Formation Of White Matter Lesions Research Articles

Brain-derived endothelial cells are neuroprotective in a chronic cerebral hypoperfusion mouse model

Whether organ-specific regeneration is induced by organ-specific endothelial cells (ECs) remains unelucidated. The formation of white matter lesions due to chronic cerebral hypoperfusion causes cognitive decline, depression, motor dysfunction, and even acute ischemic stroke. Vascular ECs are an important target for treating chronic cerebral hypoperfusion. Brain-derived ECs transplanted into a mouse chronic cerebral hypoperfusion model showed excellent angiogenic potential. They were also associated with reducing both white matter lesions and brain dysfunction possibly due to the high expression of neuroprotective humoral factors. The in vitro coculture of brain cells with ECs from several diverse organs suggested the function of brain-derived endothelium is affected within a brain environment due to netrin-1 and Unc 5B systems. We found brain CD157-positive ECs were more proliferative and beneficial in a mouse model of chronic cerebral hypoperfusion than CD157-negative ECs upon inoculation. We propose novel methods to improve the symptoms of chronic cerebral hypoperfusion using CD157-positive ECs.

Progressive Changes in Cerebral Apparent Diffusion Values in Fabry Disease: A 5-Year Follow-up MRI Study.

White matter lesions are commonly found in patients with Fabry disease. Existing studies have shown elevated diffusivity in healthy-appearing brain regions that are commonly associated with white matter lesions, suggesting that DWI could help detect white matter lesions at an earlier stage This study explores whether diffusivity changes precede white matter lesion formation in a cohort of patients with Fabry disease undergoing yearly MR imaging examinations during a 5-year period. T1-weighted anatomic, FLAIR, and DWI scans of 48 patients with Fabry disease (23 women; median age, 44 years; range, 15-69 years) were retrospectively included. White matter lesions and tissue probability maps were segmented and, together with ADC maps, were transformed into standard space. ADC values were determined within lesions before and after detection on FLAIR images and compared with normal-appearing white matter ADC. By means of linear mixed-effects modeling, changes in ADC and ΔADC (relative to normal-appearing white matter) across time were investigated. ADC was significantly higher within white matter lesions compared with normal-appearing white matter (P < .01), even before detection on FLAIR images. ADC and ΔADC were significantly affected by sex, showing higher values in men (60.1 [95% CI, 23.8-96.3] ×10-6mm2/s and 35.1 [95% CI, 6.0-64.2] ×10-6mm2/s), respectively. ΔADC increased faster in men compared with women (0.99 [95% CI, 0.27-1.71] ×10-6mm2/s/month). ΔADC increased with time even when only considering data from before detection (0.57 [95% CI, 0.01-1.14] ×10-6mm2/s/month). Our results indicate that in Fabry disease, changes in diffusion precede the formation of white matter lesions and that microstructural changes progress faster in men compared with women. These findings suggest that DWI may be of predictive value for white matter lesion formation in Fabry disease.

Toward Precision Phenotyping of Multiple Sclerosis.

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.

The Application of Consensus Weighted Gene Co-expression Network Analysis to Comparative Transcriptome Meta-Datasets of Multiple Sclerosis in Gray and White Matter.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination, which leads to the formation of white matter lesions (WMLs) and gray matter lesions (GMLs). Recently, a large amount of transcriptomics or proteomics research works explored MS, but few studies focused on the differences and similarities between GMLs and WMLs in transcriptomics. Furthermore, there are astonishing pathological differences between WMLs and GMLs, for example, there are differences in the type and abundance of infiltrating immune cells between WMLs and GMLs. Here, we used consensus weighted gene co-expression network analysis (WGCNA), single-sample gene set enrichment analysis (ssGSEA), and machine learning methods to identify the transcriptomic differences and similarities of the MS between GMLs and WMLs, and to find the co-expression modules with significant differences or similarities between them. Through weighted co-expression network analysis and ssGSEA analysis, CD56 bright natural killer cell was identified as the key immune infiltration factor in MS, whether in GM or WM. We also found that the co-expression networks between the two groups are quite similar (density = 0.79), and 28 differentially expressed genes (DEGs) are distributed in the midnightblue module, which is most related to CD56 bright natural killer cell in GM. Simultaneously, we also found that there are huge disparities between the modules, such as divergences between darkred module and lightyellow module, and these divergences may be relevant to the functions of the genes in the modules.

AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long term cognitive impairment and memory loss. Inflammasome is an intracellular multi-protein complex that initiates an innate immune response, and is involved in multiple acute and chronic neurological diseases such as ischemic stroke, Alzheimer's disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). While evidence for direct involvement of the inflammasome complex in VaD is lacking, a cytokine profile of plasma from VaD patients found IL-1β to be the most abundant.Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate the effect of chronic cerebral hypoperfusion on the inflammasome signaling pathway. To further examine the functional role of AIM2 inflammasome activation on injury following chronic cerebral hypoperfusion, mice with AIM2 deficiency (AIM2 KO) were studied.Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 KO mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS.Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

Reduction in pericyte coverage leads to blood\u2013brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion

BackgroundChronic cerebral hypoperfusion (CCH) is the leading cause of cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WMLs) in CSVD. However, the effects of CCH on BBB integrity and components and the cellular and molecular mechanisms underlying the effects of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH-induced brain damage has also not been explored.MethodsIn this study, we established a rat model of CSVD via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB were assessed using immunostaining, Western blotting, transmission electron microscopy (TEM) and RNA sequencing. We also observed the protective role of imatinib, a tyrosine kinase inhibitor, on BBB integrity and neuroprotective function following CCH. The data were analyzed using one-way or two-way ANOVA.ResultsWe noted transient yet severe breakdown of the BBB in the corpus callosum (CC) following CCH. The BBB was severely impaired as early as 1 day postoperation and most severely impaired 3 days postoperation. BBB breakdown preceded neuroinflammatory responses and the formation of WMLs. Moreover, pericyte loss was associated with BBB impairment, and the accumulation of serum protein was mediated by increased endothelial transcytosis in the CC. RNA sequencing also revealed increased transcytosis genes expression. BBB dysfunction led to brain damage through regulation of TGF-β/Smad2 signaling. Furthermore, imatinib treatment ameliorated serum protein leakage, oligodendrocyte progenitor cell (OPC) activation, endothelial transcytosis, microglial activation, and aberrant TGF-β/Smad2 signaling activation.ConclusionsOur results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis. Imatinib executes a protective role on the BBB integrity via inhibition of endothelial transcytosis. Maintenance of BBB integrity ameliorates brain damage through regulation of TGF-β/Smad2 signaling following CCH; therefore, reversal of BBB dysfunction may be a promising strategy for CSVD treatment.

Pathogeneses and Imaging Features of Cerebral White Matter Lesions of Vascular Origins.

White matter lesion (WML), also known as white matter hyperintensities or leukoaraiosis, was first termed in 1986 to describe the hyperintense signals on T2-weighted imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) maps. Over the past decades, a growing body of pathophysiological findings regarding WMLs have been discovered and discussed. Currently, the generally accepted WML pathogeneses mainly include hypoxia-ischemia, endothelial dysfunction, blood-brain barrier disruption, and infiltration of inflammatory mediators or cytokines. However, none of them can explain the whole dynamics of WML formation. Herein, we primarily focus on the pathogeneses and neuroimaging features of vascular WMLs. To achieve this goal, we searched papers with any type published in PubMed from 1950 to 2020 and cross-referenced the keywords including “leukoencephalopathy”, “leukoaraiosis”, “white matter hyperintensity”, “white matter lesion”, “pathogenesis”, “pathology”, “pathophysiology”, and “neuroimaging”. Moreover, references of the selected articles were browsed and searched for additional pertinent articles. We believe this work will supply the robust references for clinicians to further understand the different WML patterns of varying vascular etiologies and thus make customized treatment.

AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia.

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response-particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

Sex-specific differences in rim appearance of multiple sclerosis lesions on quantitative susceptibility mapping

BackgroundSusceptibility MRI techniques, such as phase and quantitative susceptibility mapping (QSM) reveal lesion heterogeneity in MS, including the presence of lesions with outer rims suggestive of iron accumulation in macrophages and microglia, indicative of chronic-active inflammatory white matter lesions (WMLs). ObjectiveTo evaluate the in vivo relationship between chronic-active WMLs (as visualized by rimmed lesions on QSM) and several clinical metrics. Methods39 patients (15 men, 24 women) with MS underwent 7 Tesla brain MRIs and clinical evaluation. Contrast patterns of lesions identified on FLAIR and quantitative susceptibility maps were reviewed and compared to demographic characteristics and disability scores. Results1279 lesions were identified on FLAIR MRI; 846 (66.2%) of these were visible on QSM, 119 (14.1%) of which had visible rims. Lesions visible on QSM were more likely to have rims in men (16.1%, vs 4.9% in women, p=0.009). In a logistic regression model accounting for several factors, male sex conferred a >10-fold risk of having ≥1 rimmed lesion(s) (p=0.026). ConclusionOur findings provide in vivo support for the body of histopathologic literature indicating sex-specific differences in MS WML formation and suggest that QSM can be used to study these sex differences in the future.

Is ischemia associated with the formation of White matter lesions in migraine?

ObjectiveWhite matter lesions (WMLs) are more common in migraine patients than in the normal population. Ischemia/hypoxia and oxidative stress are considered to play a role in WMLs formation. This study aimed to investigate ischemia-modified albumin (IMA), ferroxidase and thiol/disulfide homeostasis in migraineurs with and without WMLs. Patients and MethodsSixty-two migraineurs with WML, 59 migraineurs without WML and 61 controls were included in the study. All participants underwent brain MRI. WMLs was evaluated according to the Fazekas scale. IMA, ferroxidase, total thiol, native thiol and disulfide measurements were carried out in all participants. ResultsThe IMA levels were higher in the migraine groups compared to the control group (p < 0.001) and in the WML group compared to non-WML (p < 0.001). The total and native thiol levels were higher in the non-WML group compared to the control and WML groups (p < 0.001 for both). The disulfide levels were similar between the control and non-WML groups, but they were significantly lower in the WML group compared to the control and non-WML groups. There was no significant difference between the groups in terms of the ferroxidase levels (p = 0.092). The thiol/disulfide, IMA and ferroxidase levels were not significantly correlated with the frequency and duration of attacks, severity of pain and disability due to migraine. ConclusionIncreased serum IMA levels in migraineurs point to the role of ischemia/hypoxia, and increased total thiol and decreased disulfide levels indicate an oxidant/antioxidant imbalance in migraine. Ischemia/hypoxia may play a role in WMLs formation in migraine.

Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology (“pure” WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.

60 GENE EXPRESSION AND KETAMINE RESPONSE IN SUBJECTS WITH TREATMENT RESISTANT DEPRESSION

Susceptibility MRI techniques, such as phase and quantitative susceptibility mapping (QSM) reveal lesion heterogeneity in MS, including the presence of lesions with outer rims suggestive of iron accumulation in macrophages and microglia, indicative of chronic-active inflammatory white matter lesions (WMLs).To evaluate the in vivo relationship between chronic-active WMLs (as visualized by rimmed lesions on QSM) and several clinical metrics.39 patients (15 men, 24 women) with MS underwent 7 Tesla brain MRIs and clinical evaluation. Contrast patterns of lesions identified on FLAIR and quantitative susceptibility maps were reviewed and compared to demographic characteristics and disability scores.1279 lesions were identified on FLAIR MRI; 846 (66.2%) of these were visible on QSM, 119 (14.1%) of which had visible rims. Lesions visible on QSM were more likely to have rims in men (16.1%, vs 4.9% in women, p=0.009). In a logistic regression model accounting for several factors, male sex conferred a >10-fold risk of having ≥1 rimmed lesion(s) (p=0.026).Our findings provide in vivo support for the body of histopathologic literature indicating sex-specific differences in MS WML formation and suggest that QSM can be used to study these sex differences in the future.

