Age-related White Matter Lesions Research Articles

Hexahydrocurcumin attenuated demyelination and improved cognitive impairment in chronic cerebral hypoperfusion rats.

Age-related white matter lesions (WML) frequently present vascular problems by decreasing cerebral blood supply, resulting in the condition known as chronic cerebral hypoperfusion (CCH). This study aimed to investigate the effect of hexahydrocurcumin (HHC) on the processes of demyelination and remyelination induced by the model of the Bilateral Common Carotid Artery Occlusion (BCCAO) for 29days to mimic the CCH condition. The pathological appearance of myelin integrity was significantly altered by CCH, as evidenced by Transmission Electron Microscopy (TEM) and Luxol Fast Blue (LFB) staining. In addition, CCH activated A1-astrocytes and reactive-microglia by increasing the expression of Glial fibrillary acidic protein (GFAP), complement 3 (C3d) and pro-inflammatory cytokines. However, S100a10 expression, a marker of neuroprotective astrocytes, was suppressed, as were regenerative factors including (IGF-1) and Transglutaminase 2 (TGM2). Therefore, the maturation step was obstructed as shown by decreases in the levels of myelin basic protein (MBP) and the proteins related with lipid synthesis. Cognitive function was therefore impaired in the CCH model, as evidenced by the Morris water maze test. By contrast, HHC treatment significantly improved myelin integrity, and inhibited A1-astrocytes and reactive-microglial activity. Consequently, pro-inflammatory cytokines and A1-astrocytes were attenuated, and regenerative factors increased assisting myelin maturation and hence improving cognitive performance. In conclusion, HHC improves cognitive function and also the integrity of white matter in CCH rats by reducing demyelination, and pro-inflammatory cytokine production and promoting the process of remyelination.

Correction for: Integrated analysis of microRNA and mRNA expression profiling identifies BAIAP3 as a novel target of dysregulated hsa-miR-1972 in age-related white matter lesions.

Correction for: Integrated analysis of microRNA and mRNA expression profiling identifies BAIAP3 as a novel target of dysregulated hsa-miR-1972 in age-related white matter lesions.

Integrated analysis of microRNA and mRNA expression profiling identifies BAIAP3 as a novel target of dysregulated hsa-miR-1972 in age-related white matter lesions.

White matter lesions known as leukoaraiosis (LA) are cerebral white matter hyperintensities observed in elderly individuals. Currently, no reliable molecular biomarkers are available for monitoring their progression over time. To identify biomarkers for the onset and progression of LA, we analyzed whole blood-based, microRNA expression profiles of leukoaraiosis, validated those exhibiting significant microRNA changes in clinical subjects by means of quantitative real-time polymerase chain reactions and determined the function of miRNA in cell lines by means of microRNA mimic transfection assays. A total of seven microRNAs were found to be significantly down-regulated in leukoaraiosis. Among the microRNAs, hsa-miR-1972 was downregulated during the early onset phase of leukoaraiosis, as confirmed in independent patients, and it was found to target leukoaraiosis-dependent BAIAP3, decreasing its expression in 293T cell lines. Functional enrichment analysis revealed that significantly dysregulated miRNAs-mRNAs changes associated with the onset of leukoaraiosis were involved in neurogenesis, neuronal development, and differentiation. Taken together, the study identified a set of candidate microRNA biomarkers that may usefully monitor the onset and progression of leukoaraiosis. Given the enrichment of leukoaraiosis-associated microRNAs and mRNAs in neuron part and membrane system, BAIAP3 could potentially represent a novel target of hsa-miR-1972 in leukoaraiosis through which microRNAs are involved in the pathogenesis of white matter lesions.

