Age-related white matter hyperintensities and overactive bladder: A systematic review.

INTRODUCTION: Age-related white matter hyperintensities (ARWMHs) on brain magnetic resonance imaging have been associated with lower urinary tract symptoms/dysfunction (LUTS/LUTD), namely overactive bladder (OAB) and detrusor overactivity. We aimed to systematically review existing data on the association between ARWMH and LUTS and which clinical tools have been used for this assessment. MATERIALS AND METHODS: We searched PubMed/MEDLINE, Cochrane Library, and clinicaltrials.gov (from 1980 to November 2021) and considered original studies reporting data on ARWMH and LUTS/LUTD in patients of both sexes aged 50 or above. The primary outcome was OAB. We calculated the unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the outcomes of interest using random-effects models. RESULTS: Fourteen studies were included. LUTS assessment was heterogeneous and mainly based on the use of nonvalidated questionnaires. Urodynamics assessment was reported in five studies. ARWMHs were graded using visual scales in eight studies. Patients with moderate-to-severe ARWMHs were more likely to present with OAB and urgency urinary incontinence (UUI; OR = 1.61; 95% CI: 1.05-2.49, p = 0.03), I2 = 21.3%) when compared to patients with similar age and absent or mild ARWMH. DISCUSSION AND CONCLUSIONS: High-quality data on the association between ARWMH and OAB is scarce. Patients with moderate to severe ARWMH showed higher levels of OAB symptoms, including UUI, when compared to patients with absent or mild ARWMH. The use of standardized tools to assess both ARWMH and OAB in these patients should be encouraged in future research.

Physical activity in vascular cognitive impairment: Systematic review with meta-analysis.

BACKGROUND: Vascular cognitive impairment (VCI) is the second most common cause of cognitive impairment worldwide and includes a spectrum from vascular cognitive impairment no dementia (VCIND) to vascular dementia (VaD). There is no specific pharmacological treatment approved for VCI. Physical activity has been indicated to be a promising preventive measure for cognition, with direct as indirectly benefits, while improving several modifiable vascular risk factors, so potentially effective when considering VCI. Our aim was to conduct a systematic review with a meta-analysis approaching the potential preventive role of physical activity on VCI. METHODS: A systematic search was conducted in 7 databases. A total of 6786 studies were screened and assessed for eligibility, culminating in the inclusion of 9 observational prospective studies assessing physical activity impact irrespectively the type for quality assessment and qualitative and quantitative synthesis. Quantitative synthesis was performed using the reported adjusted HRs. Physical activity was handled as a dichotomous variable, with two groups created (high versus low physical activity). Subgroup analyses were done for risk of bias, VaD and length of follow-up. RESULTS: There was considerable methodological heterogeneity across studies. Only three studies reported significant associations. The overall effect was statistically significant (HR 0.68, 95%CI 0.54-0.86, I2 6.8%), with higher levels of physical activity associated with a smaller risk of VCI overtime, particularly VaD. CONCLUSIONS: These findings suggest that physical activity is a potential preventive factor for vascular dementia. Insufficient data is available on VCIND. Randomized studies are desired to confirm these results.

European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment.

BACKGROUND AND PURPOSE: The optimal management of post-stroke cognitive impairment (PSCI) remains controversial. These joint European Stroke Organisation (ESO) and European Academy of Neurology (EAN) guidelines provide evidence-based recommendations to assist clinicians in decision making regarding prevention, diagnosis, treatment and prognosis. METHODS: Guidelines were developed according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations. RESULTS: There was limited randomized controlled trial (RCT) evidence regarding single or multicomponent interventions to prevent post-stroke cognitive decline. Lifestyle interventions and treating vascular risk factors have many health benefits, but a cognitive effect is not proven. We found no evidence regarding routine cognitive screening following stroke, but recognize the importance of targeted cognitive assessment. We describe the accuracy of various cognitive screening tests, but found no clearly superior approach to testing. There was insufficient evidence to make a recommendation for use of cholinesterase inhibitors, memantine nootropics or cognitive rehabilitation. There was limited evidence on the use of prediction tools for post-stroke cognition. The association between PSCI and acute structural brain imaging features was unclear, although the presence of substantial white matter hyperintensities of presumed vascular origin on brain magnetic resonance imaging may help predict cognitive outcomes. CONCLUSIONS: These guidelines highlight fundamental areas where robust evidence is lacking. Further definitive RCTs are needed, and we suggest priority areas for future research.

Global Burden of Small Vessel Disease-Related Brain Changes on MRI Predicts Cognitive and Functional Decline.

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

Headache at the Chronic Stage of Ischemic Stroke.

