| 1. |
- Macfarlane, M. D., et al.
(author)
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Shape abnormalities of the caudate nucleus correlate with poorer gait and balance: Results from a subset of the ladis study
- 2015
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In: The American journal of geriatric psychiatry. - : Elsevier BV. - 1064-7481. ; 23:1, s. 59-
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Journal article (peer-reviewed)abstract
- Objective Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction. Methods Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit. Results There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB. Conclusion Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population. © 2015 American Association for Geriatric Psychiatry.
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| 2. |
- Schmidt, R., et al.
(author)
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White Matter Lesion Progression in LADIS Frequency, Clinical Effects, and Sample Size Calculations
- 2012
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In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 43:10, s. 2643-2647
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Journal article (peer-reviewed)abstract
- Background and Purpose-White matter lesion (WML) progression has been advocated as a surrogate marker in intervention trials on cerebral small vessel disease. We assessed the rate of visually rated WML progression, studied correlations between lesion progression and cognition, and estimated sample sizes for clinical trials with pure WML progression vs combined WML progression-cognitive outcomes. Methods-Those 394 participants of the Leukoaraiosis and Disability Study (LADIS) study with magnetic resonance imaging scanning at baseline and 3-year follow-up were analyzed. WML progression rating relied on the modified Rotterdam Progression Scale. The Vascular Dementia Assessment Scale global score and a composite score of specific executive function tests assessed longitudinal change in cognition. Sample size calculations were based on the assumption that treatment reduces WML progression by 1 grade on the Rotterdam Progression Scale. Results-WML progression related to deterioration in cognitive functioning. This relationship was less pronounced in subjects with early confluent and confluent lesions. Consequently, studies in which the outcome is cognitive change resulting from treatment effects on lesion progression will need between 1809 subjects per treatment arm when using executive tests and up to 18 853 subjects when using the Vascular Dementia Assessment Scale score. Studies having WML progression as the sole outcome will need only 58 or 70 individuals per treatment arm. Conclusions-WML progression is an interesting outcome for proof-of-concept studies in cerebral small vessel disease. If cognitive outcome measures are added to protocols, then sample size estimates increase substantially. Our data support the use of an executive test battery rather than the Vascular Dementia Assessment Scale as the primary cognitive outcome measure. (Stroke. 2012; 43:2643-2647.)
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| 3. |
- Benisty, S, et al.
(author)
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Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.
- 2009
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 80:5, s. 478-83
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Journal article (peer-reviewed)abstract
- 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.
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| 4. |
- Firbank, M. J., et al.
(author)
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Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study
- 2012
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In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 201:1, s. 40-45
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Journal article (peer-reviewed)abstract
- Background Brain white matter changes (WMC) and depressive symptoms are linked, but the directionality of this association remains unclear. Aims To investigate the relationship between baseline and incident depression and progression of white matter changes. Method In a longitudinal multicentre pan-European study (Leukoaraiosis and Disability in the elderly, LADIS), participants aged over 64 underwent baseline magnetic resonance imaging (MRI) and clinical assessments. Repeat scans were obtained at 3 years. Depressive outcomes were assessed in terms of depressive episodes and the Geriatric Depression Scale (GDS). Progression of WMC was measured using the modified Rotterdam Progression scale. Results Progression of WMC was significantly associated with incident depression during year 3 of the study (P = 0.002) and remained significant after controlling for transition to disability, baseline WMC and baseline history of depression. There was no significant association between progression of WMC and GDS score, and no significant relationship between progression of WMC and history of depression at baseline. Conclusions Our results support the vascular depression hypothesis and implicate WMC as causal in the pathogenesis of late-life depression.
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| 5. |
- Jokinen, H., et al.