Gadolinium leakage in ocular structures: A novel MRI finding in transient global amnesia

Background and purposeWe investigated the frequency and pattern of blood-brain barrier as well as blood-retina barrier impairment in transient global amnesia (TGA) as demonstrated by hyperintense acute reperfusion marker (HARM) and gadolinium leakage in ocular structures (GLOS) respectively on fluid attenuated inversion recovery images (FLAIR). MethodsPatients with TGA who underwent repeated MRI after intravenous contrast agent administration were identified and the presence of GLOS in the anterior chamber and vitreous body and HARM noted on FLAIR. ResultsOverall 10 patients (IQR 64.25–71.75 years; 4 (40%) patients were male) were included. On contrast-enhanced FLAIR, GLOS was observed in 3 (30%) patients; in all of these in the anterior chamber and vitreous body as well as bilateral and symmetrical. HARM was observed in none of the patients. Frequency of hippocampal DWI lesions, as well as extent of age related white matter lesions did not differ significantly between patients with and without GLOS. ConclusionsIn contrast to HARM, GLOS is a relatively common finding in TGA patients. As GLOS is thought to share its pathophysiology at least to some extent with HARM and is associated with HARM in ischemic stroke, it might be used as surrogate marker for blood-brain barrier impairment in TGA.

Quantitative histomorphometry of capillary microstructure in deep white matter.

White matter lesions represent a major risk factor for dementia in elderly people. Magnetic Resonance Imaging (MRI) studies have demonstrated cerebral blood flow reduction in age-related white matter lesions, indicating that vascular alterations are involved in developing white matter lesions. Hypoperfusion and changes in capillary morphology are generally linked to dementia. However, a quantitative study describing these microvascular alterations in white matter lesions is missing in the literature; most previous microvascular studies being on the cortex. The aim of this work is to identify and quantify capillary microstructural changes involved in the appearance of deep subcortical lesions (DSCL). We characterize the distribution of capillary diameter, thickness, and density in the deep white matter in a population of 75 elderly subjects, stratified into three equal groups according to DSCL: Control (subject without DSCL), Lesion (sample presenting DSCL), and Normal Appearing White Matter (NAWM, the subject presented DSCL but not at the sampled tissue location). Tissue samples were selected from the Cognitive Function and Aging Study (CFAS), a cohort representative of an aging population, from which immunohistochemically-labeled histological images were acquired. To accurately estimate capillary diameters and thicknesses from the 2D histological images, we also introduce a novel semi-automatic method robust to non-perpendicular incidence angle of capillaries into the imaging plane, and to non-circular deformations of capillary cross sections. Subjects with DSCL presented a significant increase in capillary wall thickness, a decrease in the diameter intra-subject variability (but not in the mean), and a decrease in capillary density. No significant difference was observed between controls and NAWM. Both capillary wall thickening and reduction in capillary density contribute to the reduction of cerebral blood flow previously reported for white matter lesions. The obtained distributions provide reliable statistics of capillary microstructure useful to inform the modeling of human cerebral blood flow, for instance to define microcirculation models for their estimation from MRI or to perform realistic cerebral blood flow simulations.

The relationship between the severity of white matter lesions and clinical characteristics of cognitive impairment in different age groups

Objective To explore the clinical characteristics of cognitive impairment in different age groups with the same severity of white matter lesions. Methods This study involved 110 consecutively recruited patients with white matter lesions(WMLs)from the Department of Neurology at Beijing Tiantan Hospital from August 2014 to March 2017.Patients were aged from 50 to 85 with a mean age of 63.1±9.7, and they were divided into an elderly group with a mean age of 71.6±5.2(range: 65-85 years)and a middle aged group with a mean age of 54.8±3.4(range: 50-60 years). The severity of white matter lesions was evaluated with the Fazekas scale.MoCA was used to evaluate the cognitive function of patients. Results For Fazekas 1, the MoCA score was 25.5±2.2 in the elderly group and 28.1±1.4 in the middle aged group(t=6.946, P=0.000); the score for visuospatial and execution abilities was 3.8±0.9 in the elderly group and 4.5±0.6 in the middle aged group(t=3.726, P=0.023); the score for delayed memory was 2.7±1.5 in the elderly group and 4.0±1.0 in the middle aged group(t=4.365, P=0.018). For Fazekas 2, the MoCA score was 22.5±2.5 in the elderly group and 24.1±1.5 in the middle aged group(t=3.361, P=0.034); the score for visuospatial and execution abilities was 2.8±1.2 in the elderly group and 3.8±0.8 in the middle aged group(t=6.473, P=0.007); the score for concentration was 4.6±1.3 in the elderly group and 5.6±0.5 in the middle aged group(t=0.491, P=0.721). For Fazekas 3: the MoCA score was 15.2±3.4 in the elderly group and 19.4±2.8 in the middle aged group(t=4.709, P=0.001); the score for visuospatial and execution abilities was 1.8±1.1 in the elderly group and 2.8±1.4 in the middle aged group(t=1.563, P=0.043); the score for concentration was 3.3±1.1 in the elderly group and 4.4±1.4 in the middle aged group(t=2.231, P=0.026); the score for orientation was 4.2 ±1.3 in the elderly group and 5.7±0.5 in the middle aged group (t=3.255, P=0.000). Conclusions WMLs can increase the risk of vascular cognitive impairment and cause decline in multiple cognitive functions in both middle aged and elderly people.Cognitive dysfunction in age-related WMLs is mainly characterized by impairment in visuospatial and execution abilities. Key words: White matter lesions; Cognitive impairment; Age

