Leukoaraiosis And Disability Research Articles

The potential role of leukoaraiosis in remodeling the brain network to buffer cognitive decline: a Leukoaraiosis And Disability study from Alzheimer's Disease Neuroimaging Initiative.

Leukoaraiosis (LA) is a phenomenon of the brain that is often observed in elderly people. However, little is known about the role of LA in cognitive impairment in neurodegeneration and disease. This cross-sectional, retrospective Leukoaraiosis And Disability (LADIS) study aimed to characterize the relationship between brain white matter connectivity properties with LA ratings in patients with Alzheimer's disease (AD) as compared with age-matched cognitively normal controls. Patients with AD (n=76) and elderly individuals with normal cognitive (NC) function (n=82) were classified into 3 groups, LA1, LA2, and LA3, according to the rating of their white matter changes (WMCs). Diffusion tensor imaging (DTI) data were analyzed by quantifying and comparing the white matter connectivity properties and gray matter (GM) volume of brain regions of interest (ROIs). The rich-club network properties in the AD LA1 and LA2 groups showed significant patterns of disrupted peripheral regions and reduced connectivity compared to those in the NC LA1 and LA2 groups, respectively. However, the rich-club network properties in the AD LA3 group showed similar patterns of disrupted peripheral regions and reduced connectivity compared to those in the NC LA3 group, despite there being significant hippocampal and amygdala atrophic differences between AD patients and NC elders. Compared to the NC LA1 group, the characteristic path length of white matter fiber connectivity in the NC LA3 group was significantly increased, and the brain's global efficiency, clustering coefficient, and network connectivity strength were significantly reduced (P<0.05, respectively). However, no significant differences (P>0.05) were observed in characteristic path length, reduced global efficiency, or the clustering coefficient between the NC LA3 and AD LA1 groups, or between the NC LA3 and AD LA2 groups. Our findings offer some insights into a potential role of LA in cognitive impairment that may predict the development of disability in older adults. The occurrence of LA, an intermediate degenerative change, during neurodegeneration and disease may potentially lead to the remodeling of the brain network through brain plasticity. LA, therefore, representing a possible compensatory mechanism to buffer cognitive decline.

Cognitive reserve moderates long-term cognitive and functional outcome in cerebral small vessel disease

BackgroundCerebral small vessel disease (SVD) is characterised by progressive white matter hyperintensities (WMH), cognitive decline and loss of functional independence. The correspondence between neuroimaging findings and the severity of clinical...

White Matter Changes and Cognitive Decline in a Ten-Year Follow-Up Period: A Pilot Study on a Single-Center Cohort from the Leukoaraiosis and Disability Study

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 [F_{2, 62} = 15.85, p = 0.000], ADAS [F_{2, 62} = 15.85, p = 0.000] and VADAS [F_{2, 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.

Early-Stage White Matter Lesions Detected by Multispectral MRI Segmentation Predict Progressive Cognitive Decline.

White matter lesions (WML) are the main brain imaging surrogate of cerebral small-vessel disease. A new MRI tissue segmentation method, based on a discriminative clustering approach without explicit model-based added prior, detects partial WML volumes, likely representing very early-stage changes in normal-appearing brain tissue. This study investigated how the different stages of WML, from a “pre-visible” stage to fully developed lesions, predict future cognitive decline. MRI scans of 78 subjects, aged 65–84 years, from the Leukoaraiosis and Disability (LADIS) study were analyzed using a self-supervised multispectral segmentation algorithm to identify tissue types and partial WML volumes. Each lesion voxel was classified as having a small (33%), intermediate (66%), or high (100%) proportion of lesion tissue. The subjects were evaluated with detailed clinical and neuropsychological assessments at baseline and at three annual follow-up visits. We found that voxels with small partial WML predicted lower executive function compound scores at baseline, and steeper decline of executive scores in follow-up, independently of the demographics and the conventionally estimated hyperintensity volume on fluid-attenuated inversion recovery images. The intermediate and fully developed lesions were related to impairments in multiple cognitive domains including executive functions, processing speed, memory, and global cognitive function. In conclusion, early-stage partial WML, still too faint to be clearly detectable on conventional MRI, already predict executive dysfunction and progressive cognitive decline regardless of the conventionally evaluated WML load. These findings advance early recognition of small vessel disease and incipient vascular cognitive impairment.

Impact of cerebral white matter changes on functionality in older adults: An overview of the LADIS Study results and future directions.

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.

Physical activity in the elderly is associated with improved executive function and processing speed: the LADIS Study.