(author)
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Diffusion changes predict cognitive and functional outcome: The LADIS study
- 2013
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In: Annals of Neurology. - : Wiley. - 0364-5134. ; 73:5, s. 576-583
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Journal article (peer-reviewed)abstract
- Objective A study was undertaken to determine whether diffusion-weighted imaging (DWI) abnormalities in normal-appearing brain tissue (NABT) and in white matter hyperintensities (WMH) predict longitudinal cognitive decline and disability in older individuals independently of the concomitant magnetic resonance imaging (MRI) findings. Methods A total of 340 LADIS (Leukoaraiosis and Disability Study) participants, aged 65 to 84 years, underwent brain MRI including DWI at baseline. Neuropsychological and functional assessments were carried out at study entry and repeated annually over a 3-year observational period. Linear mixed models and Cox regression survival analysis adjusted for demographics, WMH volume, lacunes, and brain atrophy were used to evaluate the independent effect of the DWI measures on change in cognitive performance and functional abilities. Results The mean global apparent diffusion coefficient (ADC) and the relative peak height and peak position of the ADC histogram in NABT predicted faster rate of decline in a composite score for speed and motor control. Higher mean ADC and lower peak height were also related to deterioration in executive functions and memory (specifically working memory), with peak height also being related to more rapid transition to disability and higher rate of mortality. Mean ADC in WMH had less pronounced effects on cognitive and functional outcomes. Interpretation DWI microstructural changes in NABT predict faster decline in psychomotor speed, executive functions, and working memory regardless of conventional MRI findings. Moreover, these changes are related to functional disability and higher mortality. Ann Neurol 2013;73:576–583
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| 6. |
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| 8. |
- Teodorczuk, A., et al.
(author)
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White matter changes and late-life depressive symptoms - Longitudinal study
- 2007
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In: BRITISH JOURNAL OF PSYCHIATRY. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 191, s. 212-217
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Journal article (peer-reviewed)abstract
- 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.AimsTo 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.MethodIn 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.ResultsUsing 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).ConclusionsWhite 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.
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| 9. |
- Bouazza, Naim, et al.
(author)
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General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children
- 2022
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In: British Journal of Clinical Pharmacology. - : John Wiley & Sons. - 0306-5251 .- 1365-2125. ; 88:12, s. 4985-4996
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Research review (peer-reviewed)abstract
- Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.
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| 10. |
- Frederiksen, K. S., et al.
(author)
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Physical activity in the elderly is associated with improved executive function and processing speed: the LADIS Study
- 2015
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In: International Journal of Geriatric Psychiatry. - : Wiley. - 0885-6230 .- 1099-1166. ; 30:7, s. 744-750
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Journal article (peer-reviewed)abstract
- ObjectivesPhysical 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). MethodsData 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 3years 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. ResultsTwo-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: : 0.39, 95% CI: 0.13-0.90, p=0.008; follow-up: : 0.24, 95% CI: 0.10-0.38, p=0.001) and processing speed (baseline: : 0.48, 95% CI: 0.14-0.89, p=0.005; follow-up: : 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 (: 0.11, 95% CI: 0-0.22, p=0.04). ConclusionOur 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. Copyright (c) 2014 John Wiley & Sons, Ltd.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Poggesi, A., et al.
(author)
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Cerebral white matter changes are associated with abnormalities on neurological examination in non-disabled elderly: the LADIS study
- 2013
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 260:4, s. 1014-1021
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Journal article (peer-reviewed)abstract
- Cerebral white matter changes (WMC) are associated with motor, cognitive, mood, urinary disturbances, and disability, but little is known about the prevalence of neurological signs in patients with these brain lesions. We assessed the presence and occurrence of neurological abnormalities over a 3-year period and their possible associations with WMC in a cohort of initially non-disabled elderly subjects. Data from the multicenter Leukoaraiosis And DISability study were used. A standard neurological examination was performed at baseline and at each of the annual follow-up visits. A standard MRI scan was performed at baseline and after 3-years. WMC severity was graded as mild, moderate, or severe on the Fazekas scale, while the Rotterdam scale was used to assess progression. Infarcts and their occurrence were also assessed. Six hundred and thirty-nine non-disabled subjects were enrolled (mean age 74.1 +/- A 5.0, M/F: 288/351). Severe WMC at baseline were associated with gait and stance abnormalities, upper motor signs, and fingertap slowing. This effect was independent of age, sex, lacunar and non-lacunar infarcts. The occurrence of stance abnormalities, upper motor signs, primitive reflexes and fingertap slowing during the 3-year follow-up period was associated with both baseline WMC load and their progression. The occurrence of the same abnormalities plus extrapyramidal and primitive reflexes was associated with incident lacunar infarcts. In our cohort of non-disabled elders, severe WMC were associated with the presence and the occurrence of neurological signs, independently of other vascular brain lesions, confirming that these lesions have clinical relevance.
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| 16. |
- Poggesi, A., et al.
