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Background/objectives: To examine the association between white matter hyperintensities (WMH) and cognitive domains such as memory and executive function (EF) across different clinical and biomarker categories of Alzheimer's disease (AD)., Design: Cross-sectional study., Setting: Alzheimer's Disease Neuroimaging Initiative., Participants: A total of 216 cognitively normal (CN) participants and 407 participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline., Measurements: Based on the 2018 research framework, participants were classified using AT(N) (amyloid-β deposition [A], pathologic tau [T], and neurodegeneration [(N)]) biomarkers into one of three categories: biomarker negative [A - T- (N)-], amyloid negative but other biomarker positive [A - T ± (N)+ or A - T + (N)±] or amyloid positive [A + T ± (N)±]. Linear regression models were then used to examine the association between WMH and memory composite scores and EF composite scores., Results: Higher WMH burden was associated with worse EF in both CN and MCI subgroups while a significant association between WMH and memory was only found in the MCI subgroup. Furthermore, WMH was associated with EF in the group with A - T ± (N)+ or A - T + (N)± biomarker category, but not for A - T - (N)- (normal biomarker) and A + T ± (N) ± (AD pathology). The association between higher WMH and worse memory was independent of amyloid levels in individuals with MCI with evidence of AD pathology., Conclusion: Vascular disease, as indexed by WMH, independent of AD pathology affects cognitive function in both CN and MCI subgroups. Future studies using the AT(N) research framework should consider white matter lesions as a key biomarker contributing to the clinical presentation of AD., (© 2021 The American Geriatrics Society.)

Background . A fraction of stroke survivors with chronic aphasia experience declines in language abilities over time, but the reason for this remains unclear. Objective . To evaluate the effect of leukoaraiosis on baseline aphasia severity and long-term changes in aphasia severity. This study directly compares the predictive capacity of leukoaraiosis severity to that of lesion damage, a factor known to account for a substantial proportion of variance in the degree of language impairment and recovery. Methods . Using a longitudinal database of behavioral and neuroimaging data from 35 individuals in the chronic stage of recovery after a single-event left-hemisphere stroke (9 females, mean stroke age = 55.8 ± 9.1 years, mean months poststroke at initial evaluation = 36.3 ± 40.8), we examined 2 lines of inquiry: (1) to what extent does leukoaraiosis severity at initial evaluation predict aphasia severity and (2) to what extent does leukoaraiosis severity at initial evaluation predict longitudinal change in aphasia severity. Participants underwent high-resolution magnetic resonance imaging for the purpose of lesion volume analysis and leukoaraiosis severity rating. Biographical information was also considered. Results . Lesion volume and time poststroke at initial assessment best predicted initial aphasia severity (adjusted R 2 = 0.37). Leukoaraiosis severity and initial aphasia severity significantly predicted decline in language abilities at follow-up, accounting for approximately one-third of the variance (adjusted R 2 = 0.33). More severe leukoaraiosis was associated with a 4.3 odds increase of decline. Conclusions . Leukoaraiosis is a significant risk factor for declining language abilities in aphasia and should be considered for better identification of individuals at risk for long-term decline, which can guide clinical decision making.

Background: Leukoaraiosis has been shown to impact functional outcomes after acute ischemic stroke. However, its association with domain specific recovery after ischemic stroke is uncertain. We sought to determine whether pre-existing leukoaraiosis is associated with short-term motor and cognitive recovery after stroke., Methods: We retrospectively studied ischemic stroke patients admitted to acute inpatient rehabilitation (AIR) between January 2013 and September 2015. Patient baseline characteristics, infarct volume, prestroke modified Rankin Scale, stroke cause, rehabilitation length of stay, and Functional Independence Measure (FIM) scores were recorded. Leukoaraiosis severity was graded on brain magnetic resonance imaging using the Fazekas scale. Multiple linear regression was used to determine factors independently associated with the total, cognitive, and motor FIM scores at AIR discharge, respectively., Results: Of 1600 ischemic stroke patients screened, 109 patients were included in the final analysis. After adjustment, the initial National Institute of Health Stroke Scale (β -0.541, confidence interval [CI] -0.993 to -0.888; P = 0.020) and pre-existing leukoaraiosis severity (β -1.448, CI -2.861 to -0.034; P = 0.045) independently predicted the total FIM score. Domain specific analysis showed that infarct volume (β -0.012, CI -0.019 to -0.005; P = 0.002) and leukoaraiosis severity (β -0.822, CI -1.223 to -0.410; P = 0.0001) independently predicted FIM cognitive scores at discharge from AIR. Leukoaraiosis did not predict FIM motor score (P = 0.17)., Conclusions: Leukoaraiosis severity is an independent predictor of total and cognitive, but not motor FIM scores after AIR for acute ischemic stroke. This highlights that leukoaraiosis affects poststroke recovery in a domain specific fashion, information that may aid counseling of patients and families as well as tailor rehabilitative efforts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Leukoaraiosis is one of the main contributors to mild cognitive impairment due to vascular damage (vascular MCI, VMCI), whose pathophysiology has not been fully elucidated yet. We aimed to shed light on such issue using functional MRI (fMRI). Sixteen patients with VMCI were enrolled and compared with twenty-five patients with MCI but without significant vascular damage (non-vascular MCI, NVMCI) and with fifteen healthy controls (HC). They all underwent fMRI with incidental verbal learning paradigm, using a 3T scanner. Differently from cases with NVMCI (versus HC), VMCI patients presented a higher BOLD activation in the right parieto-occipital cortex and a lower activation in the left superior and middle frontal gyri, anterior cingulum and in left fronto-opercular area when compared to HC. Cortical activation evaluated by fMRI may reflect specific patterns of damage and attempt of compensation in patients with MCI and different severity of leukoaraiosis., (Copyright © 2018. Published by Elsevier B.V.)

Leukoaraiosis, also referred to as white-matter hyperintensities (WMHs) or age-related white matter changes, is the most frequently seen lesion on brain magnetic resonance images (MRI) in the elderly. LA is a subject of intense research interest, and is correlated with stroke, cognitive impairment or dementia, disturbances, affective disorders, and poor prognoses. Rapid advances in neuroimaging have enabled greater understanding of LA associated with aging-related cognitive decline or dementia. Recently, the techniques of multimodal MRI, such as structural MRI (sMRI), resting-state functional MRI (rs-MRI), cerebrovascular reactivity (CVR), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and dynamic contrast-enhanced MRI (DCE-MRI), have been used to explore the underlying mechanism of cognitive impairment in patients with LA. These multimodal MRI techniques may provide further insights into the structural and functional changes of LA with cognitive dysfunction.

To examine neural, physiological and cognitive influences on gait speed under single and dual-task conditions. Sixty-two community-dwelling older people (aged 80.0 ± 4.2 years) participated in our study. Gait speed was assessed with a timed 20-meter walk under single and dual-task (reciting alternate letters of the alphabet) conditions. Participants also underwent tests to estimate physiological fall risk based on five measures of sensorimotor function, cognitive function across five domains, brain white matter (WM) hyperintensities and WM microstructural integrity by measuring fractional anisotropy (FA). Univariate linear regression analyses showed that global physiological and cognitive measures were associated with single (β = 0.594 and β=-0.297, respectively) and dual-task gait speed (β = 0.306 and β=-0.362, respectively). Deep WMHs were associated with dual-task gait speed only (β = 0.257). Multivariate mediational analyses showed that global and executive cognition reduced the strength of the association between deep WMHs and dual-task gait speed by 27% (β = 0.188) and 44% (β = 0.145) respectively. There was a significant linear association between single-task gait speed and mean FA values of the genu (β=-0.295) and splenium (β=-0.326) of the corpus callosum, and between dual-task gait speed and mean FA values of Superior Cerebellar Peduncle (β=-0.284), splenium of the Corpus Callosum (β=-0.286) and Cingulum (β=-0.351). Greater deep WMH volumes are associated with slower walking speed under dual-task conditions, and this relationship is mediated in part by global cognition and executive abilities specifically. Furthermore, both cerebellum and cingulum are related to dual-task walking due to their role in motor skill performance and attention, respectively.