Intrathecal IgG Synthesis and Persistent Inflammation Are Associated with White Matter Lesions in HIV-negative Patients with Cryptococcal Meningoencephalitis.

Objective Cryptococcal meningoencephalitis (CM) causes significant morbidity and mortality in human immunodeficiency virus (HIV)-negative and HIV-positive populations. White matter lesions (WMLs) have been reported in both populations of CM patients; however, the mechanisms underlying WML formation remain unknown. We herein report the relationship between the intrathecal immune response and the development of WMLs in HIV-negative patients with CM. Methods Eleven consecutive HIV-negative patients with CM who presented at one of three emergency hospitals in Japan from April 2001 to March 2018 were enrolled. For all patients, we retrospectively assessed the relationships between clinical and laboratory information and the presence of WMLs. Results At presentation, 6 patients had WMLs on magnetic resonance imaging (MRI). The cerebrospinal fluid immunoglobulin G (CSF IgG) index was significantly higher in the patients with WMLs than in those without WMLs (mean, 1.34 vs. 0.70, p=0.017). The time from the symptom onset to initial neuroimaging was also significantly longer in the patients with WMLs than in those without WMLs (median, 31.5 vs. 7.0 days; p=0.008). The clinical outcome was comparable among the patients with and without WMLs. Conclusion In HIV-negative patients with CM, a persistent, aberrant immune response to Cryptococcus, such as intrathecal IgG synthesis, may induce WML formation.

Fluid-attenuated inversion recovery MRI synthesis from multisequence MRI using three-dimensional fully convolutional networks for multiple sclerosis

Multiple sclerosis (MS) is a white matter (WM) disease characterized by the formation of WM lesions, which can be visualized by magnetic resonance imaging (MRI). The fluid-attenuated inversion recovery (FLAIR) MRI pulse sequence is used clinically and in research for the detection of WM lesions. However, in clinical settings, some MRI pulse sequences could be missed because of various constraints. The use of the three-dimensional fully convolutional neural networks is proposed to predict FLAIR pulse sequences from other MRI pulse sequences. In addition, the contribution of each input pulse sequence is evaluated with a pulse sequence-specific saliency map. This approach is tested on a real MS image dataset and evaluated by comparing this approach with other methods and by assessing the lesion contrast in the synthetic FLAIR pulse sequence. Both the qualitative and quantitative results show that this method is competitive for FLAIR synthesis.

Clinical Characteristics and Neuroimaging Findings in Internal Jugular Venous Outflow Disturbance.

Recently, internal jugular vein stenosis (IJVS) is gaining increasing attention from clinical researchers due to a series of confounding symptoms that impair the quality of life in affected individuals but cannot be explained by other well-established causes. In this study, we aimed to elucidate the clinical features, neuroimaging characteristics and pathogenesis of IJVS, and explore their possible correlations, in attempt to provide useful clues for clinical diagnosis and treatment. Forty-three eligible patients with unilateral or bilateral IJVS confirmed by contrast-enhanced magnetic resonance venography of the brain and neck were enrolled in this study. Magnetic resonance imaging along with magnetic resonance angiography or computed tomography angiography was applied to identify the radiological pattern of parenchymal or arterial lesions. Cerebral perfusion and metabolism were evaluated by single-photon emission computed tomography (SPECT). Of the 43 patients (46.0 ± 16.0 years old; 30 female), 14 (32.6%) had bilateral and 29 had unilateral IJVS. The common clinical symptoms at admission were tinnitus (60.5%), tinnitus cerebri (67.6%), headache (48.8%), dizziness (32.6%), visual disorders (39.5%), hearing impairment (39.5%), neck discomfort (39.5%), sleep disturbance (60.5%), anxiety or depression (37.5%) and subjective memory decline (30.2%). The presence of bilateral demyelination changes with cloudy-like appearance in the periventricular area and/or centrum semiovale was found in 95.3% (41/43) patients. SPECT findings showed that 92.3% (24/26) patients displayed cerebral perfusion and metabolism mismatch, depicted by bilaterally and symmetrically reduced cerebral perfusion and increased cerebral glucose consumption. IJVS may contribute to alterations in cerebral blood flow and metabolism, as well as white matter lesion formation, all of which may account for its clinical manifestations.