(author)
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Neurological abnormalities predict disability: the LADIS (Leukoaraiosis And DISability) study
- 2014
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 261:6, s. 1160-1169
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Journal article (peer-reviewed)abstract
- 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 +/- A 5.0 years, 45 % males), 327 (51.7 %) presented at the initial visit with a parts per thousand yen1 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.
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| 17. |
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| 18. |
- Teodorczuk, A., et al.
(author)
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Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study.
- 2009
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In: Psychological medicine. - 1469-8978. ; 40:4, s. 603-610
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Journal article (peer-reviewed)abstract
- BACKGROUND: Growing evidence suggests that cerebral white-matter changes and depressive symptoms are linked directly along the causal pathway. We investigated whether baseline severity of cerebral white-matter changes predict longer-term future depressive outcomes in a community sample of non-disabled older adults.MethodIn the Leukoaraiosis and Disability in the Elderly (LADIS) study, a longitudinal multi-centre pan-European study, 639 older subjects underwent baseline structural magnetic resonance imaging (MRI) and clinical assessments. Baseline severity of white-matter changes was quantified volumetrically. Depressive outcomes were assessed in terms of depressive episodes and depressive symptoms, as measured by the Geriatric Depression Scale (GDS). Subjects were clinically reassessed annually for up to 3 years. Regression models were constructed to determine whether baseline severity of white-matter changes predicted future depressive outcomes, after controlling for confounding factors. RESULTS: Baseline severity of white-matter changes independently predicted depressive symptoms at both 2 (p<0.001) and 3 years (p=0.015). Similarly, white-matter changes predicted incident depression (p=0.02). Over the study period the population became significantly more disabled (p<0.001). When regression models were adjusted to account for the influence of the prospective variable transition to disability, baseline severity of white-matter changes no longer predicted depressive symptoms at 3 years (p=0.09) or incident depression (p=0.08). CONCLUSIONS: Our results support the vascular depression hypothesis and strongly implicate white-matter changes in the pathogenesis of late-life depression. Furthermore, the findings indicate that, over time, part of the relationship between white-matter changes and depression may be mediated by loss of functional activity.
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| 19. |
- Verdelho, A., et al.
(author)
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Depressive symptoms predict cognitive decline and dementia in older people independently of cerebral white matter changes: the LADIS study
- 2013
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In: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 84:11, s. 1250-1254
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Journal article (peer-reviewed)abstract
- Objective Depressive symptoms (DS) have been associated with increased risk of cognitive decline. Our aim was to evaluate the longitudinal influence of DS on cognition in independent older people, accounting for the severity of white matter changes (WMC). Methods The LADIS (Leukoaraiosis And DISability in the elderly) prospective study evaluated the impact of WMC on the transition of independent older subjects into disability. Subjects were evaluated annually over a 3 year period with a comprehensive clinical and neuropsychological evaluation. Previous episodes of depression and current DS were assessed during each interview. Severity of DS was assessed using the self-rated 15 item Geriatric Depression Scale. A neuropsychological battery and clinical criteria for cognitive impairments were applied in all clinical visits, and cognitive compound measures were made based on neuropsychological results. MRI was performed at baseline and at year 3. Results 639 subjects were included (74.1 +/- 5 years old, 55% women, 9.6 +/- 3.8 years of schooling). Dementia was diagnosed in 90 patients and cognitive impairment not dementia in 147 patients at the last clinical evaluation. DS were an independent predictor of cognitive impairment (dementia and not dementia) during follow-up, independent of the effect of the severity of WMC, medial temporal lobe atrophy, age, education or global cognitive function at baseline. Conclusions DS are associated with an increase risk of cognitive decline, independent of the effect of WMC, probably due to an additive or synergistic effect. In this context, DS probably represent a subtle ongoing organic dysfunction
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| 20. |
- Verdelho, A., et al.
(author)
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Physical Activity Prevents Progression for Cognitive Impairment and Vascular Dementia Results From the LADIS (Leukoaraiosis and Disability) Study
- 2012
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In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 43:12, s. 3331-3335
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Journal article (peer-reviewed)abstract
- Background and Purpose-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. Methods-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. Results-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: beta=-0.45, P=0.002; hazard ratio, 0.64; 95% CI, 0.48-0.85), dementia (beta=-0.49, P=0.043; hazard ratio, 0.61; 95% CI, 0.38-0.98), and vascular dementia (beta=-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. Conclusions-Physical activity reduces the risk of cognitive impairment, mainly vascular dementia, in older people living independently. (Stroke. 2012; 43: 3331-3335.)
