Formation Of White Matter Lesions Research Articles

Literature Commentary

Background: Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)–like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction. Objective: The primary aim was to define magnetic resonance imaging (MRI) features of LMS and LHON and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON. Methods: A blinded standardized review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON, and 11 patients with LMS was conducted by 3 independent experts in the field. MS-like MRI features were assessed. Results: All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions, consistent with MS compared with male patients (relative risk 8.3). Conclusions: A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance and clinical development of MS in patients with LHON.

Pathological differences between white and grey matter multiple sclerosis lesions.

Multiple sclerosis (MS) is a debilitating disease characterized by demyelination of the central nervous system (CNS), resulting in widespread formation of white matter lesions (WMLs) and grey matter lesions (GMLs). WMLs are pathologically characterized by the presence of immune cells that infiltrate the CNS, whereas these immune cells are barely present in GMLs. This striking pathological difference between WMLs and GMLs raises questions about the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WMLs; however, since GMLs show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WMLs and GMLs, and suggest some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics of WM and GM, and local differences within WMLs and GMLs (in particular, in glial cell populations and the molecules they express), determine the pathway to demyelination. Further understanding of GML pathogenesis, considered to contribute to chronic MS, may have a direct impact on the development of novel therapeutic targets to counteract this progressive neurological disorder.

Chronic cerebral hypoperfusion and dementia

Abstract“Cerebral small vessel disease” is a general term featuring a group of disease conditions with characteristic lesions affecting mainly small vessels in the brain, such as Binswanger's disease, leukoaraiosis and lacunar infarctions. Cerebral small vessels consist of a series of blood vessels, which originate from the pial arteries on the surface of the brain, and branch into arterioles, capillaries and postcapillary venules. Each of the blood vessels has a distinct structure and function. The blood–brain barrier, which does not exist in the other organs, functions in the brain. Dysfunction of the blood–brain barrier is thought to be a major cause of cerebral small vessel diseases. Recent findings have shown that maintenance of the blood–brain barrier is kept by various types of cells, such as vascular endothelial cells, astrocytes and pericytes, which work collaboratively as a neurovascular unit. Currently, larger vessels at the arteriolar level have been studied intensively; however, the pathological condition of the neurovascular unit at the capillary level still needs to be elucidated. The bilateral carotid artery stenosis model simulates chronic cerebral hypoperfusion, formation of white matter lesions and cognitive impairments seen in humans. Using this model, we found microcirculation disturbance especially in the postcapillary venule, and postulated it as a final step leading to white matter lesions and cognitive impairment. Taken together, we suggest that chronic cerebral hypoperfusion plays a pivotal role in the pathogenesis of cerebral small vessel diseases.

MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis

BackgroundLeber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS...

Tissue transglutaminase in marmoset experimental multiple sclerosis: discrepancy between white and grey matter.

Infiltration of leukocytes is a major pathological event in white matter lesion formation in the brain of multiple sclerosis (MS) patients. In grey matter lesions, less infiltration of these cells occur, but microglial activation is present. Thus far, the interaction of β-integrins with extracellular matrix proteins, e.g. fibronectin, is considered to be of importance for the influx of immune cells. Recent in vitro studies indicate a possible role for the enzyme tissue Transglutaminase (TG2) in mediating cell adhesion and migration. In the present study we questioned whether TG2 is present in white and grey matter lesions observed in the marmoset model for MS. To this end, immunohistochemical studies were performed. We observed that TG2, expressed by infiltrating monocytes in white matter lesions co-expressed β1-integrin and is located in close apposition to deposited fibronectin. These data suggest an important role for TG2 in the adhesion and migration of infiltrating monocytes during white matter lesion formation. Moreover, in grey matter lesions, TG2 is mainly present in microglial cells together with some β1-integrin, whereas fibronectin is absent in these lesions. These data imply an alternative role for microglial-derived TG2 in grey matter lesions, e.g. cell proliferation. Further research should clarify the functional role of TG2 in monocytes or microglial cells in MS lesion formation.

The Origin of White Matter Lesions

See related article, p 1037. Incidental areas of high signal intensity on T2-weighted MRI of older individuals termed white matter hyperintensities or white matter lesions (WML) have sparked scientific and clinical interest over the past 25 years. Extensive research has provided compelling evidence that at least more extensive forms of WMLs are a consequence of and indicative for small vessel disease,1 and thus are associated with a higher risk for stroke, dementia, and mortality.2 Furthermore, the longitudinal Leukoaraiosis And Disability (LADIS) study confirmed that severe WML strongly predict global functional decline in general beyond individual associations of WML extent with cognitive functioning as well as gait, balance, and mood disorders.3 Similar data come from several other cohorts. The exact mechanism(s) of WML formation, however, are still much less clear. In this issue of the Journal, de Groot et al4 report on a very elegant study which provides convincing evidence for the gradual development of WMLs both regarding the formation of new WMLs and also their expansion and growth over time. Using diffusion tensor imaging and the fluid-attenuated inversion recovery sequence, they searched for subtle changes that might have …

White matter hyperintensities (WMH) are associated with intracranial atherosclerosis rather than extracranial atherosclerosis

There is increasing evidence for an association between WMH and large-artery atherosclerosis. We evaluated 268 patients with acute ischemic stroke to assess the relationship between intracranial (IC) atherosclerosis and WMH. The patients were classified into three groups according to the location of the stenosis; IC, extracranial (EC), and non-stenosis (NS) group. WMH were rated using the semiquantitative method of Scheltens and coworkers. The IC group had significantly more WMH score in comparison with the other groups after controlling age. The linear regression analysis showed that age was the factor most strongly associated with the total score of WMH; and the location of stenosis was positively related to WMH, especially in deep white matter. Our data show that IC stenosis is associated with WMH, indicating that IC stenosis, rather than EC stenosis, is likely to cause white matter lesions. These findings raise the possibility that occlusion of penetrating arteries, embolism to border-zone areas and a hemodynamic mechanism associated with IC stenosis leads to the formation of white matter lesions.

