White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease.

INTRODUCTION: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. METHODS: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. RESULTS: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (ß = -0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: ß = -0.03, p = 0.003, C20: ß = -0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (ß = -0.0103, p = 0.027). CONCLUSIONS: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.

The Association between Cerebral Small Vessel Disease and the Gut Microbiome: A Cross-Sectional Analysis.

BACKGROUND: Recent studies have demonstrated an association between the gut microbiome and cognitive function. However, the associations between the gut microbiome and brain parenchyma damage, and their underlying mechanisms, remain unclear. MATERIALS AND METHODS: We performed a cross-sectional sub-analysis using data from our prospective cohort study to determine the association between the gut microbiome and cerebral small vessel disease (SVD). We assessed patient demographics, risk factors, cognitive function, brain imaging, voxel-based specific regional analysis system for Alzheimer's Disease (VSRAD, indicating brain atrophy), and the gut microbiome as indicated by enterotypes and faecal microbiome metabolites. We then analysed the associations between total SVD scores, cognitive function, and the gut microbiome. RESULTS: We analysed data from 87 patients without dementia or a history of stroke, 64 of whom exhibited mild cognitive impairment. Higher total SVD scores were associated with cognitive decline and behavioural and psychological symptoms. Compared with all other patients, patients with enterotype I (Bacteroides >30%) were more likely to have cognitive decline (median scores: Mini-Mental State Examination, 25 vs. 27, P = 0.047; Clinical Dementia Rating-Sum of Boxes, 1.5 vs. 0.5, P = 0.002) and present with cerebral SVD and high VSRAD scores (1.01 vs. 0.57, P = 0.012). Furthermore, faecal metabolites were significantly higher in patients with higher total SVD scores compared with those with lower scores. Multivariable logistic regression analyses indicated that certain gut microbiomes may double the risk of white matter hyperintensity. CONCLUSIONS: The gut microbiome is associated with cerebral SVD.

Homocysteine is Associated with the Development of Cerebral Small Vessel Disease: Retrospective Analyses from Neuroimaging and Cognitive Outcomes.

OBJECTIVE: As the population ages, a growing burden of cerebral small vessel disease (cSVD) has sparked extensive concerns recently. Homocysteine (Hcy), as a traditional risk factor for atherosclerosis, may also participate in the development of cSVD. By comprehensively assessing Hcy's correlation with different MRI markers of cSVD and cognitive outcomes in a homogeneous population with cSVD, this study aims to explore the value of Hcy in the clinical management of cSVD. METHODS: 231 inpatients with MRI-confirmed cSVD were enrolled in this retrospective study (mean age 66.4±10.0 years, male sex 47.6%). Along with brain MRI and plasma total Hcy (tHcy) examination, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were also performed to assess their global cognitive function. Burdens of cSVD neuroimaging features encompassing white matter hyperintensity (WMH), lacunes of presumed vascular origin, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS) were evaluated based on brain MRI demonstrations. RESULTS: After adjusting for possible confounders, statistical analyses showed that plasma tHcy levels were not only correlated with burdens of deep/periventricular WMH (P < 0.001, P for trend < 0.001; P < 0.001, P for trend < 0.001), lacunes (P < 0.001, P for trend < 0.001), lobar CMBs (P = 0.002), and EPVS in the basal ganglia (P < 0.001, P for trend = 0.002) but also remained an independent predictor of cognitive impairment (B=-0.159, 95%CI -0.269--0.049, P = 0.005, P for trend < 0.001) in the patients with cSVD. CONCLUSIONS: Plasma tHcy levels are associated with the development of cSVD in a dose-independent manner and may predict the cognitive outcomes in cSVD patients. These findings provide a potential clue to cSVD's physiopathology and future disease management.

Systemic features of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations: a monogenic small vessel disease.

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a small vessel disease caused by C-terminal truncating TREX1 mutations. The disease is typically characterized by vascular retinopathy and focal and global brain dysfunction. Systemic manifestations have also been reported but not yet systematically investigated. METHODS: In a cross-sectional study, we compared the clinical characteristics of 33 TREX1 mutation carriers (MC+) from three Dutch RVCL-S families with those of 37 family members without TREX1 mutation (MC-). All participants were investigated using personal interviews, questionnaires, physical, neurological and neuropsychological examinations, blood and urine tests, and brain MRI. RESULTS: In MC+, vascular retinopathy and Raynaud's phenomenon were the earliest symptoms presenting from age 20 onwards. Kidney disease became manifest from around age 35, followed by liver disease, anaemia, markers of inflammation and, in some MC+, migraine and subclinical hypothyroidism, all from age 40. Cerebral deficits usually started mildly around age 50, associated with white matter and intracerebral mass lesions, and becoming severe around age 60-65. CONCLUSIONS: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations is a rare, but likely underdiagnosed, systemic small vessel disease typically starting with vascular retinopathy, followed by multiple internal organ disease, progressive brain dysfunction, and ultimately premature death.