BACKGROUND: Headache in ischemic stroke survivors after the acute stage is incompletely described. OBJECTIVE: We aimed to prospectively describe the characteristics of headache and the predictors of headache at the chronic stage after ischemic stroke. METHODS: We conducted a prospective observational cohort study including 102 acute ischemic stroke patients admitted to a Stroke Unit. Patients were interviewed at the acute and the chronic stage (12 months after stroke). Characteristics of those headaches were collected using a previously validated headache questionnaire enabling headache classification following the International Headache Society criteria. Pre-stroke headache history was registered using the same instrument. RESULTS: Forty-five patients out of 89 with completed follow-up (51%) reported headache at the chronic stage. In most of the patients, headache was sporadic, mild, pressure-like, with a duration of minutes to hours, with characteristics of tension-type headache in 51% (n = 23/45). Headache was a reactivation of pre-stroke headache in 33% (n = 15/45), different from pre-stroke headache in 44% (n = 20/45), and of new-onset in 22% (n = 10/45). Only 1 patient had a new-onset headache at the acute stage that persisted with the same characteristics at the chronic stage. Pre-stroke headache (OR = 5.3; 95% CI [2.01-13.98] P = .001) and female sex (OR = 3.5; 95% CI [1.3-9.4] P = .013) predicted headache at the chronic stage after stroke, controlling for age, severity, and location of stroke. CONCLUSIONS: Headache in ischemic stroke survivors at the chronic stage is more frequent in women and in patients with pre-stroke headache. It is most frequently a headache with different characteristics of the pre-stroke headache and only rarely a new-onset headache starting at the acute stage and persisting at the chronic stage.

Game-based interventions for neuropsychological assessment, training and rehabilitation: Which game-elements to use? A systematic review.

Game-based interventions (GBI) have been used to promote health-related outcomes, including cognitive functions. Criteria for game-elements (GE) selection are insufficiently characterized in terms of their adequacy to patients' clinical conditions or targeted cognitive outcomes. This study aimed to identify GE applied in GBI for cognitive assessment, training or rehabilitation. A systematic review of literature was conducted. Papers involving video games were included if: (1) presenting empirical and original data; (2) using video games for cognitive intervention; and (3) considering attention, working memory or inhibitory control as outcomes of interest. Ninety-one papers were included. A significant difference between the number of GE reported in the assessed papers and those composing video games was found (p < .001). The two most frequently used GE were: score system (79.2% of the interventions using video games; for assessment, 43.8%; for training, 93.5%; and for rehabilitation, 83.3%) and narrative context (79.2% of interventions; for assessment, 93.8%; for training, 73.9% and for rehabilitation, 66.7%). Usability assessment was significantly associated with six of the seven GE analyzed (p-values between p ≤ 0.001 and p. = 027). The use of GE that act as extrinsic motivation promotors (e.g., numeric feedback system) may jeopardize patients' long-term adherence to interventions, mainly if associated with progressive difficulty-increase of gaming experience. Lack of precise description of GE and absence of a theoretical framework supporting GE selection are important limitations of the available clinical literature.

Memory complaints in amnestic Mild Cognitive Impairment: More prospective or retrospective?

OBJECTIVE: Patients with amnestic Mild Cognitive Impairment (aMCI), usually considered an early stage of Alzheimer's disease, have deficits not only in retrospective memory (RM), that is, recalling of past events, words or people, but also on prospective memory (PM), the cognitive ability of remembering to execute delayed intentions in the future. This study investigated whether patients with aMCI refer more PM complaints as compared with RM complaints, and whether this might depend upon short-term vs long-term items or time-based vs event-based tasks. METHODS: Patients with aMCI (n = 178) and healthy controls (n = 160) underwent the Prospective and Retrospective Memory Questionnaire (PRMQ), a 16-item instrument to appraise differences between PM and RM complaints, as well as a general mental state examination, a subjective memory complaints questionnaire, objective memory tests, and assessment of depressive symptoms and activities of daily living. RESULTS: Patients with aMCI reported more memory complaints evaluated with the PRMQ (total score = 44.3 ± 10.8) as compared with controls (36.7 ± 9.8, P < 0.001). Using a mixed effect repeated-measures analysis of covariance (ANCOVA) showed that participants generally referred more retrospective than prospective memory complaints. Patients with aMCI had significantly more complaints on short-term memory as compared with long-term memory, and more complaints in time-based (auto-initiated) as compared with event-based tasks, than healthy controls. CONCLUSION: Patients with aMCI reported significantly more difficulties on short-term memory, presumably reflecting internal temporal lobe pathology typical of Alzheimer's disease, and more complaints on time-based tasks, which are cognitively very demanding, but did not seem particularly troubled regarding prospective memory.

The prevalence of dementia in a Portuguese community sample: a 10/66 Dementia Research Group study.

