Summary Interventions that have even quite modest effects at the individual level could drastically reduce the future burden of dementia associated with Alzheimer's disease at the population level. ...In the past three decades, both pharmacological and lifestyle interventions have been studied for the prevention of cognitive decline or dementia in randomised controlled trials of individuals mostly aged older than 50–55 years with or without risk factors for Alzheimer's disease. Several trials testing the effects of physical activity, cognitive training, or antihypertensive interventions showed some evidence of efficacy on a primary cognitive endpoint. However, most of these trials had short follow-up periods, and further evidence is needed to confirm effectiveness and establish the optimum design or dose of interventions and ideal target populations. Important innovations in ongoing trials include the development of multidomain interventions, and the use of biomarker or genetic inclusion criteria. Challenges include the use of adaptive trial designs, the development of standardised, sensitive outcome measures, and the need for interventions that can be implemented in resource-poor settings.
Summary Background Prevention strategies are urgently needed to tackle the growing burden of Alzheimer's disease. We aimed to assess efficacy of long-term use of standardised ginkgo biloba extract ...for the reduction of incidence of Alzheimer's disease in elderly adults with memory complaints. Methods In the randomised, parallel-group, double-blind, placebo-controlled GuidAge clinical trial, we enrolled adults aged 70 years or older who spontaneously reported memory complaints to their primary-care physician in France. We randomly allocated participants in a 1:1 ratio according to a computer-generated sequence to a twice per day dose of 120 mg standardised ginkgo biloba extract (EGb761) or matched placebo. Participants and study investigators and personnel were masked to study group assignment. Participants were followed-up for 5 years by primary-care physicians and in expert memory centres. The primary outcome was conversion to probable Alzheimer's disease in participants who received at least one dose of study drug or placebo, compared by use of the log-rank test. This study is registered with ClinicalTrials.gov , number NCT00276510. Findings Between March, 2002, and November, 2004, we enrolled and randomly allocated 2854 participants, of whom 1406 received at least one dose of ginkgo biloba extract and 1414 received at least one dose of placebo. By 5 years, 61 participants in the ginkgo group had been diagnosed with probable Alzheimer's disease (1·2 cases per 100 person-years) compared with 73 participants in the placebo group (1·4 cases per 100 person-years; hazard ratio HR 0·84, 95% CI 0·60–1·18; p=0·306), but the risk was not proportional over time. Incidence of adverse events was much the same between groups. 76 participants in the ginkgo group died compared with 82 participants in the placebo group (0·94, 0·69–1·28; p=0·68). 65 participants in the ginkgo group had a stroke compared with 60 participants in the placebo group (risk ratio 1·12, 95% CI 0·77–1·63; p=0·57). Incidence of other haemorrhagic or cardiovascular events also did not differ between groups. Interpretation Long-term use of standardised ginkgo biloba extract in this trial did not reduce the risk of progression to Alzheimer's disease compared with placebo. Funding Ipsen.
BACKGROUND/OBJECTIVES
Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function ...and cognitive decline in older adults and to assess the involvement of cortical beta‐amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association.
DESIGN
Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT).
SETTINGS
Thirteen memory centers (France and Monaco, 2008–2016).
PARTICIPANTS
A total of 1,334 community‐dwellers >70 years old without dementia at baseline.
MEASUREMENTS
We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD‐Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z‐score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z‐score using mixed‐effect models and (2) progression on CDR using Cox models and mixed‐effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta‐amyloid (measured with positron emission tomography).
RESULTS
Median (IQR) eGFR was 73(60–84) mL/min/1.73 m2. Two hundred sixty‐nine participants experienced progression on CDR score during follow‐up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01–1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z‐score (adjusted β‐coefficient −0.004, 95% CI −0.014; 0.006). Associations were not modified after further adjustment for beta‐amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270).
CONCLUSIONS
We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.