Background: Acute Systemic Diseases (ASD) impact on extended leukoaraiosis (ExLA) have been seldom described. We study the deterioration in daily life activities (DLA) and cognition associated with ASD events compared with the well-described impacts of stroke in patients with leukoaraiosis (L-A)., Methods: Cross-sectional surveys of aged adults from the emergency room after an acute event of ASD or stroke, hospitalized or receiving home care, were followed for one year. From 268 initial patients 206 were included in the study, all with moderate to severe L-A (Fazekas 2 and 3). The Clinical Deterioration Rating (CDR) and the modified Rankin scale with structured interview were obtained one week previous to admission and after 3 and 12 months of evolution. Comparisons were conducted within and between groups with nonparametric techniques., Results: We formed three groups of similar age, A: Inpatients with one Stroke, B: Inpatients with one ASD, and C: Outpatients with one ASD. A sudden deterioration in Rankin was evident in Group A, while in B and C impairment was progressive. Impairment in CDR was smooth in all groups while in Rankin it was always greater than in cognition (CDR). No differences were found in the associations between groups and risk factors, hypertension being the most frequent one., Conclusion: ASD in ExL-A causes a worsening of DLA and cognition similar to that observed in ExL-A with concomitant stroke indicating the need, in ageing patients, of differential diagnosis in order to achieve the best possible treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Our study aimed to investigate the changes of white matter microstructure of cortico-subcortical pathways using diffusion tensor imaging (DTI), and to explore the relationship between abnormal parameters of DTI and cognitive function underlying in patients with leukoaraiosis (LA).A total of 42 patients with LA and 42 age- and sex-matched healthy controls were recruited from Beijing Chaoyang Hospital, Capital Medical University between January 2012 and December 2012. All the subjects underwent scans of conventional magnetic resonance imaging and DTI, and a comprehensive neuropsychological battery was utilized. The regions of interest (ROIs) were located at the white matter of centrum semiovale, anterior and posterior periventricular white matter, basal ganglia, corpus callosum. The averaged values of mean diffusivity (MD) and fractional anisotropy (FA) were quantified both within white matter lesions (WMLs) and normal appearing white matter (NAWM). A linear regression analysis was performed to assess the association between diffusion parameters and decline in cognitive domains.Patients with LA were associated with comprehensive cognitive function deficits. We found that significantly decreased FA and increased MD in WMLs at the 5 ROIs than that of NAWM and controls (P < .05). The values of FA in NAWM were significantly lower and MD in NAWM were significantly higher at centrum semiovale and posterior periventricular white matter than that of controls (P < .05). The values of FA in WMLs at anterior periventricular white matter were positively related to the performances of cognition in patients with LA (P < .05). The values of FA in NAWM located at anterior periventricular white matter were positively related to the score of Digit-symbol test (r = 0.446, P = .002). The values of FA in NAWM located at anterior periventricular white matter correlated inversely with the Z scores of executive function (r = -0.418, P = .03).In our study, patients with LA exhibited significant cognitive impairment especially in the domains of executive function. The technique of DTI revealed that the reduced FA and increased MD at the corresponding regions of cortico-subcortical pathways in patients with LA. DTI may be of great help for an early pathology of white matter microstructure underlying in patients with LA.

Whether leukoaraiosis burden retards short-term recovery after minor stroke is unclear. We investigated the association between leukoaraiosis and early recovery of neurological function after a first minor ischemic stroke in 217 acute stroke patients (National Institutes of Health Stroke Scale (NIHSS) score ≤5). Leukoaraiosis severity was graded according to the Fazekas scale and categorized into none to mild (0-2; n = 143) or severe (3-6; n = 74) groups. NIHSS and Minimum Mental State Examination (MMSE) were assessed at baseline and at 30 days. Univariate analysis revealed that the severe leukoaraiosis group was older in age (P < 0.001) and had fewer low MMSE patients than non-mild group at baseline (39.1% vs 55.9%, P = 0.003). However, the MMSE improved in none to mild group but not in the severe group at 30-day (15.4% vs 36.5%, P < 0.001). At 30-day, the severe leukoaraiosis group had higher NIHSS scores than the none-mild group (P = 0.04). Multiple linear regression analyses demonstrated that leukoaraiosis severity and admission NIHSS were independently associated with the NIHSS score on day 30 (P = 0.034, 95% CI 0.004-0.091 and P = 0.001, 95% CI 0.011-0.04). Binary regression analyses showed that leukoaraiosis severity and admission MMSE were significantly associated with MMSE (dichotomized) at 30-day (OR 2.1, P < 0.01, 95% CI 1.7-2.6 and OR 5.1, P < 0.01, 95% CI 2.1-12.8). Leukoaraiosis burden is an independent predictor of worse short-term functional and cognitive recovery after a minor ischemic stroke.

Aims: To describe the contribution of white matter lesions to the long-term neuropsychological profiles of different groups of clinical diagnoses, and to identify neuropsychological predictors of cognitive impairment in a 10-year follow-up., Methods: The Lisbon subcohort of the Leukoaraiosis and Disability (LADIS) study was re-evaluated performing a clinical, functional and cognitive evaluation [including Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) and ADAS-Cog with the extension for vascular impairment (VADAS-Cog), the 9-word version of the California Verbal Learning Test (CVLT-9), the Trail-Making test and the Stroop test] as well as an MRI scan. Using clinical diagnostic criteria, participants were identified as having no cognitive impairment (NI), cognitive impairment but no dementia (CIND) or dementia (DEM), and the effect of time on clinical diagnosis and neuropsychological profiles was analyzed., Results: From the initial group of 66 participants, 37 out of 41 survivors (90%) were re-evaluated (mean age 81.40 years, 57% women). Fifteen patients (41%) had DEM, 12 (32%) CIND and 10 (27%) NI. Over time, the three groups presented distinct profiles in the MMSE [F2, 62 = 15.85, p = 0.000], ADAS [F2, 62 = 15.85, p = 0.000] and VADAS [F2, 48 = 5.87, p = 0.008]. Logistic regression analysis identified higher scores on MMSE (β = 1.14, p = 0.03, OR = 3.13, 95% CI 1.09-8.97) as predictors of NI after 10 years of follow-up., Conclusion: Higher scores on baseline MMSE were the only neuropsychological predictors of NI after 10 years., (© 2016 S. Karger AG, Basel.)