Modifiable vascular risk factors, white matter disease and cognition in early Parkinson's disease.

BACKGROUND AND PURPOSE: Dementia in Parkinson's disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors (VRFs) may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of VRFs on PD are needed. To that end, we aimed to quantitate white matter hyperintensities (WMH) in early PD, measure associations with VRFs and examine relationships between WMH and longitudinal cognition. METHODS: Participants in the Parkinson's Progression Markers Initiative study (141 patients with PD, 63 healthy controls) with adequate baseline structural brain magnetic resonance imaging data were included. Hypertension and diabetes history, and body mass index were combined to create a vascular risk score. WMH were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery. RESULTS: In the PD group, vascular risk score was associated with WMH for total brain (ß = 0.210; P = 0.021), total white matter (ß = 0.214; P = 0.013), frontal (ß = 0.220; P = 0.002) and temporal (ß = 0.212; P = 0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (ß = -0.040; P = 0.007) and greater WMH (ß = -0.029; P = 0.049). Higher temporal WMH burden was associated with great decline over time in verbal memory (ß = -0.034; P = 0.031). CONCLUSIONS: In early PD, modifiable VRFs are associated with WMH on brain magnetic resonance imaging. Temporal WMH burden predicts decline in verbal memory. WMH may serve as a surrogate marker for the effect of VRFs on cognitive abilities in PD.

A Case of Leukoencephalopathy and Small Vessels Disease Caused by a Novel HTRA1 Homozygous Mutation.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a heritable, rare small vessel disease, which is caused by HTRA1 mutations and mostly reported Japanese and Chinese population. CARASIL is an orphan disease, which presents with progressive motor and cognitive impairment, alopecia, and spondylosis. The disease typically starts with lumbago at early twenties. Ischemic strokes start at mid-twenties. Patients have no cardiovascular or any other risk factors. Multiple lacunar infarcts and leukoencephalopathy cause progressive neurologic involvement. Leukoencephalopathy and small vessel disease without any risk factors is a significant finding for the differential diagnosis of HTRA1 gene pathology. This report presents clinical and genetic features of a rare case of typical CARASIL from Turkey who was followed with uncertain diagnoses for years.

The Impact of Covert Lacunar Infarcts and White Matter Hyperintensities on Cognitive and Motor Outcomes After Stroke.

BACKGROUND AND AIMS: In addition to overt stroke lesions, co-occurring covert lesions, including white matter hyperintensities (WMH) and covert lacunar infarcts (CLI), contribute to poststroke outcome. The purpose of this study was to examine the relationship between covert lesions, and motor and cognitive outcomes in individuals with chronic stroke. METHODS: Volumetric quantification of clinically overt strokes, covert lesions (periventricular and deep: pWMH, dWMH, pCLI, dCLI), ventricular and sulcal CSF (vCSF, sCSF), and normal appearing white (NAWM) and gray matter (NAGM) was performed using structural magnetic resonance imaging. We assessed motor impairment and function, and global cognition, memory, and other cognitive domains. When correlation analysis identified more than one MR parameter relating to stroke outcomes, we used regression modeling to identify which factor had the strongest impact. RESULTS: Neuropsychological and brain imaging data were collected from 30 participants at least 6 months following a clinically diagnosed stroke. Memory performance related to vCSF (r = -0.52, P = .004). The strongest predictor of nonmemory domains was pCLI (r2 = 0.28, P = .004). Motor impairment and function were most strongly predicted by the volume of stroke and NAWM (r2 = 0.36; P = .001), and dWMH (r2 = 0.39; P = .001) respectively. CONCLUSIONS: Covert lesion type and location have important consequences for post-stroke cognitive and motor outcome. Limiting the progression of covert lesions in aging populations may enhance the degree of recovery post-stroke.

White Matter Hyperintensity-Associated Blood-Brain Barrier Disruption and Vascular Risk Factors.