BACKGROUND: Dementia imposes a high burden of disease worldwide. Recent epidemiological studies in European community samples are scarce. In Portugal, community prevalence data is very limited. The 10/66 Dementia Research Group (DRG) population-based research programmes are focused in low and middle income countries, where the assessments proved to be culture and education fair. We applied the 10/66 DRG prevalence survey methodology in Portugal, where levels of illiteracy in older populations are still high. METHODS: A cross-sectional comprehensive one-phase survey was conducted of all residents aged 65 and over of two geographically defined catchment areas in Southern Portugal (one urban and one rural site). Nursing home residents were not included in the present study. Standardized 10/66 DRG assessments include a cognitive module, an informant interview and the Geriatric Mental State-AGECAT, providing data on dementia diagnosis and subtypes, mental disorders including depression, physical health, anthropometry, demographics, disability/functioning, health service utilization, care arrangements and caregiver strain. RESULTS: We interviewed 1405 old age participants (mean age 74.9, SD = 6.7 years; 55.5% women) after 313 (18.2%) refusals to participate. The prevalence rate for dementia in community-dwellers was 9.23% (95% CI 7.80-10.90) using the 10/66 DRG algorithm and 3.65% (95% CI 2.97-4.97) using DSM-IV criteria. Pure Alzheimer's disease was the most prevalent dementia subtype (41.9%). The prevalence of dementia was strongly age-dependent for both criteria, but there was no association with sex. CONCLUSIONS: Dementia prevalence was higher than previously reported in Portugal. The discrepancy between prevalence according to the 10/66 DRG algorithm and the DSM-IV criteria is consistent with that observed in less developed countries; this suggests potential underestimation using the latter approach, although relative validity of these two approaches remains to be confirmed in the European context. We improved the evidence base to raise awareness and empower advocacy about dementia in Portugal, so that the complex needs of frail older people may be met in better ways.

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

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

BACKGROUND: Cerebral 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 symptoms has been modest, however, and thus the outcome may be affected by various host factors. We investigated the predictive value of educational and occupational attainments as proxy measures of cognitive reserve on long-term cognitive and functional outcome in patients with different degrees of WMH. METHODS: In the Leukoaraiosis and Disability (LADIS) study, 615 older individuals with WMH were evaluated with brain MRI and detailed clinical and neuropsychological assessments at 3-year follow-up. A prolonged follow-up of functional and cognitive status was administered with a structured telephone interview after up to 7 years. RESULTS: Higher levels of educational and occupational attainment were strongly related to baseline cognitive scores and predicted a slower rate of decline at 3-year follow-up in measures of processing speed, executive functions and memory independently of WMH volume and other confounders. The deleterious effect of WMH on processing speed and memory was moderated by education and occupation. Education mitigated the relation of WMH volume on 7-year cognitive status. Moreover, higher education and occupational attainments were related to favourable outcome at 7-year follow-up as defined by sustained functional independence and lower mortality. CONCLUSIONS: The results support the presumption that cognitive reserve plays a significant role as a buffer against the clinical manifestations of SVD and may in part explain high individual variability in outcome.

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 [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 (ß = 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.

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

OBJECTIVES: 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). METHODS: 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. RESULTS: 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: ß: 0.39, 95% CI: 0.13-0.90, p = 0.008; follow-up: ß: 0.24, 95% CI: 0.10-0.38, p = 0.001) and processing speed (baseline: ß: 0.48, 95% CI: 0.14-0.89, p = 0.005; follow-up: ß: 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 (ß: 0.11, 95% CI: 0-0.22, p = 0.04). CONCLUSION: 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.

Diffusion changes predict cognitive and functional outcome: the LADIS study.

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.

Digital health and patient adherence: A qualitative study in older adults.

Introduction: Computer confidence and computer self-efficacy can impact an individual's perceived ease of use and usefulness of technology, ultimately determining adherence to digital healthcare services. However, few studies focus on assessing the impact of non-clinical factors on the efficacy and adherence to digital healthcare platforms. Objective: We aimed to analyse the role of non-clinical factors (i.e. computer confidence and computer self-efficacy) in the interaction experience (IX) and the feasibility of a digital neuropsychological platform called NeuroVRehab.PT in a group of older adults with varying levels of computer confidence. Methods: Eight older adults (70.63 ± 6.1 years) evaluated the platform, and data was collected using the Think-Aloud method and a semi-structured interview. Sessions were audio-recorded and analysed through an inductive-deductive informed Thematic Analysis protocol. This study was conducted according to the Consolidated Criteria for Reporting Qualitative Research guidelines. Results: Three main themes were identified (Interaction Experience, Digital Literacy, and Attitudes toward NeuroVRehab.PT). Computer anxiety and fear of making errors were not uncommon, even among older adults who perceive themselves as confident in technology use, and negatively impacted IX. Moreover, some game elements (e.g. three-star system, progression bar) were not intuitive to all participants, leading to misleading interpretations. On the other hand, human support and the platform's realism seemed to impact participants' IX positively. Conclusions: This study shed light on the barriers raised by non-clinical factors in adopting and using digital healthcare services by older adults. Furthermore, a critical analysis of the platform's features that promote user adoption is done, and suggestions for overcoming limitations are presented.