The evidence on the clinical significance of cerebral white matter changes (WMC) has mounted over the past few decades. WMC are recognized as one of the neuroimaging features of cerebral small vessel disease, and are associated with various disturbances and a poor prognosis. The Leukoaraiosis and Disability (LADIS) Study has contributed substantially to this body of knowledge. LADIS is a European multicenter collaboration aimed at assessing the role of WMC as an independent predictor of the transition to disability in initially non-disabled patients aged 65-84 years. Besides the demonstration that severe WMC cause a more than double risk of transition from an autonomous to a dependent status after 3 years of follow-up, the LADIS Study has also provided evidence on the role of WMC in relation to the decline of cognitive and motor performances, depressive symptoms associated with aging and cerebrovascular diseases, the presence of urinary disturbances, and various neurological abnormalities. The possible role of other lesions (lacunar infarcts, cerebral atrophy, corpus callosum morphology) and microstructural abnormalities (diffusion-weighted imaging changes in normal appearing brain tissue and in WMC) has also been investigated. In the present article, we review the main results of the LADIS Study and offer some considerations for future developments in the field, paying attention to the potential use of WMC progression as a surrogate marker in intervention trials in cerebral small vessel diseases. We also discuss some therapeutic perspectives regarding the beneficial impact of physical activity on the risk of vascular cognitive impairment in patients with WMC., (© 2015 Japan Geriatrics Society.)

As the ageing population continues to increase, the prevalence of age-related cognitive impairment has been on the rise. Mild cognitive impairment (MCI) is now widely recognised as the early stage of dementia. Mild cognitive impairment is closely associated with cerebral white matter lesions (WMLs), specifically in the case of leukoaraiosis (LA). A previous diffusion tensor imaging (DTI) has demonstrated that white matter changes might damage cognitive function in LA patients, and the cognitive function might decrease with the deterioration of LA. Through consulting and analysing documents, we found that both of them share similarities in risk factors, pathogenesis, pathological changes, and imaging manifestations. The main characteristics of LA patients with MCI (LACI) are the early and apparent manifestations of delayed memory, attention, impaired executive function, and close association with dementia. This analysis of LACI may contribute to an early diagnosis of LACI and provide possible treatment for LACI.

Objective: To explore the independent risk factors and predictive factors of cognitive deterioration in patients of vascular cognitive impairment no dementia with subcortical ischemic vascular disease (VCIND-SIVD)., Methods: The clinical and neuropsychological characteristics of 96 VCIND-SIVD patients were collected and their cognitive states re-assessed after one year. The distribution of continuous and categorical variables was examined with univariate analysis. And Logistic regression in multivariate modeling was employed to identify the risk and predictive factors of cognitive deterioration., Results: After 1-year follow-up, 8 patients dropped out, 2 died and the remainder remained. There were 48 males and 38 females with an average age of 64.3 ± 5.4 years. Among them, 17 (19.8%) deteriorated into dementia, 24 (27.9%) upgraded to normal cognition and 45 (52.3%) maintained their cognitive status. They were divided into dementia group (cognition deteriorating into dementia) and control group (elevated/sustained cognition). After univariate analysis of general information and vascular risk factors, Logistic regression demonstrated that education level (P < 0.05, OR = 0.7) was a preventive factor of dementia while age (P < 0.05, OR = 1.2), hypertension (P < 0.05, OR = 5.6) and high homocysteine (P < 0.05, OR = 4.2) were independent risk factors of dementia. After univariate analysis of neuropsychological scores, Logistic regression demonstrated that visual reproduction-immediate recall (P < 0.05, OR = 3.4), digit span forward (P < 0.05, OR = 1.2), clock drawing test (P < 0.05, OR = 6.8) and completion time of London tower (P < 0.05, OR = 5.4) were predictive factors of dementia., Conclusion: VCIND-SIVD patients with low score of visual reproduction-immediate recall, digit span forward, clock drawing test and completion time of London tower should receive vigorous controls of hypertension and high homocysteine.

Background: Leukoaraiosis and its progression have longitudinally been associated with cognitive decline and dementia. Its role in acute cognitive function and response to acute cerebral ischemia is less well understood. We evaluated whether the presence and extent of leukoaraiosis, or white matter hyperintensities (WMH), had an impact on performance on tests of hemispatial neglect in acute ischemic stroke patients., Methods: A series of 206 acute ischemic right-hemispheric stroke patients at Johns Hopkins Hospital underwent brain MRI and cognitive assessment for hemispatial neglect within 5 days of symptom onset. Error rates on neglect tests were evaluated, as were dichotomized measures of neglect, including 'any', 'severe' or 'worst' neglect, based on Z scores of at least 2 on 1, 2 or 3 tests (respectively) within a neglect battery. Acute infarct volumes were measured on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery images were reviewed for WMH, using the Cardiovascular Health Study (CHS) rating scale (ranging from 0 to 9, with 9 being 'most extensive'). Linear regression was used to evaluate 'error rate on neglect test' as the dependent variable, as a measure of neglect severity, with 'WMH category' as the primary independent variable, including adjustment for age, sex, race and infarct volume (on DWI). Logistic regression was used to evaluate a binary definition of neglect (defined as above) relative to the same independent variable and covariates., Results: Each 1-point increase in CHS leukoaraiosis category was associated with 1.20-fold increased odds (95% CI: 1.00-1.43) of having any neglect, 1.23-fold increased odds (95% CI: 1.02-1.49) of having severe neglect and 1.33-fold increased odds of having worst neglect (95% CI: 1.01-1.76) after adjusting for infarct volume, age, sex and race. Increasing age and infarct size were also important predictors of neglect severity, with a 2.36% higher error rate (95% CI: 0.75-3.97%) on the line cancellation test associated with each category increase in CHS score; similar results were found for each of the neglect tests. Line cancellation neglect scores were worse in individuals with both severe WMH and large infarcts (p interaction, unadjusted=0.03)., Conclusions: More severe leukoaraiosis is associated with more hemispatial neglect after acute ischemic stroke, independent of infarct volume, age and sex. We found not only more frequent neglect but also more severe neglect, based on error rates on neglect tests, in individuals with increasing leukoaraiosis. This emphasizes the importance of preexisting brain microvascular disease in outcomes of stroke patients. Further studies of the possible mechanism behind this association are needed., (© 2014 S. Karger AG, Basel.)

