on behalf of the LADIS Study GroupBackground and Purpose-On cerebral magnetic resonance imaging (MRI), white matter hyperintensities (WMH) and lacunes are generally viewed as evidence of small vessel disease. The clinical significance of small vessel disease in terms of global cognitive function has as yet not been completely clarified. We investigated the independent contribution of WMH and lacunes to general cognitive function in a group of independently living elderly with varying degrees of small vessel disease. Methods-Data were drawn from the multicenter, multinational Leukokraurosis and Disability (LADIS) study. There were 633 independently living participants. General cognitive function was assessed using the Mini Mental State Examination (MMSE) and the modified Alzheimer Disease Assessment Scale (ADAS). On MRI, WMH was rated as mild, moderate, or severe. Lacunes were rated as none, few (1 to 3), or many (4 or more). Results-In the basic analysis, increasing severity of both WMH and lacunes was related to deteriorating score on the MMSE and ADAS. When WMH and lacunes were entered simultaneously, both MRI measures remained significantly associated with MMSE score. Increasing severity of WMH remained associated with ADAS score, whereas the association with lacunes became less prominent. These associations were independent of other risk factors for dementia, like education, depression, vascular risk factors, or stroke. Conclusion-We found WMH and lacunes to be independently associated with general cognitive function in a sample of independently living elderly. These results highlight the fact that WMH and lacunes should both be evaluated when assessing small vessel disease in relation to cognitive function. (Stroke. 2005;36:2116-2120.)

Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.

To investigate the cognitive capacities of a cohort of ischaemic or haemorrhagic stroke survivors and to identify the clinical determinants of post-stroke cognitive impairment, we evaluated 237 patients admitted to a Stroke Unit (mean age 59; SD=12.7). Three months after stroke, patients were submitted to a neuropsychological evaluation that included the Mini-Mental State Examination (MMSE), a complementary battery to assess specific cognitive domains, the Hamilton Depression Rating Scale (HDRS) and the Blessed Dementia Scale (BDS). Disturbed performance on at least one domain was detected on 131 (55%) patients: 27% had cognitive deficits other than memory, 7% had focal memory deficit, 9% had memory and other cognitive deficits and 6% had dementia. Dementia was associated with female gender (P=0.01), older age (P=0.01) and lower education level (P=0.04). Patients with memory deficits were older (P=0.01) with lower educational level (P=0.08) and more left sided lesions (P=0.02) than patients without memory deficits. In this middle aged stroke survivors cognitive impairment was common 3 months after stroke, while dementia was infrequent.

WMC severity and diabetes are independent predictors of cognitive decline in an initially nondisabled elderly population. Vascular dementia is predicted by previous stroke and WMC, while AD is predicted only by MTA.

Background: Cross-sectional studies have indicated that subcortical ischemic vascular disease (SIVD), as defined according to imaging criteria, is associated with a specific clinical and cognitive profile. Much less is known about the long-term cognitive consequences of SIVD. The aim of the study was to investigate the longitudinal cognitive performance and incident dementia in subjects with and without SIVD in a sample of older adults with white matter lesions. Methods: In the Leukoaraiosis and Disability (LADIS) study, 639 participants were examined with annual clinical and neuropsychological evaluations for 3 years. The subjects meeting the MRI criteria of SIVD at baseline were compared to the other subjects of the sample with linear mixed models. Results: The overall level of cognitive performance over the follow-up period was inferior in multiple cognitive domains in SIVD subjects as compared to the reference group. The subjects with SIVD presented significantly steeper decline of performance in the Stroop test (parts I and II), Trail Making A test, Verbal fluency test, and Mini-Mental State Examination. They also had a threefold risk of developing dementia during follow-up independently of age, sex, education and medial temporal lobe atrophy. Conclusions: SIVD, as a manifestation of cerebral small vessel disease, is related to progressive cognitive impairment and a considerable risk of developing dementia. SIVD seems to specifically contribute to the deterioration of psychomotor speed, executive control, and global cognitive function.

