Very little is known about functional change in persons in the preclinical stage of AD. As currently conceptualized, functional impairment in Alzheimer’s disease (AD) is the final and somewhat remote downstream outcome of a cascade of preceding pathophysiological and clinical events characterizing AD: amyloid deposition, neurodegenerative cellular, metabolic and network pathway changes, tissue loss and atrophy, and significant cognitive decline. Given this prevailing conceptual framework, possible functional change in preclinical AD, and related clinical trial methodology, have received relatively little attention. For example, the 2013 draft guidance of the FDA for treatment of early stage Alzheimer’s disease anticipates that persons in the preclinical phase will only show subtle cognitive deficits “in the absence of any detectable functional impairment” (1), and that in these circumstances the field may be allowed to pursue valid and reliable cognitive assessments as a single primary efficacy measure (1). This prevailing framework notwithstanding, a new perspective has recently begun to emerge concerning functional change and outcome measures in preclinical AD. The intriguing possibility that detectable functional change actually commences much earlier in the AD disease process, possibly as early as the preclinical stage, has recently been suggested (2, 3). In support of this proposition is the now well-established finding that functional impairment is clearly present in prodromal AD. Prior research by several groups (3–7) has shown that complex functional skills (Independent Activities of Daily Life, or IADLs) show impairment in patients with mild cognitive impairment (MCI) and continue to decline over time (5). In particular, financial capacity is a higher order functional skill that is highly sensitive and vulnerable to MCI and mild AD (4, 5, 8), which raises the possibility that measurable financial decline may also occur in persons with preclinical AD. It should be noted that current diagnostic criteria for preclinical AD explicitly contemplate and posit incipient subtle cognitive changes emerging in the third or “late” stage of the preclinical phase (9). Consistent with this theoretical view, recent studies have shown episodic memory impairments in older individuals with abnormal levels of brain amyloid (10, 11). The presence of detectable albeit subtle cognitive impairments in individuals with preclinical AD raises the possibility that associated subtle changes in complex functional activities may also be present and detectable. A critical factor here is the sensitivity of the functional measure employed. Detection of functional impairment in cognitively normal individuals with preclinical AD will require instruments sensitive to subclinical cognitive and functional changes. Informant report measures commonly used to characterize functional decline in late MCI and AD type dementia likely lack sensitivity to detect these very sub
{"title":"Investigating Functional Impairment in Preclinical Alzheimer's Disease.","authors":"D. Marson","doi":"10.14283/JPAD.2015.44","DOIUrl":"https://doi.org/10.14283/JPAD.2015.44","url":null,"abstract":"Very little is known about functional change in persons in the preclinical stage of AD. As currently conceptualized, functional impairment in Alzheimer’s disease (AD) is the final and somewhat remote downstream outcome of a cascade of preceding pathophysiological and clinical events characterizing AD: amyloid deposition, neurodegenerative cellular, metabolic and network pathway changes, tissue loss and atrophy, and significant cognitive decline. Given this prevailing conceptual framework, possible functional change in preclinical AD, and related clinical trial methodology, have received relatively little attention. For example, the 2013 draft guidance of the FDA for treatment of early stage Alzheimer’s disease anticipates that persons in the preclinical phase will only show subtle cognitive deficits “in the absence of any detectable functional impairment” (1), and that in these circumstances the field may be allowed to pursue valid and reliable cognitive assessments as a single primary efficacy measure (1). \u0000 \u0000This prevailing framework notwithstanding, a new perspective has recently begun to emerge concerning functional change and outcome measures in preclinical AD. The intriguing possibility that detectable functional change actually commences much earlier in the AD disease process, possibly as early as the preclinical stage, has recently been suggested (2, 3). In support of this proposition is the now well-established finding that functional impairment is clearly present in prodromal AD. Prior research by several groups (3–7) has shown that complex functional skills (Independent Activities of Daily Life, or IADLs) show impairment in patients with mild cognitive impairment (MCI) and continue to decline over time (5). In particular, financial capacity is a higher order functional skill that is highly sensitive and vulnerable to MCI and mild AD (4, 5, 8), which raises the possibility that measurable financial decline may also occur in persons with preclinical AD. \u0000 \u0000It should be noted that current diagnostic criteria for preclinical AD explicitly contemplate and posit incipient subtle cognitive changes emerging in the third or “late” stage of the preclinical phase (9). Consistent with this theoretical view, recent studies have shown episodic memory impairments in older individuals with abnormal levels of brain amyloid (10, 11). The presence of detectable albeit subtle cognitive impairments in individuals with preclinical AD raises the possibility that associated subtle changes in complex functional activities may also be present and detectable. \u0000 \u0000A critical factor here is the sensitivity of the functional measure employed. Detection of functional impairment in cognitively normal individuals with preclinical AD will require instruments sensitive to subclinical cognitive and functional changes. Informant report measures commonly used to characterize functional decline in late MCI and AD type dementia likely lack sensitivity to detect these very sub","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"2 1 1","pages":"4-6"},"PeriodicalIF":6.4,"publicationDate":"2015-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G. Crichton, M. Elias, A. Davey, A. Alkerwi, G. A. Dore
OBJECTIVES Few studies have examined whether cognitive function predicts dietary intake. The majority of research has focused on how diet can influence cognitive performance or risk for cognitive impairment in later life. The aim of this study was to examine prospective relationships between cognitive performance and dietary intake in participants of the Maine-Syracuse Longitudinal Study. DESIGN A prospective study with neuropsychological testing at baseline and nutritional assessments measured a mean of 18 years later. SETTING Community-dwelling individuals residing in central New York state. PARTICIPANTS 333 participants free of dementia and stroke. MEASUREMENTS The Wechsler Adult Intelligence Scale (WAIS) was assessed at baseline and dietary intake was measured using the Nutrition and Health Questionnaire. RESULTS Higher WAIS Scores at baseline were prospectively associated with higher intakes of vegetables, meats, nuts and legumes, and fish, but inversely associated with consumption of total grains and carbonated soft drinks. After adjustment for sample selection, socioeconomic indicators, lifestyle factors (smoking and physical activity), and cardiovascular risk factors, the relations between higher cognitive performance and greater consumption of vegetables, meat, and fish, and lower consumption of grains remained significant. CONCLUSION These data suggest that cognition early in life may influence dietary choices later in life.
{"title":"Higher Cognitive Performance Is Prospectively Associated with Healthy Dietary Choices: The Maine Syracuse Longitudinal Study.","authors":"G. Crichton, M. Elias, A. Davey, A. Alkerwi, G. A. Dore","doi":"10.14283/JPAD.2015.39","DOIUrl":"https://doi.org/10.14283/JPAD.2015.39","url":null,"abstract":"OBJECTIVES\u0000Few studies have examined whether cognitive function predicts dietary intake. The majority of research has focused on how diet can influence cognitive performance or risk for cognitive impairment in later life. The aim of this study was to examine prospective relationships between cognitive performance and dietary intake in participants of the Maine-Syracuse Longitudinal Study.\u0000\u0000\u0000DESIGN\u0000A prospective study with neuropsychological testing at baseline and nutritional assessments measured a mean of 18 years later.\u0000\u0000\u0000SETTING\u0000Community-dwelling individuals residing in central New York state.\u0000\u0000\u0000PARTICIPANTS\u0000333 participants free of dementia and stroke.\u0000\u0000\u0000MEASUREMENTS\u0000The Wechsler Adult Intelligence Scale (WAIS) was assessed at baseline and dietary intake was measured using the Nutrition and Health Questionnaire.\u0000\u0000\u0000RESULTS\u0000Higher WAIS Scores at baseline were prospectively associated with higher intakes of vegetables, meats, nuts and legumes, and fish, but inversely associated with consumption of total grains and carbonated soft drinks. After adjustment for sample selection, socioeconomic indicators, lifestyle factors (smoking and physical activity), and cardiovascular risk factors, the relations between higher cognitive performance and greater consumption of vegetables, meat, and fish, and lower consumption of grains remained significant.\u0000\u0000\u0000CONCLUSION\u0000These data suggest that cognition early in life may influence dietary choices later in life.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"2 1 1","pages":"24-32"},"PeriodicalIF":6.4,"publicationDate":"2015-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
With the aging of the world's population, the prevalence of Alzheimer's disease (AD) is rising. Yet it remains the only leading cause of death for which there is no disease-modifying treatment available, despite substantial academic and industry efforts. Disappointing clinical trials over the last several years have led to a growing consensus on the need to intervene early in the disease process, before clinical symptoms begin (1). Built on the hypothetical model of disease progression proposed by Jack et al (2, 3), which has since been supported by empirical data (4), the dominant paradigm today posits that the pathophysiologic processes underlying AD begin long before symptoms (5). However drug development at this stage is complicated by the difficulty of assessing a therapeutic benefit in subjects who are, by definition, clinically normal.