White matter changes (WMC) are common magnetic resonance imaging (MRI) findings, particularly in the elderly. Recent studies such as the Leukoaraiosis and Disability Study (LADIS) have found that WMC relate to adverse outcomes including cognitive impairment, depression, disability, unsteadiness and falls in cross-sectional and follow-up studies. Frontostriatal (or frontosubcortical) brain circuits may serve many of these functions, with the caudate nuclei playing a role in convergence of cognitive functions. This study aimed to determine whether reduced caudate volume relates to cognitive functions (executive functions, memory functions and speed of processing) and WMC. We determined caudate nuclei volumes, through manual tracing, on a subgroup of the LADIS study (n=66) from four centres with baseline and 3-year follow-up MRI scans. Regression analysis was used to assess relationships between caudate volume, cognitive function and WMC. Severity of WMC did not relate to caudate volume. Smaller caudate volumes were significantly associated with poorer executive functioning at baseline and at 3 years, but were not associated with scores of memory or speed of processing. Thus, in patients with WMC, a surrogate of small vessel disease, caudate atrophy relates to the dysexecutive syndrome, supporting the role of caudate as an important part of the frontostriatal circuit., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The Montreal Cognitive Assessment (MoCA) is more suitable than the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment. In this study, we performed a correlation analysis of MoCA/MMSE scores with daily physical activity in patients with subcortical ischemic white matter changes., Methods: Ten patients (average 75.9 ± 9.1 years old) with extensive leukoaraiosis detected on magnetic resonance imaging underwent cognitive testing, including the MMSE and the Japanese version of the MoCA (MoCA-J). Physical activity was monitored with the Kenz Lifecorder EX device (Suzuken, Nagoya, Japan) to assess daily physical activity in terms of caloric expenditure, motor activity, number of steps, and walking distance for 6 months. Correlations of individual physical activity with total and subscale scores of MMSE/MoCA-J or 6-month interval change of MoCA-J scores were assessed., Results: The total or subscale scores of the MMSE did not correlate with any parameters of physical activity. However, the mean number of steps and walking distance significantly correlated with the total MoCA-J scores (r = .67 and .64, respectively) and its visuospatial/executive subscores (r = .66 and .66, respectively). The mean interval change of MoCA-J was + .6; those who improved number of steps (n = 4; 80.5 ± 3.0 years of age) had significantly preserved MoCA-J scores compared to those who did not (n = 6; 73.0 ± 11.6 years of age; +2.0 versus - .3; P = .016)., Conclusions: These results suggest that MoCA is useful to detect a biologically determined specific relationship between physical activity and executive function. In addition, physical exercise, such as walking, may help enhance cognitive function in patients with vascular cognitive impairment of subcortical origin., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The Mini-Mental State Examination (MMSE) has been criticized as being an insufficient screening test for patients with vascular cognitive impairment because of its insensitivity to visuospatial and executive functional deficits. The Montreal Cognitive Assessment (MoCA) was designed to be more sensitive to such deficits, and thus may be a superior screening instrument for vascular cognitive impairment. Twelve patients with extensive leukoaraiosis detected on magnetic resonance imaging (average age, 76.0 ± 8.7 years) underwent neurologic and cognitive testing, including MMSE and the Japanese version of the MoCA (MoCA-J). Accepted cutoff scores of <27 for the MMSE and <26 for the MoCA-J were taken to indicate cognitive impairment. Z-scores were calculated to evaluate the discriminating ability of individual MMSE and MoCA-J subtest scores. Although there was a strong correlation between the total MMSE and total MoCA-J scores (r = 0.90; P < .0001), MMSE scores were skewed toward the higher end of the range (range, 18-30; median, 28), whereas MoCA-J scores were normally distributed (range, 9-28; median, 21). Of the 7 patients with an unimpaired MMSE score, 6 (86%) had an impaired MoCA-J score. Z-scores were >5 for 4 MMSE subtests (orientation, registration, naming, and language) but for only 1 MoCA-J subtest (naming). The MoCA-J better discriminated cognitive status in subjects with extensive leukoaraiosis. Our findings suggest that the MoCA-J is more sensitive than the MMSE in screening for cognitive impairment in patients with subcortical vascular cognitive impairment., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the role of leukoaraiosis (LA) on the cognitive function in patients with Parkinson disease (PD)., Methods: The cohort for this study included 63 patients with PD, whom were divided into 3 groups according to cognitive status:with intact cognition (PD-IC, n = 23), with mild cognitive impairment (PD-MCI, n = 23) and with dementia (PDD, n = 17). All the patients were recruited from the Department of Neurology, First Affiliated Hospital, Anhui Medical University between September 2011 and July 2012. The cognitive functions were evaluated by mini-metal state examination (MMSE), the Cambridge cognitive examination-Chinese version (CAMCOG-C), clinical dementia rating (CDR), clock drawing task (CDT) and verbal fluency test, etc. Depression symptoms were assessed by the geriatric depression scale (GDS) while motor symptoms by the Unified Parkinson's Disease Rating Scale-motor (UPDRS-motor) and the Hoehn and Yahr scale (HY). All the patients underwent magnetic resonance imaging (MRI) with a 3.0-T system. LA was rated using the semiquantitative visual rating system proposed by scheltens et al., Results: Both the PD-IC (2.43 ± 2.79) and PD-MCI (4.48 ± 4.33) groups showed significantly lower deep hyperintensities (DHs) scores than the PDD group (7.88 ± 6.69, P = 0.004 and 0.040, respectively), especially in frontal (1.09 ± 1.31; 1.83 ± 1.90; 3.24 ± 2.64, P < 0.05) and parietal areas (0.09 ± 0.29; 0.65 ± 1.03; 1.53 ± 2.32, P < 0.05). There were no significant differences in periventricular (1.57 ± 1.75; 2.52 ± 2.37; 3.24 ± 2.64, P > 0.05), basal ganglia (0.09 ± 0.42; 0.30 ± 0.77; 0.53 ± 1.33, P > 0.05) and infratentorial white matter hyperintensities scores (--; 0.13 ± 0.63; 0.18 ± 0.73, P > 0.05) among three groups. The DHs showed a significant correlation with age (P = 0.003), MMSE (P = 0.009), verbal fluency test (P = 0.009), orientation (P = 0.047) and executive function (P = 0.027) in CAMCOG-C. The multiple regression analysis showed that the MMSE scores were associated significantly with education (P < 0.001, β = 0.600), DHs (P = 0.001, β = -0.678) and HY (P = 0.035, β = -0.480). DHs were the most significantly associated with MMSE scores., Conclusion: There was a significant correlation between DHs and multiple domain cognitive impairment in PD, especially in executive function. DHs, which were the most significantly variable associated with MMSE scores, may contribute to cognitive impairment in PD.

Background: There are no reported studies on the relationship between traffic crashes and brain tissue changes in healthy drivers. The relationship between traffic crashes and leukoaraiosis, a common magnetic resonance imaging finding, was investigated in this study., Methods: A total of 3,930 automobile drivers (2,037 men and 1,893 women; age, 21-87 years) who underwent brain magnetic resonance imaging as part of total health check-ups and answered a road traffic questionnaire were examined to determine whether asymptomatic leukoaraiosis was associated with various types of traffic crashes. Multiple logistic regression analysis was performed to elucidate the relationship between leukoaraiosis and various types of traffic crashes., Results: Subcortical leukoaraiosis was diagnosed in 28.52% of all subjects, whereas periventricular leukoaraiosis was diagnosed in 9.57% of all subjects. Adjusted odds ratios for involvement in all types of traffic crashes were not significant for subjects with periventricular leukoaraiosis; however, they were significant for subjects with multiple and large multiple subcortical leukoaraiosis. Adjusted odds ratios for involvement in crashes at crossroads were 1.09 (95% confidence interval [CI], 0.60-2.00) for subjects with single subcortical leukoaraiosis, 3.35 (95% CI, 2.36-4.77) for subjects with multiple subcortical leukoaraiosis, and 2.45 (95% CI, 2.36-4.98) for subjects with large multiple subcortical leukoaraiosis. Periventricular leukoaraiosis was not significantly associated with crossroad crashes. Involvement in crashes of any type, parking lot crashes, and rear-end collisions showed no significant association with either subcortical or periventricular leukoaraiosis., Conclusions: Multiple subcortical leukoaraiosis, but not periventricular leukoaraiosis, is significantly associated with traffic crashes, in particular, crossroad crashes. This association is independent of sex, age, and driving exposure. To our knowledge, this is the first evidence describing the relationship between brain tissue changes and traffic crashes.