Needs for Care, Service Use and Quality of Life in Dementia: 12-Month Follow-Up of the Actifcare Study in Portugal.

INTRODUCTION: The intermediate stages of dementia are relatively under-researched, including in Portugal. The Actifcare (ACcess to TImely Formal Care) EU-JPND project studied people with mild-moderate dementia, namely their needs, access to and use of community services (e.g., day centers, home support). In our baseline assessment of the Portuguese Actifcare cohort, the unmet needs of some participants would call for formal support, which was not always accessible or used. We now report the main results of the 12-month follow-up, analyzing changes in needs, service (non)use, quality of life and related variables. METHODS: This was a longitudinal, observational study using a convenience sample of 54 dyads of people with dementia and their family carers. Our main outcomes were the Camberwell Assessment of Need for the Elderly (CANE) and the Resources Utilization in Dementia. Clinical-functional, quality of life, psychological distress and caregiving-related assessments were also used. RESULTS: At follow-up, the cognitive and functional status of people with dementia declined (p < 0.001), and their neuropsychiatric symptoms increased (p = 0.033). Considering CANE interviewers' ratings, the total needs of people with dementia increased at follow-up (p < 0.001) but not the unmet needs. Quality of life was overall stable. The use of formal care did not increase significantly, but informal care did in some domains. Carers' depressive symptoms increased (p = 0.030) and perseverance time decreased (p = 0.045). However, carers' psychological distress unmet needs were lower (p = 0.007), and their stress and quality of life remained stable. CONCLUSION: People with dementia displayed complex biopsychosocial unmet needs. Their cognitive-functional decline over one year was not accompanied by a corresponding increase in any pattern of unmet need, nor of service use. Reliance on informal care (namely supervision) may have contributed to this. Caregiving-related outcomes evolved according to different trends, although stability was almost the rule. Primary carers were even more present at follow-up, without an apparently heavier toll on their own needs, burden, and quality of life. Overall, this longitudinal study comprehensively assessed Portuguese community-dwelling people with dementia. Despite the lack of generalizability, participants' needs remained overall stable and partly unmet over one year. Longer follow-up periods are needed to understand such complex processes.

Depressive symptoms predict cognitive decline and dementia in older people independently of cerebral white matter changes: the LADIS study.

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.

Quality of life in patients with cognitive impairment: validation of the Quality of Life-Alzheimer's Disease scale in Portugal.

BACKGROUND: Quality of Life-Alzheimer's Disease (QOL-AD) is a widely used scale for the study of quality of life in patients with dementia. The aim of this study is the transcultural adaptation and validation of the QOL-AD scale in Portugal. METHODS: Translation and transcultural adaptation was performed according to state-of-the-art recommendations. For the validation study, 104 patient/caregiver pairs were enrolled. Patients had mild cognitive impairment or mild-to-moderate dementia (due to Alzheimer's disease or vascular dementia). Participants were recruited in a dementia outpatient clinic setting and a long-term care dementia ward. An additional comparison group of 22 patients without cognitive impairment, and their proxies, was recruited in a family practice outpatient clinic. Sociodemographic information on patients and caregivers was obtained. Acceptability, reliability, and construct validity were analyzed. RESULTS: Internal consistency of the Portuguese version of QOL-AD was good for both patient and caregiver report (Cronbach's α = 0.867 and 0.858, respectively). Construct validity was confirmed by the correlation of patient reported QOL-AD with patient geriatric depression scale scores (ρ = -0.702, p < 0.001) and satisfaction with life scale scores (ρ = 0.543, p < 0.001). Caregiver ratings were correlated with neuropsychiatric inventory (NPI) total score (ρ = -0.404, p < 0.001), NPI-distress (ρ = -0.346, p < 0.001), and patient Mini-Mental State Examination (ρ = 0.319, p < 0.01). QOL-AD patient ratings were higher than caregiver ratings (p < 0.001). Both patient- and caregiver-rated QOL-AD scores were lower in patients with cognitive impairment than in the comparison group without cognitive impairment (p < 0.01). CONCLUSIONS: A Portuguese version of QOL-AD with consistent psychometric properties was obtained and is proposed as a useful tool for research and clinical purposes.

Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study.

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: ß=-0.45, P=0.002; hazard ratio, 0.64; 95% CI, 0.48-0.85), dementia (ß=-0.49, P=0.043; hazard ratio, 0.61; 95% CI, 0.38-0.98), and vascular dementia (ß=-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.

White matter lesion progression in LADIS: frequency, clinical effects, and sample size calculations.

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.