{"title":"Cognitive/Clinical Endpoints for Pre-Dementia AD Trials","authors":"Aisen Ps","doi":"10.14283/JPAD.2015.62","DOIUrl":"https://doi.org/10.14283/JPAD.2015.62","url":null,"abstract":"With the aging of the world's population, the prevalence of Alzheimer's disease (AD) is rising. Yet it remains the only leading cause of death for which there is no disease-modifying treatment available, despite substantial academic and industry efforts. Disappointing clinical trials over the last several years have led to a growing consensus on the need to intervene early in the disease process, before clinical symptoms begin (1). Built on the hypothetical model of disease progression proposed by Jack et al (2, 3), which has since been supported by empirical data (4), the dominant paradigm today posits that the pathophysiologic processes underlying AD begin long before symptoms (5). However drug development at this stage is complicated by the difficulty of assessing a therapeutic benefit in subjects who are, by definition, clinically normal.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"2 1","pages":"82-84"},"PeriodicalIF":6.4,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Brown, S. Hendrix, M. Cecchi, J. Scott, J. Silcox, K. Brighton, D. Hedges
Event-related potentials (ERPs) are a physiological measure of cognitive function that have shown diagnostic and prognostic utility in Alzheimer’s disease (AD). In this study, we used a novel eigenvector-based technique to better understand brain electrophysiological differences between subjects with mild AD and healthy controls (HC). Using ERPs from 75 subjects with mild AD and 95 HC, we first calculated cognitive task eigenvectors within each subject from three conditions and then calculated second-order eigenvector components to compare the AD group to the HC group. A MANOVA of the three second-level components discriminated between AD and HC multivariately (Wilks’ lambda=.4297, p<0.0001, R2 = .5703), and also on each of the three components univariately (all 3 p-values<0.0001). The eigenvector-based technique used in this study accurately discriminated between the mild AD group and HC. As such, this analysis method adds to our understanding of the differences in ERP signal between AD and HC, and could provide a sensitive biomarker for diagnosis and monitoring of AD progression.