P.071 Multi-parametric MRI at 7 T enables differentiation of MS and age-related white matter lesions

Background: MRI criteria are used to support multiple sclerosis diagnosis and evolution. However, normal age-related lesions (ARLs) can be cofounded with MS white matter lesion (MSL). Methods: Two Multiparametric 7T MRI scans 4 motnhs apart from 5 relapsing MS (RMS) patients were analyzed and compared to 5 matched healthy controls (HC) aiming to differentiate MSLs from ARLs. Six-echo GRE, FLAIR and MPRAGE sequences were acquired. Results: Average size of ARLs was 51 mm3 and of MSLs was 69 mm3 (p=0.27). Both have the same general appearance on FLAIR and MPRAGE contrasts, but different contrast on the R2* and QS maps. Inter-visit variation on MPRAGE was significantly higher in MSLs. Inter-visit signal change in the other contrasts (QSM, R2* and FLAIR) was not significant. Conclusions: R2*, QS maps and inter-visit variation using MPRAGE allowed differentiating MSLs from ARLs in 5 RMS with mean long term disease duration. This could improve correct early diagnosis and accurate lesion load accumulation evolution.

Late-onset major depression is associated with age-related white matter lesions in the brainstem.

Age-related white matter lesions (ARWMLs) have been identified in various clinical conditions such as reduced gait speed, cognitive impairment, urogenital dysfunction, and mood disturbances. Previous studies indicated an association between ARWML and late-onset major depression. However, most of these focused on the extent of supratentorial ARWML and neglected presence and degree of infratentorial lesions. In 45 patients (mean age 73.7 ± 6.3 years, 17 (37.8%) men, 28 (62.2%) women) with late-onset major depression, MRI findings (3.0-T MR system, Magnetom Trio, Siemens Medical Systems, Erlangen, Germany) were analyzed with emphasis on the extent of supratentorial and infratentorial, as well as brainstem ARWMLs, and compared with control subjects. ARWMLs were determined by semiquantitative rating scales (modified Fazekas rating scale, Scheltens' rating scale), as well as a semiautomatic volumetric assessment, using a specific software (MRIcron). Supratentorial and infratentorial, as well as brainstem ARWMLs, were assessed both on fluid attenuated inversion recovery and T2-weighted images. Patients with late-onset major depression had significantly higher infratentorial ARWML rating scores (5 (5-7) vs 4.5 (3-6), p = 0.003) on T2-weighted images and volumes (1.58 ± 1.35 mL vs 1.05 ± 0.81 mL, p = 0.03) on T2-weighted images, as well as fluid attenuated inversion recovery images (2.07 ± 1.35 mL vs 1.52 ± 1.10 mL, p = 0.04), than normal controls. In more detail, in particular, the pontine ARWML rating subscore was significantly higher in patients with late-onset major depression (1 (1-2) vs 1 (1-1), p = 0.004). The extent and localization of brainstem ARWML might be of importance for the pathophysiology of late-onset major depression. In particular, this may hold true for pontine ARWML. Copyright © 2016 John Wiley & Sons, Ltd.