Background and Purpose— Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease–related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods— Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network–based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results— The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi ( P <0.001 for global cognitive function, processing speed, executive functions, and memory and P <0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on Z scores strongly predicted cognitive and functional outcomes ( P <0.001) even above the contribution of the individual brain changes. Conclusions— Global burden of small vessel disease–related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.

Background and purpose: Age related white matter changes (ARWMC) are frequent in non-demented old subjects and are associated with impaired cognitive function. Our aim was to study the influence of vascular risk factors and ARWMC on the neuropsychological performance of an independent elderly population, to see if vascular risk factors impair cognition in addition to the effects of ARWMC. Methods: Independent subjects, aged 65-84 years, with any degree of ARWMC were assessed using a comprehensive neuropsychological battery including the Mini-Mental State Examination (MMSE), VADASCog (Alzheimer's disease assessment scale) and the Stroop and Trail Making test. Vascular risk factors were recorded and ARWMC (measured by MRI) were graded into three classes. The impact of vascular risk factors and ARWMC on neuropsychological performance was assessed by linear regression analyses, with adjustment for age and education. Results: 638 patients (74.1 (5) years old, 55% women) were included. Patients with severe ARWMC performed significantly worse on global tests of cognition, executive functions, speed and motor control, attention, naming and visuoconstructional praxis. Diabetes interfered with tests of executive function, attention, speed and motor control, memory and naming. Arterial hypertension and stroke influenced executive functions and attention. The effect of these vascular risk factors was independent of the severity of ARWMC, age and education. Conclusion: ARWMC is related to worse performance in executive function, attention and speed. Diabetes, hypertension and previous stroke influenced neuropsychological performance, independently of the severity of ARWMC, stressing the need to control vascular risk factors in order to prevent cognitive decline in the elderly. C erebral age related white matter changes (ARWMC) are frequently described on brain imaging in demented and non-demented elderly subjects.1 2 Some demographic and vascular risk factors are associated with a higher risk of developing ARWMC, with major emphasis on age, hypertension and stroke. [3][4][5][6] On the other hand, recent epidemiological evidence indicates that vascular risk factors play a role in the development of cognitive impairment and dementia, including degenerative dementia.7-11 ARWMC can be a mediator between vascular risk factors and cognitive decline, while some demographic characteristics can contribute towards protecting cognitive function.12 Our aim was to study the influence of ARWMC and vascular risk factors on the neuropsychological performance of non-disabled independent elderly people with ARWMC and to analyse if vascular risk factors had an independent effect on cognitive performance. METHODSThe LADIS (Leukoaraiosis and Disability) study is a prospective multinational European project investigating the independent impact of ARWMC on the transition to disability in the elderly. The rationale, methodology and baseline assessment have been described previously.12 13 Investigators were provided with a specifically developed han...

Objective: To examine the independent contributions and combined interactions of medial temporal lobe atrophy (MTA), cortical and subcortical atrophy, and white matter lesion (WML) volume in longitudinal cognitive performance. Methods:A total of 477 subjects with age-related WML were evaluated with brain MRI and annual neuropsychological examinations in 3-year follow-up. Baseline MRI determinants of cognitive decline were analyzed with linear mixed models controlling for multiple confounders.Results: MTA and subcortical atrophy predicted significantly steeper rate of decline in global cognitive measures as well as compound scores for psychomotor speed, executive functions, and memory after adjusting for age, gender, education, lacunes/infarcts, and WML volume. Cortical atrophy independently predicted decline in psychomotor speed. WML volume remained significantly associated with cognitive decline even after controlling for the atrophy scores. Moreover, significant synergistic interactions were found between WML and atrophy measures in overall cognitive performance across time and the rate of cognitive decline. Synergistic effects were also observed between baseline lacunar infarcts and all atrophy measures on change in psychomotor speed. The main results remained robust after exclusion of subjects with clinical stroke or incident dementia, and after additional adjustments for progression of WML and lacunes.Conclusions: Brain atrophy and WML are independently related to longitudinal cognitive decline in small vessel disease. MTA, subcortical, and cortical atrophy seem to potentiate the effect of WML and lacunes on cognitive decline. Neurology ® 2012;78:1785-1792