Objective: To examine the concept of leukoaraiosis thresholds on working memory, visuoconstruction, memory, and language in dementia., Methods: A consecutive series of 83 individuals with insidious onset/progressive dementia clinically diagnosed with Alzheimer disease (AD) or small vessel vascular dementia (VaD) completed neuropsychological measures assessing working memory, visuoconstruction, episodic memory, and language. A clinical MRI scan was used to quantify leukoaraiosis, total white matter, hippocampus, lacune, and intracranial volume. We performed analyses to detect the lowest level of leukoaraiosis associated with impairment on the neuropsychological measures., Results: Leukoaraiosis ranged from 0.63% to 23.74% of participants' white matter. Leukoaraiosis explained a significant amount of variance in working memory performance when it involved 3% or more of the white matter with curve estimations showing the relationship to be nonlinear in nature. Greater leukoaraiosis (13%) was implicated for impairment in visuoconstruction. Relationships between leukoaraiosis, episodic memory, and language measures were linear or flat., Conclusions: Leukoaraiosis involves specific threshold points for working memory and visuoconstructional tests in AD/VaD spectrum dementia. These data underscore the need to better understand the threshold at which leukoaraiosis affects and alters the phenotypic expression in insidious onset dementia syndromes.

Objective: To explore the syndrome factors of leukoaraiosis patients with mild cognitive impairment (LACI), thus providing evidence for syndrome typing., Methods: The prospective schedule was adopted including 103 LACI patients (as the LACI group) and 100 leukoaraiosis patients without mild cognitive impairment (as the control group). Syndrome factors were extracted from the patients' symptoms with frequency statistics and factor analysis., Results: Fifteen common factors were extracted from the LACI group, and 12 common factors from the control group. After analyzed the distribution of syndrome factors in the LACI group, the most common factors were ranked as follows: yang deficiency (33.98%), phlegm (22.33%), yin deficiency (19.42%), qi deficiency (10.68%), fire (9.71%), blood deficiency and blood stasis (3.88%). As for the control group, the most common factors were ranked as follows: yang deficiency (31.00%), qi deficiency (27.00%), yin deficiency and fire (24.00%), blood deficiency and blood stasis (12.00%), phlegm and yang deficiency and blood deficiency (6.00%)., Conclusions: The main syndrome factors of LACI were yang deficiency, phlegm, yin deficiency, and fire. The secondary syndrome factors were qi deficiency, blood deficiency, and blood stasis. It was mainly involved with Shen and Pi, with secondary organs as Gan and Xin. Deficiency syndrome is its pathogenesis. Phlegm and fire, and other pathological factors are essential for its development and aggravation, with more syndrome factors accompanied in complex condition.

Objective: To explore the pathological changes in patients with leukoaraiosis (LA) by magnetic resonance spectroscopy (MRS) and examine its relationship with cognitive function., Methods: Twenty-three LA patients and 23 age and gender-matched healthy subjects were recruited from the Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University between August 2010 and November 2010. All participants underwent the neuropsychological tests. Multi-voxel chemical shift imaging was performed and the regions of interest were positioned in bilateral frontal white matter. The relative metabolite ratios, involving N-acetyl aspartate/choline ratio (NAA/Cho), N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine (Cho/Cr), were estimated. The correlation of the MRS data and the performance of cognitive function was analyzed., Results: The LA patients were associated with a worse performance of mini mental state examination (MMSE) versus the healthy controls (24 ± 3 vs 28 ± 1, P < 0.05). Univariate analysis of the MRS data revealed the ratios of NAA/Cho and NAA/Cr significantly decreased in bilateral frontal white matter lesions in the LA group versus the control group (1.72 ± 0.20 vs 1.96 ± 0.36, 1.67 ± 0.17 vs 1.85 ± 0.21, P < 0.05). The values of NAA/Cr and NAA/Cho in normal appearing white matter increased versus the LA group (1.83 ± 0.24 vs 1.72 ± 0.20, 1.78 ± 0.28 vs 1.67 ± 0.17) and decreased versus the control group (1.83 ± 0.24 vs 1.96 ± 0.36, 1.78 ± 0.28 vs 1.85 ± 0.21). But no significant differences were found (P > 0.05). The ratio of Cho/Cr did not differ among 3 groups (P > 0.05). The pathological change of NAA/Cr in white matter lesion in LA patients was markedly correlated with the performance of MMSE (r = 0.47, P < 0.05)., Conclusion: NAA may be a marker of axonal loss/dysfunction in LA patients. And the changes of NAA/Cr have a positive correlation with cognitive impairment.

Objective: To explore the characteristics of cognitive impairment in patients with leukoaraiosis (LA)., Methods: Forty-six LA patients and 38 age and gender-matched healthy subjects were recruited from the Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University between September 2010 and March 2011. All participants underwent the neuropsychological tests recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards (NINDS/CSN). The were divided into 3 different groups (mild, moderate and severe) according to the Fazekas scale. The differences of neuropsychological performances were compared among 3 groups., Results: The LA patients were associated with comprehensive cognitive function deficits, including MMSE (24.4 ± 3.2 vs 28.3 ± 1.2), MoCA (20.4 ± 3.0 vs 26.2 ± 0.8), digital span forward (5.7 ± 0.9 vs 6.8 ± 1.0), digital span backward (3.5 ± 0.7 vs 4.1 ± 0.7), Stroop-B (69 ± 13 vs 43 ± 5), Stroop-C (141 ± 42 vs 65 ± 10), trail making test-A (73 ± 15 vs 31 ± 7), trail making test-B (126 ± 18 vs 82 ± 6) and digit symbol test (25 ± 6 vs 37 ± 5, P < 0.05). However, there was no difference in the performance of verbal fluency (12.7 ± 2.5 vs 13.4 ± 2.5, P > 0.05). Correlation analysis showed that the severity of LA had a negative correlation with the performance of MoCA (r = -0.601, P = 0.002)., Conclusions: The LA patients are closely correlated with cognitive impairments of attention, memory, executive function and information processing speed. It may be attributed to the frontal-subcortical circuitry dysfunction.

Background/aims: Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging., Methods: CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS)., Results: 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015)., Conclusion: The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease., (Copyright © 2012 S. Karger AG, Basel.)

White matter alterations, leukoaraiosis (LA) on structural MRI, are associated with cognitive deficits and increased risk of dementia. LA may also impact on subjective memory complaints in otherwise healthy older adults. Little is known about the interplay between LA memory complaints and cognition. We investigated cognitive phenotypes associated with LA in 42 non-demented older adults categorized as having subjective cognitive complaints with no objective cognitive impairment-the subjective cognitive impairment group (SCI; n = 12), amnesic mild cognitive impairment (aMCI; n = 20), or healthy controls (HC; n = 11). We measured LA severity on MRI with a 40-point visual rating scale. Controlling for age and Mini-Mental State Examination (MMSE) score, analyses revealed multiple between-group differences. Follow-up linear regression models investigating the underlying contributors to each clinic group's cognitive profile indicated that LA contributed to learning slope variance (after accounting for age and MMSE) but only for the SCI group. Although the SCI group showed a significantly steeper learning slope when compared to HC and aMCI, increasing LA severity negatively impacted this group's rate of learning. This, in conjunction with the significant contribution of age on SCI learning slope performance variance suggests that greater LA burden at a younger age may contribute to subtle changes in learning for individuals with subjective cognitive complaints.