White Matter Lesion Assessment in Patients with Cognitive Impairment and Healthy Controls: Reliability Comparisons between Visual Rating, a Manual, and an Automatic Volumetrical MRI Method—The Gothenburg MCI Study

Age-related white matter lesions (WML) are a risk factor for stroke, cognitive decline, and dementia. Different requirements are imposed on methods for the assessment of WML in clinical settings and for research purposes, but reliability analysis is of major importance. In this study, WML assessment with three different methods was evaluated. In the Gothenburg mild cognitive impairment study, MRI scans from 152 participants were used to assess WML with the Fazekas visual rating scale on T2 images, a manual volumetric method on FLAIR images, and FreeSurfer volumetry on T1 images. Reliability was acceptable for all three methods. For low WML volumes (2/3 of the patients), reliability was overall lower and nonsignificant for the manual volumetric method. Unreliability in the assessment of patients with low WML with manual volumetry may mainly be due to intensity variation in the FLAIR sequence used; hence, intensity standardization and normalization methods must be used for more accurate assessments. The FreeSurfer segmentations resulted in smaller WML volumes than the volumes acquired with the manual method and showed deviations from visible hypointensities in the T1 images, which quite likely reduces validity.

Genetics of age-related white matter lesions from linkage to genome wide association studies

White matter lesions are a frequent phenomenon in the elderly and contribute to the development of disability. The mechanisms underlying these brain lesions are still not fully understood with age and hypertension being the most well established risk factors. The heritability of white matter lesions is consistently high in different populations. Candidate gene studies strongly support the role of genes involved in the renin–angiotensin system, as well as Notch3 signaling. The recent genome wide association study by the CHARGE consortium identified a novel locus on chromosome 17q25 harboring several genes such as TRIM65 and TRIM47 which pinpoint to possible novel mechanisms leading to white matter lesions.

Callosal tissue loss parallels subtle decline in psychomotor speed. A longitudinal quantitative MRI study. The LADIS Study

Cross-sectional studies have suggested that corpus callosum (CC) atrophy is related to impairment in global cognitive function, mental speed, and executive functions in the elderly. Longitudinal studies confirming these findings have been lacking. We investigated whether CC tissue loss is associated with change in cognitive performance over time in subjects with age-related white matter lesions (WML). Two-hundred-fifty-three subjects, aged 65–84 years, were evaluated by using repeated MRI and neuropsychological evaluation at baseline and after 3 years. The effect of overall and regional CC tissue loss on cognitive decline was analyzed with hierarchical linear regression models. After controlling for age, sex, education, and baseline cognitive performance, the rates of tissue loss in the total CC area, and in rostrum/genu and midbody subregions were significantly associated with decline in a compound measure of cognitive speed and motor control, but not in those of executive functions, memory, or global cognitive function. Total CC area and midbody remained significant predictors of speed also after adjusting for baseline WML volume, WML progression, and global brain atrophy. However, the relationship between anterior CC and speed performance was mediated by WML volume. In conclusion, the overall and regional rate of CC tissue loss parallels longitudinal slowing of psychomotor performance. The adverse effect of CC tissue loss on psychomotor function may be driven by altered interhemispheric information transfer between homologous cortical areas.

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3′-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3′-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.

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

: 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.

Automated classification of periventricular and subcortical white matter lesions on MRI

Age-related white matter lesions (WMLs) are often subdivided into periventricular and subcortical WMLs. We previously reported that periventricular lesions seem more relevant for cognitive decline and dementia. However, whether this differentiation is relevant remains debated. The interpretation of studies on the discrepancies in aetiology and clinical course is impeded by the use of different visual classification methods with limited reproducibility. We developed a fully automated method to classify periventricular and subcortical WMLs and validated this against the results from a visual rating. The automated classification method was developed and tested on 490 persons from the Rotterdam Scan Study, a population-based cohort study on diseases among the elderly. For each subject 3 different MR sequences, a WML segmentation obtained with an automated method, and a semi-quantitative lesion classification by two trained observers were available. For the automated WML classification, the lesions were classified based on their three-dimensional distance to the ventricles, which were segmented using an automated method. Maximizing the Pearson correlation coefficient between the automatically classified WML volumes and the rating assigned by the observers on a random subset of 100 subjects, suggested a distance of 7mm as the optimal cut-off distance to distinguish periventricular from subcortical WMLs. This was validated in the remaining 390 persons by computing correlations between the automated and observer-based lesion scores. Subsequently, we assessed whether the automated classification replicated previous findings of a different effect of periventricular and subcortical lesion loads on the risk of dementia. Correlation coefficients between automated and visual ratings were 0.71 (p-value<0.001) for periventricular WMLs and 0.60 (p-value<0.001) for subcortical WMLs. The hazard ratios of dementia per standard deviation increase, adjusted for sex and age, were 1.87 (95%-CI: 1.39-2.52) for periventricular lesions and 1.45 (95%-CI: 1.13-1.86) for subcortical lesions. Adjusted for each other, the hazard ratio slightly increased for periventricular WMLs (1.98 (95%-CI: 1.26-3.13)), but attenuated for subcortical WMLs (0.93 (95%-CI: 0.60-1.44)). The automated WML classification is comparable to that of trained observers. The results support the notion that periventricular and subcortical WMLs bear different risks on the development of dementia.