Abstract Background We used the database of the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the psychometric properties of the Clinical Dementia Rating Sum of Boxes (CDR-SB) to ...consider its utility as an outcome measure for clinical trials in early and mild, as well as later, stages of Alzheimer's disease (AD). Methods We assessed internal consistency, structural validity, convergent validity, and 2-year internal and external responsiveness of the CDR-SB using data from 382 subjects with early or mild AD at entry into the ADNI study. Results The CDR-SB assesses both cognitive and functional domains of AD disability. Mean scores declined nearly linearly; CDR-SB cognitive and functional subsums contributed equally to total scores at both very mild (early) and mild stages of the disease. Conclusions The CDR-SB has psychometric properties that make it attractive as a primary outcome measure that comprehensively assesses both cognitive and functional disability in AD patients. It may prove particularly useful for studies in early, predementia stages of AD.
A better insight into older adults' understanding of and attitude towards cognitive disorders and their prevention, as well as expectations and reasons for participation in prevention trials, would ...help design, conduct, and implement effective preventive interventions. This qualitative study aimed at exploring the knowledge and perceptions of cognitive disorders and their prevention among participants in a prevention trial.
Semi-structured interviews were conducted among the participants of a multinational randomised controlled trial testing the efficacy of a lifestyle-based eHealth intervention in preventing cardiovascular disease or cognitive decline in community dwellers aged 65+. Participants were probed on their reasons for participation in the trial and their views on general health, cardiovascular disease, ageing, and prevention. The subset of data focusing on cognitive disorders (15 interviewees; all in Finland) was considered for this study. Data were analysed using content analysis.
Participants' knowledge of the cause and risk factors of cognitive disorders and prevention was limited and superficial, and a need for up-to-date, reliable, and practical information and advice was expressed. Cognitive disorders evoked fear and concern, and feelings of hopelessness and misery were frequently expressed, indicating a stigma. Strong heredity of cognitive disorders was a commonly held belief, and opinions on the possibility of prevention were doubtful, particularly in relation to primary prevention. Family history and/or indirect experiences of cognitive disorders was a recurrent theme and it showed to be linked to both the knowledge of and feelings associated with cognitive disorders, as well as attitude towards prevention. Indirect experiences were linked to increased awareness and knowledge, but also uncertainty about risk factors and possibility of prevention. Distinct fear and concerns, particularly over one's own cognition/risk, and high motivation towards engaging in prevention and participating in a prevention trial were also identified in connection to this theme.
Family history and/or indirect experiences of cognitive disorders were linked to sensitivity and receptiveness to brain health and prevention potential. Our findings may be helpful in addressing older adults' expectations in future prevention trials to improve recruitment, maximise adherence, and facilitate the successful implementation of interventions.
Abstract Background Clinical measures continue to be used as primary endpoints for disease-modifying trials for Alzheimer’s disease (AD). Currently, two co-primary endpoints must be specified, which ...measure cognitive and functional impairments. Generally, the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is one of the co-primary endpoints, but high variability in this measure results in large sample sizes. We evaluated the psychometric properties of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to assess its suitability as a single primary endpoint as an alternative to the traditional co-primary approach. Methods Internal consistency, structural and convergent validity, and 2-year internal and external responsiveness of the CDR-SB were assessed in 667 very mild to moderate (global Clinical Dementia Rating, 0.5–2) AD patients from the REAL.FR (Réseau sur la Maladie d'Alzheimer Français) study. Results The CDR-SB showed good internal consistency (Cronbach’s alpha = 0.88), and acceptable structural (separate “cognitive” and “functional” factors) and convergent validity. Variability in mean changes over time was low, leading to excellent internal responsiveness (effect size = 1.2; standardized response mean = 1.17 at 2 years) and smaller sample sizes as compared with the ADAS-Cog. External responsiveness was acceptable when compared with “clinically meaningful” changes on the Activities of Daily Living scale but only borderline acceptable when compared with the ADAS-Cog and Instrumental Activities of Daily Living. Levels of missing data and floor/ceiling effects were low. Conclusions The CDR-SB measures cognitive and functional impairment simultaneously, and has excellent 2-year internal responsiveness. This makes it a promising candidate as a sole primary endpoint for AD trials, although more work is required to determine the clinical relevance of CDR-SB changes, and its usefulness as an endpoint at other disease stages.
Summary Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when ...deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimer's disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimer's disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimer's disease, and for trials in severe Alzheimer's disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.
