Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

on behalf of the LADIS Study GroupBackground and Purpose-We studied the natural course of white matter hyperintensities (WMH) and lacunes, the main MRI representatives of small vessel disease, over time and evaluated possible predictors for their development. Methods-Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (nϭ396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes. Results-WMH progressed (meanϮSDϭ1.9Ϯ1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximumϭ9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes. Conclusion-WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.

Objective To assess the impairment in daily living activities in older people with age related changes in white matter according to the severity of these changes. Design Observational data collection and follow-up of a cohort of older people undergoing brain magnetic resonance imaging after non-disabling complaints. Setting 11 European centres. Participants 639 non-disabled older patients (mean age 74.1 (SD 5.0), 45.1% men) in whom brain magnetic resonance imaging showed mild, moderate, or severe age related changes in white matter (Fazekas scale). Magnetic resonance imaging assessment also included cerebral infarcts and atrophy. Main outcome measure Transition from no disability (defined as a score of 0 or 1 on the instrumental activities of daily living scale) to disability (score ≥2) or death over three year follow-up. Secondary outcomes were incident dementia and stroke. Results Over a mean follow-up period of 2.42 years (SD 0.97, median 2.94 years), information on the main outcome was available for 633 patients. The annual rate of transition or death was 10.5%, 15.1%, and 29.5%, respectively, for patients with mild, moderate, or severe age related changes in white matter (Kaplan-Meier log rank test P<0.001). In a Cox model comparing severe with mild changes and adjusted for clinical factors of functional decline, the risk of transition to disability or death was more than twofold higher (hazard ratio 2.36, 95% confidence interval 1.65 to 3.81). The other predictors were age group, history of atrial fibrillation, and complaint of gait disturbances. The effect of severe changes remained significant independently of baseline degree of atrophy and number of infarcts. Incident stroke and dementia only slightly modified this effect. ConclusionThe three year results of the LADIS study suggest that in older adults who seek medical attention for non-disabling complaints, severe age related changes in white matter independently and strongly predict rapid global functional decline.

The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes. KeywordsCerebral small vessel disease, endothelium, inflammation, lacunar infarcts, white-mater hyperintensities The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain.1 Age/hypertension-related SVDs and cerebral amyloid angiopathy are the most common sporadic forms of SVD. Among a few genetic forms of SVD, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by NOTCH3 gene mutations, is the most frequent one. It is a systemic arteriopathy although the clinical symptoms are those caused by brain dysfunction. The effects of both sporadic and inherited SVD on the brain parenchyma are represented by lesions mainly located in the subcortical structures, and include lacunar infarcts, ischemic white-matter lesions, and intracerebral hemorrhage. An international working group has recently published the STRIVE (STandards for ReportIng Vascular changes on nEuroimaging) to provide definitions and imaging standards for markers and consequences of SVD.2 According to this consensus, changes currently seen on neuroimaging related to SVD include lacunes, recent small subcortical infarcts, white-matter hyperintensities (WMH), perivascular spaces (PVS), microbleeds (MB), and brain atrophy.Over the last few decades, evidence has being accumulated regarding prevalence, clinical significance, and

White-matter lesions cannot be considered as mere incidental findings, at least in patients who show severe lesions. The pathogenesis of white-matter lesions must be clarified further and strategies found to delay their progression.

White matter changes pre-date and are associated with the development of depressive symptoms. This has implications for treatment and prevention of depression in later life.

The Trail Making Test part B (TMT-B) is highly sensitive to age-related changes in the brain and cognitive function. However, the precise contribution of periventricular hyperintensities (PVH), deep white matter hyperintensities (DWMH), and medial temporal lobe atrophy (MTA) to task performance remains unspecified. Similarly, diminished performance may be due to deficient flexibility functions, but also to other age-related cognitive decline (e.g., mental slowing). The aim of the present study was to determine neuroanatomical (PVH, DWMH, MTA) and neuropsychological (working memory, executive function, speed and attention, episodic memory) predictors of TMT-B performance in elderly people. Results showed that MTA was the strongest predictor of TMT-B performance. The predictive value of the neuropsychological scores differed among the various TMT-B variables. For example, all neuropsychological domains predicted the TMT-B total completion time, whereas only executive function predicted the ratio score (TMT-B/A). We conclude that MTA is a very important predictor of TMT-B performance in elderly people. Furthermore, multiple cognitive functions are involved in TMT-B performance and a mild decline in any of these functions may result in diminished TMT-B performance. Therefore it is crucial to use the ratio score when one wishes to examine executive function ability.

Our results support the vascular depression hypothesis and strongly implicate white-matter changes in the pathogenesis of late-life depression. Furthermore, the findings indicate that, over time, part of the relationship between white-matter changes and depression may be mediated by loss of functional activity.