Quantitative analysis of magnetic resonance images during white matter lesion formation in chronic hypertensive model rat

Background: The preclinical diagnosis of hypertensive cerebral vascular dementia (CVD) is important in an aging society. Cerebral white matter lesions (CWMLs) accompanied by hypertension are often visualized by MRI in the early stage, but after the onset of cognitive dysfunction.

Update on disease-modifying therapies for multiple sclerosis

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). It predominantly affects young women and is one of the most common causes of disability in...

Cilostazol reduces blood brain barrier dysfunction, white matter lesion formation and motor deficits following chronic cerebral hypoperfusion

Cerebral small vessel disease (CSVD) is a pathological process leading to lacunar infarcts, leukoaraiosis and cerebral microbleeds. Dysfunction of the blood brain barrier (BBB) has been proposed as a mechanism in the progression cerebral small vessel disease. A rodent model commonly used to study some aspects of CSVD is bilateral common carotid artery occlusion (BCCAO) in the rat. In the present study it was determined that gait impairment, as determined by a tapered beam test, and BBB permeability increased following BCCAO. Cilostazol, a type III phosphodiesterase inhibitor, has been shown to have anti-apoptotic effects and prevent white matter vacuolation and rarefaction induced by BCCAO in rats. In this study the protective effect of cilostazol administration on the increase BBB permeability following BCCAO was determined as well as the effect on plasma levels of circulating microparticles (MPs), cerebral white matter rarefaction, glial activation and gait disturbance. The effect of cilostazol on in vitro endothelial barriers was also evaluated. Cilostazol treatment improved BBB permeability and reduced gait disturbance, visual impairment and microglial activation in optic tract following BCCAO in vivo. It also reduced the degree of cell death and the reduction in trans-endothelial electrical resistance (TEER) in artificial endothelial barriers in vitro induced by MP treatment of in vitro barriers.

White Matter Lesions, Carotid and Coronary Atherosclerosis in Late-Onset Depression and Healthy Controls

Cerebral white matter lesions (WMLs) are more common in individuals with late-onset or late-life depression. It has been proposed that carotid atherosclerosis may predispose to WMLs by inducing cerebral hypoperfusion. This hemodynamic effect of carotid atherosclerosis could be important for the formation of WMLs in depression. The case-control study included 29 patients with late-onset major depressive disorder and 27 controls matched for sex, age, and tobacco use. WML volume, carotid intima-media thickness, and coronary plaque volume were assessed using magnetic resonance imaging, ultrasound scan, and coronary computed tomography (CT) angiography, respectively. The mean age for the total sample was 59.7 ± 4.7 years. There was no difference in carotid intima-media thickness between patients and controls (p = 0.164), whereas a higher WML volume in the patients was found (p = 0.051). In both patients and controls, WML volume was associated with carotid but not with coronary atherosclerosis. In adjusted multiple linear regression, a 0.1mm increase in averaged carotid intima-media thickness was associated with a 52% (95% CI: 8.4-112, p = 0.032) increase in WML volume. The association between carotid intima-media thickness and WML volume was, however, similar in patients and controls. In older persons aged between 50 and 70 years, WMLs do not seem to be a part of generalized atherosclerotic disease, but seem to be dependent on atherosclerosis in the carotid arteries. Carotid atherosclerosis, however, could not explain the higher WML load observed in the depressed patients, and thus, studies are needed to establish the mechanisms linking depression and WMLs.

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.