Cognitive function correlates with frontal white matter apparent diffusion coefficients in patients with leukoaraiosis

Diffusion weighted imaging (DWI) displays a high sensitivity to white matter changes, even in areas where no lesions are visible. Correlation with vascular risk factors and cognitive dysfunction seems to be feasible using this technique. We aimed to test relations between age, blood pressure and cognitive function,with lesion load and average Apparent Diffusion Coefficient (ADC) values in lesioned (LWM) and in normal appearing white matter (NAWM), in patients with age related white matter lesions (ARWML). Subjects were 29 patients (mean age 72.6 +/- 5.2 years) with different severity of ARWML on MRI and no (or mild) disability assessed by the Instrumental Activities of Daily Living Scale. Imaging lesion load was quantified in bilateral frontal, temporal, parieto-occipital, basal ganglia and infratentorial regions, using a simple visual rating scale; ADC was measured bilaterally in Regions of Interest in parieto-occipital and frontal NAWM, and in frontal periventricular LWM. Neuropsychological examination consisted of Raven Colored Progressive Matrices, Rey's Complex Figure, Digit Canceling. Symbol digit Substitution, Inverse Digit Repetition and Verbal Fluency tests. Visual scales scores and ADC were significantly higher in frontal and parieto-occipital regions. Both were significantly correlated to age and blood pressure, in frontal (visual scale scores and ADC) and parieto-occipital regions (ADC). Attention skills were negatively correlated to ADC in LWM and NAWM in frontal regions and with frontal region visual scale scores. Our findings suggest that severity of white matter ischemic changes is correlated with worse cognitive function, as well as advanced age and higher blood pressure.A higher vulnerability of frontal white matter to vascular disease seems to play an important role in executive dysfunction, mainly determined by impairment of attentional skills.DWI results suggest this could be true even for NAWM.

Age‐related white matter lesions are associated with reduction of the apparent diffusion coefficient in the cerebellum

Cerebellar apparent diffusion coefficient (ADC) was found to be increased after acute cerebral hemispheric stroke. There are no data on cerebellar ADC changes in patients with chronic, age-related white matter lesions (ARWML). We aimed to determine longitudinal ADC variations on cerebral hemispheric and cerebellar white matter regions of patients with ARWML in order to study relations between ADC changes in both regions. ADC was measured serially (1-year interval) on lesioned periventricular frontal white matter, frontal and parietoccipital normal appearing white matter and middle cerebellar peduncles, on 19 aged patients with ARWML, which also underwent gait assessment. We compared regional ADC at 0 and 1 year and calculated variation percentages for each region. Correlation analysis was made between ADC variation in cerebellar regions and in contralateral hemispheric regions and between cerebellar ADC at 1 year and walking speed. After 1 year, ADC was higher on lesioned periventricular frontal white matter and lower on cerebellar regions. ADC variations on these regions were negatively correlated. Cerebellar ADC measured after 1 year was positively correlated with walking speed. This suggests a link between vascular disease progression inside frontal lesions and ADC reduction in contralateral cerebellar peduncles. Chronic ischemia in frontal white matter could have interrupted frontal-cerebellar circuits, producing hypometabolism in cerebellar regions (and worse performance on motor tasks), decreased perfusion and hence ADC reduction.