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| 21. |
- Baezner, H, et al.
(author)
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Association of gait and balance disorders with age-related white matter changes: the LADIS study.
- 2008
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In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 70:12, s. 935-42
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Journal article (peer-reviewed)abstract
- OBJECTIVE: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. METHODS: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. RESULTS: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 +/- 2.1 in the mild, 9.9 +/- 2.0 in the moderate, 8.9 +/- 2.6 in the severe group; p < 0.001). Walking speed correlated with the severity of ARWMC (1.24 +/- 0.28 m/second in the mild, 1.18 +/- 0.32 m/second in the moderate, and 1.09 +/- 0.31 m/second in the severe group; p < 0.001). Balance was best in individuals with mild ARWMC (single leg stance time: 18.9 +/- 10.8 seconds) compared with moderate and severe ARWMC (16.4 +/- 10.8 and 13.6 +/- 11.2 seconds) (p < 0.001). Physically inactive individuals had a higher risk of a pathologic SPPB score (moderate vs mild ARWMC: odds ratio 1.60, 95% CI 1.02 to 2.52; severe vs mild ARWMC: odds ratio 1.75, 95% CI 1.09 to 2.80). CONCLUSIONS: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.
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| 22. |
- Blahak, C, et al.
(author)
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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.
- 2009
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 80:6, s. 608-13
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Journal article (peer-reviewed)abstract
- 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 ARWMC in a large cohort of elderly non-disabled individuals with reported falls was analysed, using the cross sectional data of the Leukoaraiosis and Disability (LADIS) study. Detailed anatomical distributions of ARWMC assessed by MRI studies were analysed with respect to falls and balance performance. RESULTS: The severity of global ARWMC was significantly associated with a history of falls in the year prior to study inclusion (22.2% in the mild, 31.6% in the moderate and 37.3% in the severe ARWMC group according to the Fazekas scale; p = 0.002). Analysing the anatomical distribution of ARWMC, using the semiquantitative Scheltens scale, in multivariate analysis, periventricular (p = 0.006) and frontal deep (p = 0.033) ARWMC were independently associated with falls. Furthermore, logistic regression identified frontal deep (p = 0.003) ARWMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances. CONCLUSION: The association of frontal and periventricular ARWMC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC.
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| 23. |
- Gouw, Alida A, et al.
(author)
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Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period: the Leukoaraiosis and Disability study.
- 2008
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In: Stroke; a journal of cerebral circulation. - 1524-4628. ; 39:5, s. 1414-20
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Journal article (peer-reviewed)abstract
- BACKGROUND AND PURPOSE: We studied the natural course of white matter hyperintensities (WMH) and lacunes, the main MRI representatives of small vessel disease, over time and evaluated possible predictors for their development. METHODS: Baseline and repeat MRI (3-year follow-up) were collected within the multicenter, multinational Leukoaraiosis and Disability study (n=396). Baseline WMH were scored on MRI by the Fazekas scale and the Scheltens scale. WMH progression was assessed using the modified Rotterdam Progression scale (absence/presence of progression in 9 brain regions). Baseline and new lacunes were counted per region. WMH and lacunes at baseline and vascular risk factors were evaluated as predictors of WMH progression and new lacunes. RESULTS: WMH progressed (mean+/-SD=1.9+/-1.8) mostly in the subcortical white matter, where WMH was also most prevalent at baseline. The majority of new lacunes, which were found in 19% of the subjects (maximum=9), also appeared in the subcortical white matter, mainly of the frontal lobes, whereas most baseline lacunes were located in the basal ganglia. Baseline WMH and lacunes predicted both WMH progression and new lacunes. Furthermore, previous stroke, diabetes, and blood glucose were risk factors for WMH progression. Male sex, hypertension, systolic blood pressure, previous stroke, body mass index, high-density lipoprotein, and triglyceride levels were risk factors for new lacunes. CONCLUSIONS: WMH and lacunes progressed over time, predominantly in the subcortical white matter. Progression was observed especially in subjects with considerable WMH and lacunes at baseline. Moreover, the presence of vascular risk factors at baseline predicted WMH progression and new lacunes over a 3-year period.
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| 24. |
- Kreisel, S. H., et al.
