认知损害患者脑白质胆碱能通路的对照研究

目的：对伴轻度认知损害（ MCI）的晚发型抑郁症（ LOD）患者脑白质胆碱能通路的改变进行对照性研究,并分析其与患者认知功能各领域受损的关系。方法：对伴MCI的LOD患者（研究组,n＝25）磁共振成像的胆碱能通路高信号评分（ CHIPS）,同时评定蒙特利尔认知评估量表（ MoCA）,分析CHIPS评分与MoCA各认知领域的关系;并与不伴MCI的LOD患者（对照组,n＝25）进行对照。结果：①研究组MoCA总分、视空间与执行功能、延迟记忆、注意及工作记忆得分,均显著低于对照组,差异有统计学意义（t＝2．091～2．398,P＝0．041～0．028）;②研究组CHIPS显著高于对照组,差异有统计学意义（t＝2．097,P＝0．042）;③研究组CHIPS评分与MoCA总分、视空间与执行功能、延迟记忆得分显著负相关（r＝－0．434,－0．398,－0．483;P＜0．05）。结论：脑白质胆碱能通路受损,在LOD患者MCI的发生中可能起了一定的作用,尤其与其视空间与执行功能、记忆及延迟记忆的损害有关。     

Stereological Investigation of Age‐Related Changes of the Capillaries in White Matter

We, for the first time, investigated the age‐related changes of the capillaries in white matter using immunohistochemistry and stereological techniques. Ten young female (7 months) and 10 aged female (27 months) rats were used. The total length, total volume, and total surface area of the capillaries in white matter of aged rats were all significantly lower than those of young rats. The age‐related changes of the capillaries in white matter may have important implications for age‐related white matter atrophy and age‐related cognitive impairments. Anat Rec 293:1400–1407, 2010. © 2010 Wiley‐Liss, Inc.     

Demyelination Induces the Decline of the Myelinated Fiber Length in Aged Rat White Matter

To determine the exact reason for the age‐related decline of the myelinated fiber length in white matter, we performed this study. In middle‐aged rats, there was age‐related loss of the unmyelinated fibers with large diameters. The demyelination of the myelinated fibers with small diameters in middle‐aged rat white matter might make the age‐related decrease of the unmyelinated fibers with small diameters in the white matter unnoticeable. However, in old‐aged female rats, the unmyelinated fibers with large and small diameters significantly degenerated together and that the unmyelinated fibers formed from the demyelination of the myelinated fibers could not replenish the age‐related loss of the unmyelinated fibers in the white matter. In conclusion, this study suggested that demyelination of myelinated fibers with small diameters in aged white matter might be the key mechanism of the significant decline of the myelinated fiber length in aged white matter. Anat Rec, 292:528–535, 2009. © 2009 Wiley‐Liss, Inc.     

融合白质fMRI的dMRI纤维追踪重建研究

基于弥散磁共振成像(dMRI)的纤维束重建,是分析大脑白质结构的主要工具.现有的纤维追踪成像算法受dMRI分辨率及成像机理约束,在构建大脑白质灰质边界区域的纤维时成像性能和准确性大大下降.为克服该缺陷,提出一种结合功能磁共振成像(fMRI)的新型dMRI纤维追踪成像算法.该算法引入表征白质中fMRI信号各向异性的空间相...     

Age‐Related Changes of the Oligodendrocytes in Rat Subcortical White Matter

The age‐related changes, of the oligodendrocytes in rat subcortical white matter, were investigated in this study. The oligodendrocytes in subcortical white matter were labeled with anti‐2′,3′‐cyclic nucleotide 3′‐phosphodiesterase antibody (anti‐CNPase antibody, a specific marker of oligodendrocytes). The total number of CNPase⁺ cells was estimated with an unbiased stereological technique, the optical fractionator. In this study, we found that the total number of CNPase⁺ cells in the young male rats and aged male rats was 14.4 ± 1.2 × 10⁶ and 9.0 ± 1.0 × 10⁶, respectively. The total number of the CNPase⁺ cells in the subcortical white matter of aged rats was significantly decreased by 37.5% when compared to young male rats. This study demonstrated that there was an aged‐related decrease of the oligodendrocytes in subcortical white matter. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Molecular Changes in White Matter Adjacent to an Active Demyelinating Lesion in Early Multiple Sclerosis

A stereotactic biopsy of a 17-year-old woman revealed an active inflammatory demyelinating lesion compatible with pattern III multiple sclerosis (MS) according to Lucchinetti et al . The biopsy included a white matter region distant from the active inflammatory demyelinating lesion with abnormal MRI signal, lacking histopathological signs of demyelination and/or oligodendrocyte apoptosis. Expression analysis of this area revealed a strong up-regulation of neuronal nitric oxide synthase (nNOS). Furthermore, detection of nitrotyrosine provided evidence for reactive nitrogen species (RNS)-mediated damage to oligodendrocytes. Concomitantly, genes involved in neuroprotection against oxidative stress such as heme oxygenase 1 were up-regulated. Even though a single case report, this study shows earliest molecular changes in white matter surrounding an actively demyelinating lesion during the first manifestation of MS, pointing toward a more widespread pathological process. Therapeutic targeting of the identified mechanisms of tissue injury might be crucial to prevent further lesion formation or secondary tissue damage.