{"title":"A NOVEL EIGENVECTOR-BASED METHOD TO DETECT MILD ALZHEIMER’S DISEASE USING EVENT-RELAT","authors":"B. Brown, S. Hendrix, M. Cecchi, J. Scott, J. Silcox, K. Brighton, D. Hedges","doi":"10.14283/jpad.2015.79","DOIUrl":"https://doi.org/10.14283/jpad.2015.79","url":null,"abstract":"Event-related potentials (ERPs) are a physiological measure of cognitive function that have shown diagnostic and prognostic utility in Alzheimer’s disease (AD). In this study, we used a novel eigenvector-based technique to better understand brain electrophysiological differences between subjects with mild AD and healthy controls (HC). Using ERPs from 75 subjects with mild AD and 95 HC, we first calculated cognitive task eigenvectors within each subject from three conditions and then calculated second-order eigenvector components to compare the AD group to the HC group. A MANOVA of the three second-level components discriminated between AD and HC multivariately (Wilks’ lambda=.4297, p<0.0001, R2 = .5703), and also on each of the three components univariately (all 3 p-values<0.0001). The eigenvector-based technique used in this study accurately discriminated between the mild AD group and HC. As such, this analysis method adds to our understanding of the differences in ERP signal between AD and HC, and could provide a sensitive biomarker for diagnosis and monitoring of AD progression.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"FOREWORD: AD DRUG DEVELOPMENT IS NOT BROKEN: CLINICAL TRIALS IN ALZHEIMER’S DISEASE 2014 CONFERENCE, PHILADELPHIA","authors":"J. Touchon","doi":"10.14283/jpad.2014.33","DOIUrl":"https://doi.org/10.14283/jpad.2014.33","url":null,"abstract":"","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2014-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66891982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Mosconi, J. Murray, W. Tsui, Yi Li, M. Davies, Schantel Williams, E. Pirraglia, N. Spector, R. Osorio, Lidia Glodzik, P. McHugh, M. J. Leon
OBJECTIVES Epidemiological evidence linking diet, one of the most important modifiable environmental factors, and risk of Alzheimer's disease (AD) is rapidly increasing. Several studies have shown that higher adherence to a Mediterranean diet (MeDi) is associated with reduced risk of AD. This study examines the associations between high vs. lower adherence to a MeDi and structural MRI-based brain atrophy in key regions for AD in cognitively normal (NL) individuals with and without risk factors for AD. DESIGN Cross-sectional study. SETTING Manhattan (broader area). PARTICIPANTS Fifty-two NL individuals (age 54+12 y, 70% women) with complete dietary information and cross-sectional, 3D T1-weighted MRI scans were examined. MEASUREMENTS Subjects were dichotomized into those showing higher vs. lower adherences to the MeDi using published protocols. Estimates of cortical thickness for entorhinal cortex (EC), inferior parietal lobe, middle temporal gyrus, orbitofrontal cortex (OFC) and posterior cingulate cortex (PCC) were obtained by use of automated segmentation tools (FreeSurfer). Multivariate general linear models and linear regressions assessed the associations of MeDi with MRI measures. RESULTS Of the 52 participants, 20 (39%) showed higher MeDi adherence (MeDi+) and 32 (61%) showed lower adherence (MeDi-). Groups were comparable for clinical, neuropsychological measures, presence of a family history of AD (FH), and frequency of Apolipoprotein E (APOE) ε4 genotype. With and without controlling for age and total intracranial volume, MeDi+ subjects showed greater thickness of AD-vulnerable ROIs as compared to MeDi- subjects (Wilk's Lambda p=0.026). Group differences were most pronounced in OFC (p=0.001), EC (p=0.03) and PCC (p=0.04) of the left hemisphere. Adjusting for gender, education, FH, APOE status, BMI, insulin resistance scores and presence of hypertension did not attenuate the relationship. CONCLUSION NL individuals showing lower adherence to the MeDi had cortical thinning in the same brain regions as clinical AD patients compared to those showing higher adherence. These data indicate that the MeDi may have a protective effect against tissue loss, and suggest that dietary interventions may play a role in the prevention of AD.