(author)
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Deterioration of Gait and Balance over Time: The Effects of Age-Related White Matter Change - The LADIS Study
- 2013
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In: Cerebrovascular Diseases. - : S. Karger AG. - 1015-9770 .- 1421-9786. ; 35:6, s. 544-553
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Journal article (peer-reviewed)abstract
- Background: Cross-sectional studies have shown an association between the severity of age-related white matter change (ARWMC) and lower body motor function. However, the association between prevalent ARWMC and incident deterioration of balance and gait remains insufficiently investigated. This study investigates if the degree of prevalent ARWMC has a differential effect on lower body motor function as it changes over time, hypothesizing that individuals with more severe baseline white matter pathology experience greater clinical deterioration independent of potential confounders. This is of clinical relevance: given the increasing use of neuroimaging, incidental white matter pathology is common; being able to delineate natural trajectories of balance and gait function given ARWMC may improve patient advice and help optimize allocation of care. Methods: 639 non-disabled elderly individuals with prevalent ARWMC (grading of severity of ARWMC using the Fazekas scale) were followed up yearly for 3 years, as part of the Leukoaraiosis and Disability Study. The primary outcome variable, reflecting the temporal course of gait and balance function, was the change of scores on the Short Physical Performance Battery (SPPB) over time versus the severity of ARWMC. We used linear mixed modelling to analyse change over time. Explorative analysis was carried out investigating the effect of age on potential deterioration of gait and balance function. We used propensity scores to adjust for multiple confounders that affect both the exposure (i. e. ARWMC) and outcome. Results: Subjects' lower body motor function deteriorated by 2.6% per year. However, after adjustment for baseline motor impairment and potential confounders, only subjects with moderate [-0.22 points per year on the SPPB (equals -2.3%); 95% CI -0.35 to -0.09, p < 0.001] or severe [-0.46 points per year (equals -4.7%); 95% CI -0.63 to -0.28, p < 0.0001] ARWMC show a loss of function. Age shows differential effects: relatively younger elderly subjects have similar temporal dynamics in SPPB change independent of their individual degree of ARWMC severity; however, subjects with severe ARWMC and who are older than 75.9 years deteriorate significantly more rapidly than their counterparts with only mild or moderate white matter pathology. Conclusion: Only moderate and severe ARWMC is independently associated -on average -with a deterioration of gait and balance. Albeit the possibility of unmeasured confounding and other methodological constraints, there is nonetheless evidence of large interindividual variability: some subjects with moderate or severe ARWMC stay stable over time or even show improvement. Furthermore, there is explorative analysis showing that younger elderly subjects may be able to better compensate even severe ARWMC. These individuals' gait and balance function stays relatively stable over time, whereas their older counterparts deteriorate significantly. This may point towards a threshold effect given ARWMC.
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| 25. |
- Poggesi, A, et al.
(author)
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2001–2011: a decade of the LADIS (Leukoaraiosis And DISability) Study: what have we learned about white matter changes and small-vessel disease?
- 2011
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In: Cerebrovascular diseases (Basel, Switzerland). - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 32:6, s. 577-588
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Journal article (peer-reviewed)abstract
- 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 substudies 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.
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| 26. |
- Russu, A., et al.
(author)
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Joint Modeling of Efficacy, Dropout, and Tolerability in Flexible-Dose Trials : A Case Study in Depression
- 2012
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In: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 91:5, s. 863-871
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Journal article (peer-reviewed)abstract
- Many difficulties may arise during the modeling of the time course of Hamilton Rating Scale for Depression (HAM D) scores in clinical trials for the evaluation of antidepressant drugs: (i) flexible designs, used to increase the chance of selecting more efficacious doses, (ii) dropout events, and (iii) adverse effects related to the experimental compound. It is crucial to take into account all these factors when designing an appropriate model of the HAM D time course and to obtain a realistic description of the dropout process. In this work, we propose an integrated approach to the modeling of a double-blind, flexible-dose, placebo-controlled, phase II depression trial that comprises response, tolerability, and dropout. We investigate three different dropout mechanisms in terms of informativeness. Goodness of fit is quantitatively assessed with respect to response (HAM D score) and dropout data. We show that dropout is a complex phenomenon that may be influenced by HAM D evolution, dose changes, and occurrence of drug-related adverse effects.
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| 27. |
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