BACKGROUND: White matter hyperintensities (WMH), the hallmark of vascular cognitive impairment, are associated with vascular risk factors (VRF). WMH can also be associated with blood-brain barrier (BBB) disruption. The purpose of this study was to look for associations between VRF and BBB disruption in stroke patients with WMH. METHODS: Magnetic resonance images of stroke patients were reviewed for the presence of WMH. Blood-brain permeability images were retrospectively generated. The degree of BBB permeability was compared with the presence of VRF using logistic regression. Patterns and extent of WMH were classified using Fazekas scores. RESULTS: Sixty-five patients were included in this study. None of the VRF tested were associated with an increase in BBB disruption. Hypertension was significantly associated with less BBB disruption (P = .04). Nonhypertensive patients in our study had a different pattern of WMH than hypertensive patients, with less involvement of the periventricular white matter. CONCLUSIONS: We found that in stroke patients with WMH, those with hypertension had less BBB disruption and greater involvement of the periventricular white matter when compared with patients who did not have a history of hypertension. Further investigation is needed to determine if the development of WMH in stroke patients with a history of hypertension has a different pathophysiology from patients who develop WMH in the absence of hypertension.

Using DTI to assess white matter microstructure in cerebral small vessel disease (SVD) in multicentre studies.

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized ß =0.268), mental flexibility (ß =0.306), verbal fluency (ß =0.376), and Montreal Cognitive Assessment (MoCA) (ß =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies.

Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia.

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid ß (Aß) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

Chronic Use of Aspirin and Total White Matter Lesion Volume: Results from the Women's Health Initiative Memory Study of Magnetic Resonance Imaging Study.

OBJECTIVE: To investigate the relationship between aspirin and subclinical cerebrovascular heath, we evaluated the effect of chronic aspirin use on white matter lesions (WML) volume among women. METHODS: Chronic aspirin use was assessed in 1365 women who participated in the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Differences in WML volumes between aspirin users and nonusers were assessed with linear mixed models. A number of secondary analyses were performed, including lobe-specific analyses, subgroup analyses based on participants' overall risk of cerebrovascular disease, and a dose-response relationship analysis. RESULTS: The mean age of the women at magnetic resonance imaging examination was 77.6 years. Sixty-one percent of participants were chronic aspirin users. After adjusting for demographic variables and comorbidities, chronic aspirin use was nonsignificantly associated with 4.8% (95% CI: -6.8%, 17.9%) larger WML volumes. These null findings were confirmed in secondary and sensitivity analyses, including an active comparator evaluation where aspirin users were compared to users of nonaspirin nonsteroidal anti-inflammatory drugs or acetaminophen. CONCLUSIONS: There was a nonsignificant difference in WML volumes between aspirin users and nonusers. Further, our results suggest that chronic aspirin use may not have a clinically significant effect on WML volumes in women.

Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. METHODS: Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. RESULTS: Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. CONCLUSIONS: The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.

White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis.

BACKGROUND: While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. OBJECTIVE: The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. METHODS: Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). RESULTS: A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance (R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. CONCLUSION: Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients.

The Cognition and Affect after Stroke - a Prospective Evaluation of Risks (CASPER) study: rationale and design.

BACKGROUND: Cognitive impairment and neuropsychiatric syndromes, like depression and apathy, are frequent residual consequences of stroke. These have a large impact on quality of life and long-term prognosis. Several factors are involved in the development of these residual syndromes, although their exact role and their interrelationships remain still rather unclear. The Cognition and Affect after Stroke: a Prospective Evaluation of Risks (CASPER) study has been primarily designed to examine whether stroke-specific (e.g. lesion location, volume, type, severity), cerebrovascular and neurodegenerative (e.g. white matter changes, atrophy, microbleeds, perivascular spaces), inflammatory, endothelial, and (epi)genetic markers are associated with cognitive impairment, post-stroke depression, and post-stroke apathy, and whether they predict their course over 12 months. The secondary aims are to investigate how the above-mentioned markers interact with each other, and to determine if patients with apathy and depression after stroke differ in pathogenesis, course, and outcome (e.g. functional outcome, neurocognitive performance, quality of life). METHODS/DESIGN: CASPER is a 1-year prospective clinical cohort follow-up study in 250 stroke patients recruited at the neurological in- and outpatient services at Maastricht University Medical Center (MUMC+, Maastricht, The Netherlands), and Zuyderland Medical Center (Sittard and Heerlen, The Netherlands). At baseline (3 months post-stroke), a neuropsychological assessment, neuropsychiatric interview, blood sample, and brain magnetic resonance imaging (MRI) scan are conducted. Assessment of neuropsychiatric and neurocognitive status are repeated 6 and 12 months later. DISCUSSION: The CASPER study investigates stroke-specific, vascular, neurodegenerative, inflammatory, and genetic markers of the development of vascular cognitive impairment, depression, and apathy after stroke. This creates the possibility to study not only the contribution of these individual markers but also their joint contribution, which differentiates this study from earlier stroke cohorts who lacked long-term follow-up data, a large sample size, an extensive MRI protocol, and markers from the blood. The knowledge we derive from this study might help in identifying markers that are associated with, or can predict the onset, maintenance, and progression of vascular cognitive impairment, depression, and apathy after stroke, and could provide new insights into possibilities for treatment and rehabilitation that result in better functional outcome after stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT02585349.