Physical activity reduces the risk of cognitive decline but may affect cognitive domains differently. We examined whether physical activity modifies processing speed, executive function and memory in a population of non-dementia elderly subjects with age-related white matter changes (ARWMC). Data from the Leukoaraiosis And DISability (LADIS) study, a multicenter, European prospective cohort study aimed at examining the role of ARWMC in transition to disability, was used. Subjects in the LADIS study were clinically assessed yearly for 3 years including MRI at baseline and 3-year follow-up. Physical activity was assessed at baseline, and cognitive compound scores at baseline and 3-year assessment were used. Two-hundred-eighty-two subjects (age, y (mean (SD)): 73.1 (± 5.1); gender (f/m): 164/118); MMSE (mean (SD)): 28.3 (± 1.7)) who had not progressed to MCI or dementia, were included. Multiple variable linear regression analysis with baseline MMSE, education, gender, age, stroke, diabetes and ARWMC rating as covariates revealed that physical activity was associated with better scores at baseline and 3-year follow-up for executive function (baseline: β: 0.39, 95% CI: 0.13-0.90, p = 0.008; follow-up: β: 0.24, 95% CI: 0.10-0.38, p = 0.001) and processing speed (baseline: β: 0.48, 95% CI: 0.14-0.89, p = 0.005; follow-up: β: 0.15, 95% CI: 0.02-0.29, p = 0.02) but not memory. When including baseline cognitive score as a covariate in the analysis of 3-year follow-up scores, executive function remained significant (β: 0.11, 95% CI: 0-0.22, p = 0.04). Our findings confirm previous findings of a positive effect of physical activity on cognitive functions in elderly subjects, and further extends these by showing that the association is also present in patients with ARWMC.

Neurological abnormalities predict disability: the LADIS (Leukoaraiosis And DISability) study.

To investigate the role of neurological abnormalities and magnetic resonance imaging (MRI) lesions in predicting global functional decline in a cohort of initially independent-living elderly subjects. The Leukoaraiosis And DISability (LADIS) Study, involving 11 European centres, was primarily aimed at evaluating age-related white matter changes (ARWMC) as an independent predictor of the transition to disability (according to Instrumental Activities of Daily Living scale) or death in independent elderly subjects that were followed up for 3 years. At baseline, a standardized neurological examination was performed. MRI assessment included age-related white matter changes (ARWMC) grading (mild, moderate, severe according to the Fazekas' scale), count of lacunar and non-lacunar infarcts, and global atrophy rating. Of the 633 (out of the 639 enrolled) patients with follow-up information (mean age 74.1 ± 5.0 years, 45 % males), 327 (51.7 %) presented at the initial visit with ≥1 neurological abnormality and 242 (38 %) reached the main study outcome. Cox regression analyses, adjusting for MRI features and other determinants of functional decline, showed that the baseline presence of any neurological abnormality independently predicted transition to disability or death [HR (95 % CI) 1.53 (1.01-2.34)]. The hazard increased with increasing number of abnormalities. Among MRI lesions, only ARWMC of severe grade independently predicted disability or death [HR (95 % CI) 2.18 (1.37-3.48)]. In our cohort, presence and number of neurological examination abnormalities predicted global functional decline independent of MRI lesions typical of the aging brain and other determinants of disability in the elderly. Systematically checking for neurological examination abnormalities in older patients may be cost-effective in identifying those at risk of functional decline.

Physical Activity Prevents Progression for Cognitive Impairment and Vascular Dementia

We aimed to study if physical activity could interfere with progression for cognitive impairment and dementia in older people with white matter changes living independently. The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes on the transition of independent elderly subjects into disability. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and cognitive assessment with classification of cognitive impairment and dementia according to usual clinical criteria. Physical activity was recorded during the clinical interview. MRI was performed at entry and at the end of the study. Six hundred thirty-nine subjects were included (74.1±5 years old, 55% women, 9.6±3.8 years of schooling, 64% physically active). At the end of follow-up, 90 patients had dementia (vascular dementia, 54; Alzheimer disease with vascular component, 34; frontotemporal dementia, 2), and 147 had cognitive impairment not dementia. Using Cox regression analysis, physical activity reduced the risk of cognitive impairment (dementia and not dementia: β=-0.45, P=0.002; hazard ratio, 0.64; 95% CI, 0.48-0.85), dementia (β=-0.49, P=0.043; hazard ratio, 0.61; 95% CI, 0.38-0.98), and vascular dementia (β=-0.86, P=0.008; hazard ratio, 0.42; 95% CI, 0.22-0.80), independent of age, education, white matter change severity, medial temporal atrophy, previous and incident stroke, and diabetes. Physical activity reduces the risk of cognitive impairment, mainly vascular dementia, in older people living independently.