Preventive interventions for dementia are urgently needed and must be tested in randomised controlled trials (RCTs). Selection (volunteer) bias may limit efficacy, particularly in trials testing ...multidomain interventions and may also be indicative of disparities in intervention uptake in real-world settings. We identified factors associated with participation and adherence in a 3-year RCT of multidomain lifestyle intervention and/or omega-3 supplementation for prevention of cognitive decline and explored reasons for (non-) participation.
Ancillary study during recruitment and follow-up of the 3-year Multidomain Alzheimer Preventive Trial (MAPT) conducted in in 13 memory centres in France and Monaco, involving 1630 community-dwelling dementia-free individuals aged ≥ 70 who were pre-screened for MAPT (1270 participated in MAPT; 360 declined to participate).
Response rates were 76% amongst MAPT participants and 53% amongst non-participants. Older individuals (odds ratio 0.94 95% confidence interval 0.91-0.98 and those with higher anxiety (0.61 0.47-0.79) were less likely to participate in the trial. Those with higher income (4.42 2.12-9.19) and family history (1.60 1.10-2.32) or greater fear (1.73 1.30-2.29) of dementia were more likely to participate, as were those recruited via an intermediary (e.g. pension funds, local Alzheimer's associations, University of the 3rd Age, sports clubs) (2.15 1.45-3.20). MAPT participants living in larger towns (0.71 0.55-0.92) and with higher depressive symptoms (0.94 0.90-0.99) were less likely to adhere to the interventions. Greater perceived social support (1.21 1.03-1.43) and cognitive function (1.37 1.13-1.67) predicted better adherence. Descriptively, the most frequent reasons for accepting and refusing to participate were, respectively, altruism and logistical constraints, but underlying motivations mainly related to (lack of) perceived benefits.
Disparities in uptake of health interventions persist in older age. Those most at risk of dementia may not participate in or adhere to preventive interventions. Barriers to implementing lifestyle changes for dementia prevention include lack of knowledge about potential benefits, lack of support networks, and (perceived) financial costs.
NCT00672685 (ClinicalTrials.gov).
Nutrition and Cognition in Aging Adults Coley, Nicola; Vaurs, Charlotte; Andrieu, Sandrine
Clinics in geriatric medicine,
08/2015, Letnik:
31, Številka:
3
Journal Article
Recenzirano
Numerous longitudinal observational studies have suggested that nutrients, such as antioxidants, B vitamins, and ω-3 fatty acids, may prevent cognitive decline or dementia. There is very little ...evidence from well-sized randomized controlled trials that nutritional interventions can benefit cognition in later life. Nutritional interventions may be more effective in individuals with poorer nutritional status or as part of multidomain interventions simultaneously targeting multiple lifestyle factors. Further evidence, notably from randomized controlled trials, is required to prove or refute these hypotheses.
OBJECTIVETo evaluate the relationship of white matter hyperintensities (WMH) with decline in lower extremity function (LEF) over approximately 3 years in dementia-free older adults with memory ...complaints.
METHODSWe obtained brain MRI data from 458 community-dwelling adults, aged 70 years or over, at baseline, and from 358 adults over an average follow-up of 963 days. We evaluated LEF using the Short Physical Performance Battery (SPPB). We related baseline WMH volumes and progression to SPPB scores over time, using mixed-effect linear regressions. For the secondary analyses, we categorized baseline WMH volume into quartiles, and dichotomized the WMH progression to compare fast and slow progression.
RESULTSBaseline WMH volume (β = −0.017, 95% confidence interval CI −0.025 to −0.009), as well as WMH progression (β = −0.002, 95% CI −0.003 to −0.001), significantly associated with a decline in SPPB performance in adjusted analyses. Compared with the lowest quartile of baseline WMH volume, the highest quartile associated with a decline in SPPB performance (β = −0.301, 95% CI −0.558 to −0.044). Fast progression also associated with a decline in SPPB performance. We found clinically meaningful differences in the SPPB, with higher scores in participants with slow progression of WMH, at both 24 and 36 months.
CONCLUSIONSBaseline level and WMH progression associated with longitudinal decline in SPPB performance among older adults. We detected clinically meaningful differences in SPPB performance on comparing fast with slow progression of WMH, suggesting that speed of WMH progression is an important determinant of LEF during aging.
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