Over the last 20 years, evidence about the clinical correlates of cerebral white matter changes (WMC; also called leukoaraiosis)has been accumulating. WMC are now listed among the neuroimaging expressions of cerebral small-vessel disease and are no longer considered an innocuous finding because they are associated, in cross-sectional surveys, with various disturbances and, in follow-up studies, with poor prognosis. The Leukoaraiosis And DISability (LADIS) study has contributed substantially to this body of knowledge.LADIS is a European multicenter collaboration that was started in 2001 with the aim of assessing the independent role of WMC in predicting disability in subjects aged 65–84. The main results of the LADIS study have been released in 2009 with the demonstration that severe WMC more than double the risk of transition from an autonomous to a dependent status after 3 years of follow-up. The LADIS study has also contributed more focused sub-studies assessing the possible role of WMC in the decline of cognitive and motor performances,depressive symptoms associated with aging and cerebrovascular diseases, urinary disturbances, and also the role of other brain lesions (lacunar infarcts, cerebral atrophy,and corpus callosum morphology). The LADIS study provides a good example of harmonization of instruments (MRI protocol, clinical, neuropsychological, and functional scales)within an international collaboration. Currently, the LADIS study is providing data about the natural history of WMC. In this paper, we review the background and the main results of the LADIS study. This review puts forward some considerations for future studies in the field., (Copyright © 2011 S. Karger AG, Basel)

Memory complaints are frequent in the elderly but its implications in cognition over time remain a controversial issue. Our objective was to evaluate the risk of self perceived memory complaints in the evolution for future dementia. The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes (WMC) on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Dementia and subtypes of dementia were classified. Self perceived memory complaints in independent elderly were collected during the interview. MRI was performed at entry and at the end of the study. 639 subjects were included (74.1 ± 5 years old, 55% women, 9.6 ± 3.8 years of schooling). At end of follow-up, 90 patients were demented (vascular dementia, 54; Alzheimer's disease (AD) and AD with vascular component, 34; frontotemporal dementia, 2). Using Cox regression analysis, we found that self perceived memory complaints were a strong predictor of AD and AD with vascular component during the follow-up (β = 2.7, p = 0.008; HR = 15.5, CI 95% [2.04, 117.6]), independently of other confounders, namely depressive symptoms, WMC severity, medial temporal lobe atrophy, and global cognition status at baseline. Self perceived memory complaints did not predict vascular dementia. In the LADIS study, self perceived memory complaints predicted AD but not vascular dementia in elderly subjects with WMC living independently.

Background and Purpose: The mechanisms by which leukoariosis impacts on clinical and cognitive functions are not yet fully understood. We hypothesized that ultrastructural abnormalities of the normal-appearing brain tissue (NABT) assessed by diffusion-weighted imaging played a major and independent role., Methods: In addition to a comprehensive clinical, neuropsychologic, and imaging work-up, diffusion-weighted imaging was performed in 340 participants of the multicenter leukoariosis and disability study examining the impact of white matter hyperintensities (WMH) on 65- to 85-year old individuals without previous disability. WMH severity was rated according to the Fazekas score. Multivariate regression analysis served to assess correlations of histogram metrics of the apparent diffusion coefficient (ADC) of whole-brain tissue, NABT, and of the mean ADC of WMH with cognitive functions., Results: Increasing WMH scores were associated with a higher frequency of hypertension, a greater WMH volume, more brain atrophy, worse overall cognitive performance, and changes in ADC. We found strong associations between the peak height of the ADC histogram of whole-brain tissue and NABT with memory performance, executive dysfunction, and speed, which remained after adjustment for WMH lesion volume and brain atrophy and were consistent among centers. No such association was seen with the mean ADC of WMH., Conclusions: Ultrastructural abnormalities of NABT increase with WMH severity and have a strong and independent effect on cognitive functions, whereas diffusion-weighted imaging metrics within WMH have no direct impact. This should be considered when defining outcome measures for trials that attempt to ameliorate the consequences of WMH progression.

Objective: To apply diffusion tensor imaging (DTI) for investigating the correlation between leukoaraiosis (LA) lesion's fraction anisotropy (FA) as well as average diffusion coefficient (DCavg) and LA severity, so as to explore DTI changes in microstructure of white marrow with normal ordinary MRI and its correlation with cognitive function., Methods: Sixty LA patients and 30 healthy elderly people accepted DTI examination to detect the value of DCavg and FA of LA lesion and normal white marrow. The Mini-Mental State Examination (MMSE) was used for assessing cognitive function., Results: LA severity (0 grade to 3 grade) was positively associated with DCavg, i.e. the more severe was LA, the higher DCavg was (0.66 +/- 0.05 to 1.09 +/- 0.06, P < 0.05); and it was negatively associated with FA, i.e. the more severe was LA, the lower FA was (0.42 +/- 0.04 to 0.26 +/- 0.03, P < 0.05). Neuropsychology tests (Mini-Mental State Examination, MMSE) had a significant relationship with DCavg and FA of normal appearing white matter (NAWM) in LA patients (P < 0.05), especially in anterior horn (Pearson Correlation Coefficient 0.422, P < 0.05) and in centrum semiovale (Pearson Correlation Coefficient -0.495, P < 0.01)., Conclusions: In DTI examination, DCavg and FA of LA displays characteristic changes. Therefore, DTI can detect the macrostructaral changes of white marrow with normal MRI and these changes are related to cognitive function.

Objectives: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes., Methods: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders., Results: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (beta = -0.61; p = 0.043), and worse compound scores for speed and motor control (beta = -0.25; p = 0.006), executive functions (beta = -0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (beta = -0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus., Conclusion: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Background: This study is to investigate the association between single and combined vascular brain changes (white matter lesions [WMLs], lacunar infarctions) and the cognitive domains of memory, processing speed, and motor function in the elderly adults., Methods: In a sample of 268 participants aged 65-83 years of the MEMO (Memory and Morbidity in Augsburg Elderly) population-based study in Augsburg, Germany, cerebral magnetic resonance imaging (MRI) was performed and a detailed neuropsychological test battery applied. Analysis of covariance determined the effects of vascular brain changes on domains of cognitive functioning., Results: Strong associations of large WMLs and of MRI-defined lacunar infarction with three different domains of cognitive function even after adjustment for age, gender, and education were found. The combined occurrence of both lesions affected about one in 10 participants and was associated with a strong decrease in cognitive function in all domains. The difference between the groups with only one lesion type (either large WMLs or MRI-defined infarction) and participants affected by both was significant in the domains of processing speed and memory, even after adjustment for important confounders such as age, gender, education, and comorbidities. The effects of both lesion types on cognitive function were not more than additive., Conclusions: Our study shows that both large WMLs and MRI-defined lacunar infarction contribute to impairments in different cognitive domains. The results suggest that their combined occurrence is associated with stronger reductions in cognitive function than each of the two brain lesion types alone.

The aim of our study was to investigate the effects of silent brain lesions on cognitive function of community-dwelling elderly individuals. Brain magnetic resonance imaging and other medical examinations were performed on 350 nondemented elderly individuals (121 male and 229 female, average age 72.4 years) who resided in the rural community of Sefuri Village, Saga, Japan. The mini mental state examination and modified Stroop test (MST) were used to identify cognitive impairment. White matter lesions (WMLs) and cerebral atrophy on magnetic resonance imaging were measured quantitatively. Multivariate analyses were done using a logistic regression model with a software package. Cognitive impairment defined by mini mental state examination score less than 24 was present in 55 individuals (15.7%). They had a lower educational level, significantly larger quantity of WMLs, and more remarkable cerebral atrophy. Frontal lobe dysfunction was detected in 52 individuals (14.9%) through prolonged MST score (>36 seconds). Impaired frontal lobe function was related to number of silent lacunar infarcts, larger WMLs, and more prominent cerebral atrophy. MST score in individuals with two or more infarcts was significantly more prolonged compared with MST score in those without infarction. These results suggest that WMLs may cause rather diffuse cognitive decline, whereas multiple lacunar infarcts are specifically involved in frontal lobe dysfunction. Silent ischemic lesions in apparently healthy elderly individuals seem to form a distinctive group of people with vascular cognitive impairment without dementia. This group should be the primary target of prevention of vascular dementia.