Corpus Callosum Tissue Loss and Development of Motor and Global Cognitive Impairment: The LADIS Study

Objective: To examine the impact of corpus callosum (CC) tissue loss on the development of global cognitive and motor impairment in the elderly. Methods: This study was based on the Leukoaraiosis and Disability (LADIS) study. Assessment of cognitive and motor functions and magnetic resonance imaging (MRI) were done at baseline and at a 3-year follow-up in nondemented elderly subjects. Results: 328 of 639 LADIS subjects had MRIs at baseline and at the 3-year follow-up, which allowed for assessment of CC. Logistic regression revealed differential tissue loss rates in posterior CC in subjects converting to dementia, compared to nonconverters (p < 0.05). Anterior and posterior CC tissue loss was significantly correlated with self-perceived memory impairment in nonconverters (p < 0.05). CC tissue loss was also significantly associated with impaired single leg stance time (p < 0.01). Conclusion: The present longitudinal study on CC supports the role of callosal tissue loss in the development of global cognitive as well as motor impairment.

Self-Perceived Memory Complaints Predict Progression to Alzheimer Disease. The LADIS Study

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.

What does the corpus callosum tell us about brain changes in the elderly?

Evaluation of: Ryberg C, Rostrup E, Paulson OB et al. On behalf of the LADIS study group. Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3 year follow-up of the LADIS study cohort. J. Neurol. Sci. 307(1–2), 100–105 (2011).The corpus callosum is the largest hemispheric interconnection bundle in the human brain. Its anterior–posterior fiber caliber gradient can help in understanding the pathophysiological mechanisms underlying white matter changes both in old age and dementia. Here, the Leukoaraiosis and Disability (LADIS) study, a longitudinal cohort study, which shows an association between corpus callosum atrophy and cognitive and motor decline in the elderly, provides the possibility to consider the use of multimodal macro-microstructural imaging of corpus callosum as a marker of structural brain changes of physiological and pathological aging.

Lacunar infarct and cognitive decline

Evaluation of: Jokinen H, Gouw AA, Madureira S et al. Incident lacunes influence cognitive decline: the LADIS study. Neurology 76(22), 1872–1878 (2011).Lacunar infarcts or lacunes result from occlusion of a single penetrating artery and account for approximately a quarter of cerebral infarctions. The short-term prognosis of symptomatic lacunar infarct is favorable – that is, low early mortality and a high proportion of symptom-free patients at hospital discharge – but the prognosis in the mid- and long-term is less favorable as there is an increased risk of death, recurrence of stroke and vascular-type dementia. This unfavorable prognosis is mostly related to asymptomatic progression of small-vessel disease. Therefore, the consideration of lacunar infarct as a relatively benign disorder is misleading. Whereas the clinical relevance of lacunar infarct to lacunar syndromes is widely accepted, the degree to which lacunes affect cognitive function remains unclear. The reviewed article presents new data from the multinational Leukoaraiosis and Disability (LADIS) study, which shows that an increase in silent lacunes parallels significantly with longitudinal cognitive decline in executive functions and psychomotor speed. The study is discussed in the context of the current state and knowledge regarding cognitive impairment in ischemic cerebral small-vessel disease, in particular regarding its health consequences.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: A 3-year follow-up of the LADIS study cohort

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population.On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior–posterior regions (CC1–CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed.CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness).In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly.

Neuropsychological Predictors of Dementia in a Three-Year Follow-Up Period: Data from the LADIS Study

Background: White matter changes (WMC) are related to cognitive deficits and dementia. Our aim was to determine the extent to which the performance in neuropsychological tests would be able to predict the clinical diagnosis of dementia. Methods: The LADIS (Leukoaraiosis and Disability) is a prospective study that evaluates the impact of WMC on the transition of independent elderly to disability. The subjects were evaluated at baseline and yearly during 3 years with a comprehensive clinical, functional and neuropsychological protocol. At each visit, dementia was classified according to clinical criteria. The performance in the neuropsychological batteries was compared according to the clinical diagnosis of dementia. Results: From the initially enrolled 639 subjects, 480 were evaluated at year 3. Dementia was diagnosed in 90 participants. The demented subjects had worse performance in almost all the baseline cognitive tests. Using receiver operating characteristic curves, we found that the Vascular Dementia Assessment Scale (VADAS) battery had higher sensitivity and specificity rates (area under the curve = 82%) to identify dementia compared with the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale. Worse performance on baseline MMSE (β = 0.33; p < 0.001) and VADAS (β = –0.07; p = 0.02) were predictors of dementia (regression analyses). Conclusion: Performance on the MMSE and the VADAS battery were important predictors of dementia at a 3-year period.