Supratentorial Age-Related White Matter Changes Predict Outcome in Cerebellar Stroke

Little is known about the relevance of age related white matter lesions (WMLs) concerning outcome after first-ever territorial stroke. Based on an index patient, we hypothesized that age and pre-existent WMLs rather than infarct volume and topography determine outcome. Thirty-four consecutive patients with magnetic resonance diffusion-weighted imaging-proven isolated acute cerebellar infarction were prospectively entered on our stroke data registry. Patients with pre-existent neurological deficits, hemorrhagic, or malignant cerebellar infarction were excluded. Patients were stratified using Rankin and Barthel disability scales into groups: I complete recovery, II moderate, and III significant disability 14 days after stroke onset. Initial neurological and functional scores were similar among all the groups with vertigo, nausea, unsteadiness, and limb ataxia being the most common. Infarct volume, vascular territories, and comorbidity did not predict clinical outcome. In contrast, presence and severity of supratentorial WMLs and age significantly determined outcome by functional tests. In patients with isolated cerebellar infarction functional outcome correlated with the coexistence of age-related WMLs rather than stroke volume and topography. This reflects the loss of compensatory network integrity as the equivalent of functional incapacity beyond local lesion disturbances.

Discrimination of white matter lesions and multiple sclerosis plaques by short echo quantitative 1H—magnetic resonance spectroscopy

Multiple sclerosis (MS) plaques and age related white matter lesions (WML) are of similar morphological appearance on T2 weighted MRI. Therefore their differentiation is sometimes crucial. Proton magnetic resonance spectroscopy ((1)H-MRS) adds metabolic information to conventional imaging and may help to distinguish inflammatory MS plaques from vascular related WML. This study was performed to evaluate the metabolite pattern in MS plaques and WML. 15 MS patients, 14 elderly individuals with WML and 16 controls were investigated by conventional MRI and short echo quantitative (1)H-MRS (TE: 30ms, TR: 3000ms). The mean metabolite concentrations in normal control white matter (NCWM), MS plaques and WML were: t-NAA: 8.96 mmol/l (SD: 0.93) vs 6.79 mmol/l (SD: 1.99) vs 7.18 mmol/l (SD: 1.41); Cho:1.66 mmol/l (SD: 0.4) vs 1.49 mmol/l (SD: 0.45) vs 1.46 mmol/l (SD: 0.34); PCr:5.64 mmol/l (SD: 0.83) vs 4.9mmol/l (SD: 1.3) vs 4.95 mmol/l (SD: 0.86); myo-Ins: 4.57 mmol/l (SD:1.05) vs 6.34 mmol/l (SD: 2.03) vs 4.5 mmol/l (SD: 0.96). t-NAA reduction in MS plaques and WML was significant compared with controls (p <or= 0.001). MS plaques showed significantly elevated myo- Ins concentrations compared with controls (p = 0.002) and to WML (p = 0.003). In summary MS plaques and WML show a decrease in their t-NAA concentrations compared with controls. Elevated concentrations of myo-Ins in MS plaques but not in WML makes this metabolite of special interest for their differentiation.

Role of White Matter Lesions in Cognitive Impairment of Vascular Origin

White matter changes are detected with high frequency by neuroimaging techniques in aged subjects with cerebrovascular risk factors or diseases and in cognitively impaired patients. Their direct role in causing cognitive deterioration has not been established, although their frequency is higher in demented subjects than in normal controls, and they are associated with specific cognitive deficits, particularly those related to impairment of frontal lobe functions. The aim of this paper is to critically review the existing knowledge about the role of white matter lesions in cognitive impairment of vascular origin. After reviewing the scarce evidence and the numerous clues suggesting a possible role of white matter lesions in causing mental decline, proposals are advanced about elements that could be a basis for revised criteria for vascular dementia for clinical trials. Finally, some items requiring future joint investigations in the fields of age-related white matter lesions are identified.

Alzheimer's disease: longitudinal CT studies of ventricular change.

A 3-year longitudinal study was conducted with 50 Alzheimer's disease patients and 45 elderly control subjects. All study participants received an extensive evaluation that included brain CT at baseline and follow-up. Quantitation of ventricular size, using both linear and volume methods, revealed highly significant cross-sectional and longitudinal differences between the Alzheimer patients and control subjects. Specifically, the annual rate of change in ventricular volume was approximately 9% in the Alzheimer patients and approximately 2% in the controls. The presence of age-related white matter lesions had no effect on the clinical course of the patients or on the changes in ventricular size. Among the Alzheimer patients, the rate of clinical decline was strongly related to the rate of change in ventricular size. Baseline ventricular measurements were of no value in predicting the subsequent rate of clinical deterioration or ventricular enlargement. The results suggest that changes in ventricular size closely reflect the clinical changes in Alzheimer patients.