Objectives: To determine whether self-perceived memory impairment is associated with the severity of white matter changes (WMC) and is related to cognitive impairment., Methods: Data were drawn from the multinational Leukoaraiosis and Disability Study (LADIS), which investigates the impact of WMC on global functioning. WMC severity was rated using the Fazekas scale. Medial temporal lobe atrophy (MTA) was scored visually and mean values were calculated. The neuropsychological battery consisted of the Mini-Mental State Examination, a modified version of the VADAS-Cog, Trail making and Stroop tests. A question about self-perceived memory impairment was used as a measure for presence of memory complaints. Cognitive performance was analysed test-by-test and in three main domains: memory, executive functions and speed/motor control. The Geriatric Depression Scale (GDS) was used as a measure of depressive symptoms., Results: Six hundred and thirty-eight subjects were included in this study. No association was found between memory complaints and the severity of WMC. Subjects with memory complaints (n = 399) had a higher GDS score [t((637)) = -7.15; p<0.02] and performed worse on almost all cognitive tests and on the three cognitive domains. Multiple linear regression showed that the worse performance on the memory domain was associated with memory complaints independently of depressive symptoms, WMC severity and MTA (R(2) = 0.183; F = 17.09, beta = -0.126; p<0.05)., Conclusion: In a sample of non-disabled elderly subjects with WMC, self-perceived memory impairment is significantly associated with objective memory impairment independently of the WMC severity, depressive symptoms and MTA.

Background: The neuropathology of behavioural and psychological symptoms is much less understood than the neuropathology of cognitive impairment in AD. On MRI, medial temporal lobe atrophy (MTA) is presumed to reflect Alzheimer- type pathology. White matter hyperintensities (WMH) are considered markers of vascular pathology., Aim: We investigated differences in prevalence of behavioural and psychological symptoms in AD according to the presence of MTA and WMH on MRI., Methods: Behavioural and psychological symptoms of 111 consecutive AD patients were assessed using the Neuropsychatric Inventory (NPI). Symptoms were considered present when the score was > or =1. On MRI, MTA was rated using the five-point Scheltens-scale and WMH using the four-point Fazekas-scale. Both MRI measures were dichotomised (MTA: absent 0/1, present 2-4; WMH absent 0/1, present 2/3)., Results: Of the 111 AD patients, 60(55%) had MTA, and 32(29%) had WMH. The presence of MTA was associated with the presence of WMH (chi (2) = 11.8, p < 0.001). The prevalence of behavioural and psychological symptoms--defined as a NPI score of > or =1 on at least one symptom--was 74%.The median NPI score of the total study population was 6(0-41). There was no difference in prevalence according to MTA (p = 0.53) or WMH (p = 0.18). On inspection of individual NPI items, neither MTA, nor WMH was related to any of the symptoms., Conclusions: There were no differences in prevalence of behavioural and psychological symptoms according to MTA or WMH, as rated on MRI. This suggests that the occurrence of those symptoms depends on other determinants, such as coping style or genetic make-up.

Background and Purpose: Leukoaraiosis (LA) might interrupt intra- and interhemispheric communication and thus induce cognitive impairments and dementia. It remains unclear, however, if there is a volume threshold of LA that is needed before either the signs of dementia and/or a specific pattern of neuropsychological impairment become manifest. Roman et al has suggested that 25% of white matter may need to be involved before white matter alterations influence the clinical signs associated with dementia. The purpose of this study is to ascertain the threshold of MRI-LA as measured with a visual rating scale needed to induce specific patterns of neuropsychological impairment associated with dementia., Methods: One hundred fifteen patients with dementia received a comprehensive neuropsychological examination and the severity of MRI-LA was measured using a 40-point LA scale., Results: Patients were categorized into low (mean LA=4.21+/-2.92; 3.22%-17.82%), moderate (mean LA=12.58+/-2.54; 25.01%-37.80%), and severe (mean LA=22.36+/-4.04; 45.80%-66.00%) LA groups. Patients in the mild LA group obtained markedly lower scores on tests of episodic memory compared with working memory, a neuropsychological profile often associated with Alzheimer disease. Patients with moderate LA displayed equal impairment on neuropsychological tests. Patients in the severe LA group obtained significantly lower scores on tests of working memory as compared with episodic memory., Conclusions: These data provide evidence that a threshold of moderate MRI-LA as measured with a visual rating scale is associated with greater and/or equal impairment on tests of working memory versus episodic memory and provides a benchmark to assess the effect of MRI-LA on the clinical presentation of dementia.

Background and Purpose: Associations between regional white matter lesion pathology and neuropsychological performance across the aging spectrum are not well understood and, to date, research has been largely contradictory and inconclusive. The current study set out to clarify some of the inconsistencies in the literature by relating volumetric analyses of white matter lesions (deep white matter lesions and periventricular lesions) to neuropsychological performance in a large clinical sample of older adults diagnosed with mild cognitive impairment., Methods: Seventy older adults with mild cognitive impairment were administered a comprehensive neuropsychological battery. White matter lesions identified on T2-weighted FLAIR images were quantified using a semi-automated volumetric approach (pixel thresholding)., Results: Results showed that, in contrast to performance on memory and naming tasks, total white matter lesions strongly predicted executive impairments, slowed processing speed, and visuospatial/construction difficulties. In addition, separate regression analyses demonstrated that results were primarily accounted for by deep white matter lesions (but not periventricular lesions), most likely due to frontal-subcortical circuitry disruption. Moreover, deep white matter lesions, but not periventricular lesions, significantly predicted overall poorer neuropsychological functioning after controlling for age, education, and level of depression., Conclusions: Taken together, findings demonstrate a differential influence of lesion type on cognitive impairment in mild cognitive impairment and implicate deep white matter lesions as being most detrimental in terms of neuropsychological functioning. Clinical, theoretical, and methodological implications of these results are discussed.

Background and Aims: 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)., Methods: 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., Results: 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., Conclusion: 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.

Background: Evidence from cross-sectional studies suggests a link between cerebral age-related white matter changes and depressive symptoms in older people, although the temporal association remains unclear., Aims: To investigate age-related white matter changes on magnetic resonance imaging (MRI) as an independent predictor of depressive symptoms at 1 year after controlling for known confounders., Method: In a pan-European multicentre study of 639 older adults without significant disability, MRI white matter changes and demographic and clinical variables, including cognitive scores, quality of life, disability and depressive symptoms, were assessed at baseline. Clinical assessments were repeated at 1 year., Results: Using logistic regression analysis, severity of white matter changes was shown to independently and significantly predict depressive symptoms at 1 year after controlling for baseline depressive symptoms, quality of life and worsening disability (P<0.01)., Conclusions: 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.