{"title":"Mediterranean Diet and Magnetic Resonance Imaging-Assessed Brain Atrophy in Cognitively Normal Individuals at Risk for Alzheimer's Disease.","authors":"L. Mosconi, J. Murray, W. Tsui, Yi Li, M. Davies, Schantel Williams, E. Pirraglia, N. Spector, R. Osorio, Lidia Glodzik, P. McHugh, M. J. Leon","doi":"10.14283/jpad.2014.17","DOIUrl":"https://doi.org/10.14283/jpad.2014.17","url":null,"abstract":"OBJECTIVES\u0000Epidemiological evidence linking diet, one of the most important modifiable environmental factors, and risk of Alzheimer's disease (AD) is rapidly increasing. Several studies have shown that higher adherence to a Mediterranean diet (MeDi) is associated with reduced risk of AD. This study examines the associations between high vs. lower adherence to a MeDi and structural MRI-based brain atrophy in key regions for AD in cognitively normal (NL) individuals with and without risk factors for AD.\u0000\u0000\u0000DESIGN\u0000Cross-sectional study.\u0000\u0000\u0000SETTING\u0000Manhattan (broader area).\u0000\u0000\u0000PARTICIPANTS\u0000Fifty-two NL individuals (age 54+12 y, 70% women) with complete dietary information and cross-sectional, 3D T1-weighted MRI scans were examined.\u0000\u0000\u0000MEASUREMENTS\u0000Subjects were dichotomized into those showing higher vs. lower adherences to the MeDi using published protocols. Estimates of cortical thickness for entorhinal cortex (EC), inferior parietal lobe, middle temporal gyrus, orbitofrontal cortex (OFC) and posterior cingulate cortex (PCC) were obtained by use of automated segmentation tools (FreeSurfer). Multivariate general linear models and linear regressions assessed the associations of MeDi with MRI measures.\u0000\u0000\u0000RESULTS\u0000Of the 52 participants, 20 (39%) showed higher MeDi adherence (MeDi+) and 32 (61%) showed lower adherence (MeDi-). Groups were comparable for clinical, neuropsychological measures, presence of a family history of AD (FH), and frequency of Apolipoprotein E (APOE) ε4 genotype. With and without controlling for age and total intracranial volume, MeDi+ subjects showed greater thickness of AD-vulnerable ROIs as compared to MeDi- subjects (Wilk's Lambda p=0.026). Group differences were most pronounced in OFC (p=0.001), EC (p=0.03) and PCC (p=0.04) of the left hemisphere. Adjusting for gender, education, FH, APOE status, BMI, insulin resistance scores and presence of hypertension did not attenuate the relationship.\u0000\u0000\u0000CONCLUSION\u0000NL individuals showing lower adherence to the MeDi had cortical thinning in the same brain regions as clinical AD patients compared to those showing higher adherence. These data indicate that the MeDi may have a protective effect against tissue loss, and suggest that dietary interventions may play a role in the prevention of AD.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1 1","pages":"23-32"},"PeriodicalIF":6.4,"publicationDate":"2014-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Vellas, I. Carrié, S. Gillette‐Guyonnet, J. Touchon, T. Dantoine, J. Dartigues, M. Cuffi, S. Bordes, Y. Gasnier, P. Robert, L. Bories, O. Rouaud, F. Desclaux, K. Sudres, M. Bonnefoy, A. Pesce, C. Dufouil, S. Lehéricy, M. Chupin, J. F. Mangin, P. Payoux, D. Adel, P. Legrand, D. Catheline, C. Kanony, M. Zaim, L. Molinier, N. Costa, J. Delrieu, T. Voisin, C. Faisant, F. Lala, F. Nourhashemi, Y. Rolland, G. A. van Kan, C. Dupuy, C. Cantet, P. Cestac, S. Belleville, S. Willis, M. Cesari, M. Weiner, M. Soto, P. Ousset, S. Andrieu
OBJECTIVE The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans). DESIGN PATIENTS 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). INTERVENTIONS 1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. BASELINE POPULATION For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.
