Changes in white matter as determinant of global functional decline in older independent outpatients: Three year follow-up of LADIS (leukoaraiosis and disability) study cohort

Department of Neurological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134 Firenze, Italy.
BMJ (online) (Impact Factor: 17.45). 02/2009; 339(7715):b2477. DOI: 10.1136/bmj.b2477
Source: PubMed

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

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Available from: Giovanna Carlucci, Sep 26, 2015
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    • "The value of a detailed description of the cognitive consequences of age-related WM changes extends to age-related neurocognitive disorders, such as dementia and depression (Madden et al., 2012). WM hyperintensities have not only been linked with global functional decline in old age but also with an increased risk of dementia and late-life depression (Debette & Markus, 2010; Firbank et al., 2012; Inzitari et al., 2009). Interestingly, increased RT inconsistency appears to be a feature of both depression and dementia (Kaiser et al., 2008; Tse, Balota, Yap, Duchek, & McCabe, 2010). "
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    ABSTRACT: White matter (WM) change plays an important role in age-related cognitive decline. In this review, we consider methodological advances with particular relevance to the role of WM in age-related changes in processing speed. In this context, intra-individual variability in processing speed performance has emerged as a sensitive proxy of cognitive and neurological decline while neuroimaging techniques used to assess WM change have become increasingly more sensitive. Together with a carefully designed task protocol, we emphasize that the combined implementation of intra-individual variability and neuroimaging techniques hold promise for specifying the WM-processing speed relationship with implications for normative and clinical samples. (JINS, 2014, 20, 1-6).
    Journal of the International Neuropsychological Society 02/2014; 20(3):1-6. DOI:10.1017/S1355617713001458 · 2.96 Impact Factor
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    • "Although we found no significant association between ESR1 rs2234693 or rs9340799 and the volume of gray matter, white matter, HC, or CC area in either men or women, the C allele of rs2234693 and the G allele of rs9340799 were associated with significantly smaller volumes of WML in women. WML are thought to reflect small-vessel cerebrovascular disease (LADIS Study Group, 2011; Raz et al., 2007), which increases in occurrence with age (Ylikoski et al., 1995) and which has been associated with poorer cognitive performance (Inzitari et al., 2009), mild cognitive impairment (Ritchie et al., 2010), and an increased risk of dementia (Debette and Markus, 2010; Mortamais et al., 2013), particularly in women (Sawada et al., 2000). In line with this, previous studies have also reported significant associations between rs2234693 and cognitive function (Yaffe et al., 2002), the risk of Alzheimer's disease (Sundermann et al., 2010), and cardiovascular disease in older women (Herrington et al., 2002b; Schuit et al., 2004); however, the direction of the association has not been consistently found. "
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    ABSTRACT: Structural imaging studies suggest gender differences in brain volumes; however, whether hormone treatment (HT) can protect against age-related structural changes remains unknown, and no prior neuroimaging study has investigated potential interactions between HT and estrogen receptor (ESR) polymorphisms. Magnetic resonance imaging was used to measure gray and white matter, hippocampal volume, corpus callosum, cerebrospinal fluid (CSF), total intracranial volume (ICV) and white matter lesions (WML) in 582 non-demented older adults. In multivariable analysis, when compared to women who had never used HT, men and women currently on treatment, but not past users, had significantly smaller ratios of gray matter to ICV and increased atrophy (CSF/ICV ratio). Hippocampal and white matter volume as well as the corpus callosum area were not significantly different across groups. ESR2 variants were not significantly associated with brain measures, but women with the ESR1 rs2234693 C allele had significantly smaller WML. Furthermore this association was modified by HT use. Our results do not support a beneficial effect of HT on brain volumes in older women, but suggest the potential involvement of ESR1 in WML.
    Neurobiology of aging 10/2013; 35(3). DOI:10.1016/j.neurobiolaging.2013.09.026 · 5.01 Impact Factor
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    • "Age-related white matter lesions (WML) mainly affect information processing speed and executive function [1] and entail an increased risk for cognitive decline and disability [2]. In a meta-analytic study, high hazard ratios were also reported for incident stroke (3.3) and dementia (1.9) [3], but results from studies on WML association to dementia subtypes are inconclusive [4] [5] [6]. "
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    ABSTRACT: Age-related white matter lesions (WML) are a risk factor for stroke, cognitive decline, and dementia. Different requirements are imposed on methods for the assessment of WML in clinical settings and for research purposes, but reliability analysis is of major importance. In this study, WML assessment with three different methods was evaluated. In the Gothenburg mild cognitive impairment study, MRI scans from 152 participants were used to assess WML with the Fazekas visual rating scale on T2 images, a manual volumetric method on FLAIR images, and FreeSurfer volumetry on T1 images. Reliability was acceptable for all three methods. For low WML volumes (2/3 of the patients), reliability was overall lower and nonsignificant for the manual volumetric method. Unreliability in the assessment of patients with low WML with manual volumetry may mainly be due to intensity variation in the FLAIR sequence used; hence, intensity standardization and normalization methods must be used for more accurate assessments. The FreeSurfer segmentations resulted in smaller WML volumes than the volumes acquired with the manual method and showed deviations from visible hypointensities in the T1 images, which quite likely reduces validity.
    Journal of aging research 01/2013; 2013(59):198471. DOI:10.1155/2013/198471
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