A Novel Brainstem Hemorrhage Model by Autologous Blood Infusion in Rat: White Matter Injury, Magnetic Resonance Imaging, and Neurobehavioral Features.

BACKGROUND: Primary brainstem hemorrhage (BSH) has the highest mortality and morbidity as a subtype of intracerebral hemorrhage. A major limitation of BSH research is the lack of a corresponding animal model. The purpose of this study was to establish a novel rat model of BSH and to characterize the resulting brain injury, especially focusing on white matter injury. METHODS: BSH was produced by stereotactically injecting autologous whole blood into the pons. Time course of hematoma resolution was observed by 7-T magnetic resonance imaging. White matter injury was evaluated in detail by multiple parameters including diffuse tensor imaging (DTI), demyelination, axonal injury, oligodendrocyte degeneration, and oligodendrocyte precursor cell proliferation. Brain water content and neurobehavior were also evaluated. RESULTS: Blood infusion (30 µL) led to a stable, reproducible hematoma in the right basotegmental pons. The hematoma absorption started, became obvious, and was nearly completed at 7, 14, and 30 days, respectively. Hematoma caused obvious brain edema at 3 days. White mater injury was observed pathologically, which was in line with decreased fractional anisotropy (FA) in DTI in the pons. FA reduction was also noticed in the cerebral peduncle and medulla. Behavioral abnormality persisted for at least 14 days and neurofunction was recovered within 1 month. CONCLUSIONS: This novel model can produce a stable hematoma resulting in brain edema, white matter injury, and neurofunctional deficits, which could be useful for future investigation of pathophysiological mechanisms and new treatment evaluation after BSH.

Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP).

Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/- mice may play a central role in ALSP pathology.

Cerebral white matter lesions in patients with cirrhosis - causative for hepatic encephalopathy or bystanders?

BACKGROUND & AIMS: Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function. METHODS: 55 cirrhotic patients underwent neurological examination, psychometric testing and magnetic resonance imaging. T2-weighted images were reviewed for white matter lesions by a neuroradiologist and a neurologist, independently. Patients were allocated into three groups: (i) no or <5, (ii) 6-15 and (iii) more than 15 lesions. Allocation was confirmed by a senior neuroradiologist blinded for the clinical data. The patient groups were compared concerning age, underlying liver disease, mortality, MELD Score, history of HE, treatment for HE, cerebrovascular risk factors and psychometric test results. Regression analysis was performed to identify risk factors for the presence and extent of white matter lesions. RESULTS: Patient groups 2 and 3 were older and showed worse results in the psychometric tests than group 1 (P < 0.05). Correlation analyses showed a significant relationship between the number of white matter lesions and the grade of HE (P < 0.001) and cognitive function (P < 0.05), but no interrelationship between the lesions and cerebrovascular risk factors or other factors tested. CONCLUSIONS: Focal white matter lesions in patients with cirrhosis do not represent cerebrovascular small-vessel disease but are related to the pathology of HE. Further studies are needed to clarify the mechanisms behind in detail.

Reduced white matter integrity and cognitive deficits in maintenance hemodialysis ESRD patients: a diffusion-tensor study.

OBJECTIVES: The purpose of this investigation was to examine the association between cognition disorders and microstructural white matter (WM) changes in maintenance hemodialysis end-stage renal disease (ESRD) patients. METHODS: Twenty-six maintenance hemodialysis ESRD patients and 28 healthy controls underwent diffusion tensor imaging (DTI), Mini Mental State Examination (MMSE), Trial Marking Test-A&B (TMT-A&B), and white matter hyperintensity (WMH) assessment. Tract-based spatial statistics (TBSS) analyses was performed to evaluate WM changes in the patients. Relationships between behavioural performances, clinical data, and the DTI index were tested, respectively, by correlation analysis at the voxel level. RESULTS: ESRD patients showed significant decreased fractional anisotropy (FA) in 14 WM regions, and increased mean diffusivity (MD) and radial diffusivity (RD) in widespread regions. Significant positive correlations between FA values and MMSE scores were found in the right anterior corona radiata and the left anterior thalamic radiation; significant negative correlations between the TMT-B time consumption and FA values were identified in the bilateral superior longitudinal fasciculus. Positive linear relationships between MD, RD values, and the duration of hemodialysis were found in several WM regions. CONCLUSION: Structural damages to radiation and associative fibre tracts, caused by brain oedema and WM demyelination, may account for the cognitive deficits in ESRD patients.