Leukoaraiosis and disability: The LADIS (leukoaraiosis and disability) study experience

Background: Age-related white matter changes (ARWMC) are frequently detected on neuroimaging and have been associated with motor, cognitive, urinary, and mood disorders. The LADIS Study primarily aims to assess ARWMC as a determinant of global functional decline in the elderly.

Longitudinal Cognitive Decline in Subcortical Ischemic Vascular Disease – The LADIS Study

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.

MRI-Defined Subcortical Ischemic Vascular Disease: Baseline Clinical and Neuropsychological Findings

Background: Subcortical ischemic vascular disease (SIVD) is a common, but often overlooked cause of vascular cognitive impairment. Diagnostic research criteria for SIVD are based on magnetic resonance imaging (MRI) findings including substantial white matter lesions (WML) and multiple lacunar infarcts. Empirical studies validating these imaging criteria are still few. The purpose of the study was to describe the clinical and cognitive characteristics of the MRI-defined SIVD in a mixed sample of functionally independent elderly subjects with WML. Methods: The subjects of the Leukoaraiosis and Disability (LADIS) study, aged 65–84 years, underwent comprehensive clinical and neuropsychological examinations, and brain MRI at the baseline assessment. The subjects meeting the SIVD imaging criteria (n = 89) were compared to the other subjects of the sample (n = 524). Results: SIVD was associated with lower education, hypertension and, independently, with obesity. The subjects with SIVD had more often motor impairment, a history of falls, and subtle impairment in activities of daily living, but they did not differ for depressive symptoms. SIVD subjects performed significantly inferiorly in tests of global cognitive function, psychomotor speed, attention and executive functions, verbal fluency, and working memory. Conclusion: In this population of nondisabled older adults with WML, SIVD was related to specific clinical and functional characteristics. Neuropsychological features included psychomotor slowing as well as deficits in attention and executive functions.

Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study

Background:Global age related white matter changes (ARWMC) are associated with progressive gait disturbances and falls, hypothesised to result from interruptions of cortico-subcortical circuits controlling balance, posture and locomotion.Methods:The location of...

Quantitation of brain tissue changes associated with white matter hyperintensities by diffusion‐weighted and magnetization transfer imaging: The LADIS (leukoaraiosis and disability in the elderly) study

To explore the value of diffusion-weighted imaging (DWI) and magnetization transfer imaging (MTI) for the improved detection and quantification of cerebral tissue changes associated with ageing and white matter hyperintensities (WMH). DWI (n = 340) and MTI (n = 177) were performed in nine centers of the multinational Leukoaraiosis And DISability (LADIS) study investigating the impact of WMH on 65- to 85-year-old individuals without prior disability. We assessed the apparent diffusion coefficient (ADC) and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT) and within WMH and related them to subjects' age and WHM severity according to the Fazekas score. ADC and MTR values showed a significant inter-site variation, which was stronger for the MTR. After z-transformation multiple regression analysis revealed WMH severity and age as significant predictors of global ADC and MTR changes. Only lesional ADC, but not MTR was related to WMH severity. ADC and MTR are both sensitive for age and WMH related changes in NABT. The ADC is more sensitive for tissue changes within WMH and appears to be more robust for multicenter settings.

FC01-03 Depressive symptoms predict cognitive decline in an elderly non disabled population with white matter changes. Results of the LADIS study

Aims:Depressive symptoms (DS) in the elderly have been implicated in cognitive decline, and are more frequent in patients with white matter changes (WMC). Our aim was to ascertain if DS influence cognition in an elderly population with WMC.Methods:The LADIS (Leukoaraiosis and Disability) is a prospective European study that evaluates the impact of WMC on the transition of independent elderly subjects into disability. Subjects were enrolled due to minor complaints without impact in daily-living activities, and presence of WMC. Subjects were evaluated at baseline and yearly during 3 years with a comprehensive clinical and functional protocol. DS were recorded with the Geriatric Depression Scale (GDS). Major depression was classified according to the DSM-IV criteria. Dementia and cognitive decline not dementia were diagnosed according to usual clinical criteria. MRI was performed at entry and at the end of the study. WMC severity was rated according to the Fazeka's scale.Results:639 subjects were included (74.1 ± 5 years old, 55% women, 9.6±3.8 years of schooling). 89% (568), 78.4% (501), and 75% (480) of the patients from the initial sample were followed-up in clinical visit at year 1, 2 and 3. At the end of the study 90 patients were demented and 147 patients had cognitive impairment not dementia. Using survival Cox regression we found that depressive symptoms were independent predictors of cognitive impairment independently of age, education, gender, WMC severity and temporal atrophy.Conclusion:Depressive symptoms are independent predictor of cognitive decline in an independent elderly population with WMC.