Caffeine, Cognitive Functioning, and White Matter Lesions in the Elderly: Establishing Causality from Epidemiological Evidence

The present study examines the epidemiological evidence for a causal relationship between caffeine consumption and cognitive deterioration in the elderly. Using a population of 641 elderly persons, we examined cognitive functioning, caffeine consumption, magnetic resonance imaging volumetrics, and other factors known to affect cognitive performance. Our findings demonstrate the association between caffeine consumption and lower cognitive change over time to be statistically significant for women only, taking into account multiple confounders, to be dose-dependent and temporarily related (caffeine consumption precedes cognitive change). Mean log transformed white matter lesion/cranial volume ratios were found to be significantly lower in women consuming more than 3 units of caffeine per day after adjustment for age (-1.23 SD=0.06) than in women consuming 2-3 units (-1.04 SD=0.04) or one unit or less (-1.04 SD=0.07, -35% in cm3 compared to low drinkers). This observation is coherent with biological assumptions that caffeine through adenosine is linked to amyloid accumulation and subsequently white matter lesion formation. The significant relationship observed between caffeine intake in women and lower cognitive decline is highly likely to be a true causal relationship and not a spurious association.

Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition

Chronic cerebral ischemia is thought to induce white matter lesions (WMLs), which contribute to subcortical vascular dementia. Although glial activation and protease upregulation are believed to modify WML pathology, effective therapy remains elusive. Here, we compare the efficacy of microglial cell transplantation and mesenchymal stem cell (MSC) transplantation in protecting against WML development in a chronic cerebral hypoperfusion rat model. A microglial cell line (HMO6), MSC cell line (B10) or vehicle (phosphate-buffered saline; PBS) was intravenously injected, and the appearance and severity of WMLs were evaluated. Transplanted HMO6 and B10 cells migrated to sites of WMLs, including the corpus callosum (CC) and caudoputamen (CP), reduced the severity of WMLs, and inhibited the accumulation and activation of microglia and astrocytes. Transplantation of both cell types reduced the level of matrix metalloproteinase (MMP)-2 mRNA in microglia of the CC. MMP-2 protein level and activity were also both greatly reduced in the same region. Our results indicate that transplantation of either microglial cells or mesenchymal stem cells could inhibit chronic cerebral ischemia-induced WML formation by decreasing MMP-2 expression in microglia and decreasing MMP-2 activity in the CC region.

White matter atrophy and lesion formation explain the loss of structural integrity of white matter in aging

The importance of macrostructural white matter changes, including white matter lesions and atrophy, in intact brain functioning is increasingly being recognized. Diffusion tensor imaging (DTI) enables measurement of the microstructural integrity of white matter. Loss of white matter integrity in aging has been reported, but whether this is inherent to the aging process itself or results from specific white matter pathology is unknown. In 832 persons aged 60 years and older from the population-based Rotterdam Study, we measured fractional anisotropy (FA) and directional diffusivities in normal-appearing white matter using DTI. All subjects' DTI measures were projected onto a common white matter skeleton to enable robust voxelwise comparison. With increasing age, multiple regions showed significant decreases in FA or increases in axial or radial diffusivity in normal-appearing white matter. However, nearly all of these regional changes were explained by either white matter atrophy or by white matter lesions; each of which related to changes in distinct brain regions. These results indicate that loss of white matter integrity in aging is primarily explained by atrophy and lesion formation and not by the aging process itself. Furthermore, white matter atrophy and white matter lesion formation relate to loss of integrity in distinct brain regions, indicating the two processes are pathophysiologically different.

Total Cerebral Blood Flow and Total Brain Perfusion in the General Population: The Rotterdam Scan Study

Reduced cerebral perfusion may contribute to the development of cerebrovascular and neurodegenerative diseases. Little is known on cerebral perfusion in the general population, as most measurement techniques are too invasive for application in large groups of healthy individuals. Total cerebral blood flow (tCBF) can be noninvasively measured by magnetic resonance imaging (MRI) but is highly correlated with brain volume. We calculated total brain perfusion by dividing tCBF by brain volume, and we investigated determinants of total brain perfusion in comparison with tCBF. Secondly, we studied whether persons with a low tCBF or low total brain perfusion have a larger volume of white matter lesions (WML). This study is based on 892 persons aged 60 to 91 years from the Rotterdam Study, a population-based cohort study. We performed two-dimensional (2D) phase-contrast MRI for tCBF measurement. Brain volume and WML volume were quantitatively assessed. Cardiovascular determinants were assessed by interview and physical examination. We assessed associations between cardiovascular determinants and flow measures with linear regression models, adjusted for age and sex. Associations between tCBF or total brain perfusion and WML volume were assessed using general linear models. We found that determinants of tCBF and total brain perfusion differed largely due to the large influence of brain volume on tCBF values. Persons with low total brain perfusion had a significantly larger WML volume compared with those with high total brain perfusion. Prospective studies are required to unravel whether hypoperfusion contributes to WML formation or that tissue damage, manifested by WML, leads to brain hypoperfusion.

Progesterone therapy attenuates fetal brain cytokine levels and decreases infection-mediated white matter injury

Maternal infection during pregnancy can contribute to fetal brain injury through initiation of the fetal inflammatory response. We have previously shown that combination antibiotic/interleukin-10 therapy blunts cytokine levels in the fetal brain and reduces white matter lesion formation in pups born to infected dams. This study was designed to test the hypothesis that progesterone attenuates the fetal inflammatory response to infection.