Background: Age-related white matter changes (ARWMCs), frequently detected on neuroimaging, are associated with motor, cognitive, urinary, and mood disorders. The LADIS (LeukoAraiosis and DISability) Study primarily aims to assess ARWMCs as a determinant of global functional decline in the elderly population., Methods: We enrolled 639 patients (mean age, 74.1 +/- 5.0 years; 45.1% male) referred for nondisabling complaints, who had ARWMCs detected on brain magnetic resonance imaging (MRI) of mild, moderate, or severe grade according to the Fazekas scale. At the 1-year follow-up, 619 were reassessed using the Instrumental Activities of Daily Living (IADL) scale. Of these, 506 were totally independent at baseline, and 113 were impaired in only 1 item of the IADL scale. We studied the 1-year transition to 2 or more activities limited and selective functional impairments as cofactors of functional decline., Results: The rate of transition was 9%, 15%, and 26%, in the mild, moderate, and severe ARWMC group, respectively. Comparing the severe with the mild ARWMC groups and adjusting for age and for other predictors of decline, the risk was more than 2-fold higher (odds ratio; 2.38; 95% confidence interval, 1.29-4.38) in patients with 0 or 1 activity limited, and 3-fold higher (odds ratio, 3.02; 95% confidence interval, 1.34-6.78) among patients fully independent at baseline. Both motor and cognitive deterioration predominantly explained the effect of ARWMCs on global functional decline., Conclusion: Elderly patients who are functionally independent and who have severe ARWMCs are at considerable risk of becoming more dependent in a short period, mostly owing to motor and cognitive deterioration.

Background/aims: The Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) is a widely used rating instrument. The Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) includes additional tests reflecting mental speed and executive functions. The objective of this study was to compare the results of the two scales among subjects with various degrees of white matter hyperintensities (WMHs)., Methods: In the multicentre, multinational Leukoaraiosis and Disability in the Elderly (LADIS) study, 616 non-disabled subjects between the ages of 65 and 84 were examined using MRI, the ADAS-cog and VADAS-cog. The WMH rating from the MRI divided the patients into groups of mild (n = 280), moderate (n = 187) and severe (n = 149) degrees of change., Results: Covariance analysis controlling for the effect of age and education revealed that the ADAS-cog differentiated only the mild and severe WMH groups, while the differences between all three groups were highly significant with the VADAS-cog., Conclusions: The VADAS-cog significantly differentiated between all the white matter groups. In comparison, the ADAS-cog differentiated only severe changes. Accordingly, the VADAS-cog may be a more sensitive endpoint in studies of patients with white matter load and vascular burden of the brain., ((c) 2007 S. Karger AG, Basel.)

Background: This study investigates the effect of leukoaraiosis on patients presenting with cognitive impairment after lacunar stroke., Methods: Fourty-six patients with cognitive impairment and newly discovered lacunar stroke detected by brain magnetic resonance imaging underwent neuropsychological testing., Results: Patients with both lacunar infarct and leukoaraiosis performed less well on cognitive measures, compared to those with lacunar infarcts alone. Additionally, leukoaraiosis severity inversely correlated with cognitive performance., Conclusions: In patients with lacunar stroke, presence of leukoaraiosis is associated with worse performance in multiple cognitive domains. These findings suggest lacunar infarcts plus leukoaraiosis is a common etiology for vascular dementia.

Background: Interpretation of treatment trials in vascular dementia is confounded by the presence of coexistent Alzheimer disease (AD) pathology. The younger onset genetic disease cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) offers a model of pure vascular dementia, in which such confounding is unlikely. To validate CADASIL's use as a model it is important to show it results in a similar cognitive impairment., Methods: The same neuropsychological assessment was administered to patients with CADASIL (n = 34, 14 of whom had had stroke), sporadic small vessel disease (SVD) presenting with lacunar stroke and having confluent leukoaraiosis (n = 54), and healthy controls (n = 25)., Results: A similar pattern of neuropsychological impairment was seen in the two diseases, with prominent early executive dysfunction. Patients with CADASIL and SVD performed worse than controls on Trails switching test (CADASIL p = 0.006; SVD p < 0.001), and on verbal fluency test (CADASIL p = 0.015; SVD p = 0.004). The SVD group also performed worse on immediate (p = 0.050) and delayed (p = 0.049) memory. When only patients with CADASIL with stroke were included in analysis with SVD subjects, all of whom had had stroke, a very similar cognitive profile was seen. The only difference was on verbal fluency, where CADASIL subjects performed worse (p = 0.044)., Conclusion: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and small vessel disease show a similar pattern of cognitive deficits. This suggests that CADASIL provides a model of pure vascular dementia relevant for sporadic small vessel disease vascular dementia.

The relationship between age-related white matter changes and cognitive performance in independent elderly people is still not clear. The Leukoaraiosis and Disability in the Elderly study (LADIS) involves 11 European centers. It aims to assess the role of the age-related white matter changes as an independent factor in the transition to disability, and in cognitive performance of an independent elderly population. A comprehensive neuropsychological battery was constructed in order to harmonize the cognitive assessment across countries. Patients were evaluated at baseline and during the 3-year follow-up with the Mini-Mental State Examination, a modified version of the VADAS-Cog (Alzheimer's Dementia Assessment Scale plus tests of Delayed recall, Symbol digit, Digit span, Maze, Digit cancellation and Verbal fluency), Trail making and Stroop test. Six hundred thirty-eight patients (mean age 74 +/- 5 years; mean educational level 10 +/- 4, F/M: 351/287) were included in this study. Neuropsychological data were analyzed test by test and also grouped in three compound measures (executive, memory and speed/motor control domains). Older subjects (>74 years) performed significantly worse than younger subjects on the ADAS-Mod and on the tests of memory (t(631) = 3.25; p = 0.001), executive functions (t(581) = 4.68; p = 0.001) and speed/motor control (t(587) = 4.01; p = 0.001). Participants with higher educational level (>8 years of school) showed better performances on the compound measures for memory (t(631) = 3.25; p = 0.001), executive functions (t(581) = 4.68; p = 0.001) and speed/motor control (t(587) = 4.01; p = 0.001). Using multiple regression analysis models to study the influence of demographic variables on cognitive performance, age and education remained important variables influencing test performance. In the LADIS population baseline data, older age and lower educational levels negatively influence neuropsychological performance.

Cerebral small-vessel disease is common in older people and may contribute to the development of dementia. The objective of the present study was to evaluate the relationship between measures of cerebral small-vessel disease on MRI and the rate of decline in specific cognitive domains in participants from the prospective, population-based Rotterdam Scan Study. Participants were 60-90 years of age and free from dementia at baseline in 1995-1996. White matter lesions (WML), cerebral infarcts and generalized brain atrophy were assessed on the baseline MRI. We performed neuropsychological testing at baseline and repeatedly in 1999-2000 and in 2001-2003. We used random-effects models for repeated measures to examine the association between quantitative MRI measures and rate of decline in measures of global cognitive function, information processing speed, executive function and memory. There were a total of 2266 assessments for the 832 participants in the study, with an average time from the initial to last assessment of 5.2 years. Increasing severity of periventricular WML and generalized brain atrophy and the presence of brain infarcts on MRI were associated with a steeper decline in cognitive function. These structural brain changes were specifically associated with decline in information processing speed and executive function. The associations between MRI measures of cerebral small-vessel disease and cognitive decline did not change after additional adjustment for vascular risk factors or depressed mood. After exclusion of participants with an incident stroke, some of the associations of periventricular WML, brain infarcts and generalized brain atrophy with measures of information processing speed and executive function were no longer significant. This may indicate that stroke plays an intermediate role in the relationship between cerebral small-vessel disease and cognitive decline. Our results suggest that in older people cerebral small-vessel disease may contribute to cognitive decline by affecting information processing speed and executive function.