{"title":"MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA.","authors":"B. Vellas, I. Carrié, S. Gillette‐Guyonnet, J. Touchon, T. Dantoine, J. Dartigues, M. Cuffi, S. Bordes, Y. Gasnier, P. Robert, L. Bories, O. Rouaud, F. Desclaux, K. Sudres, M. Bonnefoy, A. Pesce, C. Dufouil, S. Lehéricy, M. Chupin, J. F. Mangin, P. Payoux, D. Adel, P. Legrand, D. Catheline, C. Kanony, M. Zaim, L. Molinier, N. Costa, J. Delrieu, T. Voisin, C. Faisant, F. Lala, F. Nourhashemi, Y. Rolland, G. A. van Kan, C. Dupuy, C. Cantet, P. Cestac, S. Belleville, S. Willis, M. Cesari, M. Weiner, M. Soto, P. Ousset, S. Andrieu","doi":"10.14283/jpad.2014.34","DOIUrl":"https://doi.org/10.14283/jpad.2014.34","url":null,"abstract":"OBJECTIVE\u0000The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloïd deposit (AV45 PET scans).\u0000\u0000\u0000DESIGN PATIENTS\u00001680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study).\u0000\u0000\u0000INTERVENTIONS\u00001/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24.\u0000\u0000\u0000BASELINE POPULATION\u0000For cognition, the mean MMSE at baseline was 28.1 (± 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4-m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 ± 8.1 µg/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloïd deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1 1","pages":"13-22"},"PeriodicalIF":6.4,"publicationDate":"2014-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Dacks, S. Andrieu, D. Blacker, A. Carman, Allan M. Green, F. Grodstein, V. Henderson, B. James, R. Lane, J. Lau, P. Lin, B. Reeves, R. Shah, B. Vellas, K. Yaffe, K. Yurko-Mauro, D. Shineman, D. Bennett, H. Fillit
Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.
{"title":"Dementia Prevention: optimizing the use of observational data for personal, clinical, and public health decision-making.","authors":"P. Dacks, S. Andrieu, D. Blacker, A. Carman, Allan M. Green, F. Grodstein, V. Henderson, B. James, R. Lane, J. Lau, P. Lin, B. Reeves, R. Shah, B. Vellas, K. Yaffe, K. Yurko-Mauro, D. Shineman, D. Bennett, H. Fillit","doi":"10.14283/jpad.2014.35","DOIUrl":"https://doi.org/10.14283/jpad.2014.35","url":null,"abstract":"Worldwide, over 35 million people suffer from Alzheimer's disease and related dementias. This number is expected to triple over the next 40 years. How can we improve the evidence supporting strategies to reduce the rate of dementia in future generations? The risk of dementia is likely influenced by modifiable factors such as exercise, cognitive activity, and the clinical management of diabetes and hypertension. However, the quality of evidence is limited and it remains unclear whether specific interventions to reduce these modifiable risk factors can, in turn, reduce the risk of dementia. Although randomized controlled trials are the gold-standard for causality, the majority of evidence for long-term dementia prevention derives from, and will likely continue to derive from, observational studies. Although observational research has some unavoidable limitations, its utility for dementia prevention might be improved by, for example, better distinction between confirmatory and exploratory research, higher reporting standards, investment in effectiveness research enabled by increased data-pooling, and standardized exposure and outcome measures. Informed decision-making by the general public on low-risk health choices that could have broad potential benefits could be enabled by internet-based tools and decision-aids to communicate the evidence, its quality, and the estimated magnitude of effect.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 2 1","pages":"117-123"},"PeriodicalIF":6.4,"publicationDate":"2014-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Berres, W. Kukull, A. Miserez, A. Monsch, Sarah E. Monsell, R. Spiegel
INTRODUCTION The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo-controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample. METHODS Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB. RESULTS The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score. CONCLUSION An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration.
{"title":"A Novel Study Paradigm for Long-term Prevention Trials in Alzheimer Disease: The Placebo Group Simulation Approach (PGSA): Application to MCI data from the NACC database.","authors":"M. Berres, W. Kukull, A. Miserez, A. Monsch, Sarah E. Monsell, R. Spiegel","doi":"10.14283/jpad.2014.5","DOIUrl":"https://doi.org/10.14283/jpad.2014.5","url":null,"abstract":"INTRODUCTION The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo-controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample. METHODS Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB. RESULTS The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score. CONCLUSION An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 2 1","pages":"99-109"},"PeriodicalIF":6.4,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Richard S. Isaacson, N. Haynes, A. Seifan, D. Larsen, S. Christiansen, J. C. Berger, Joseph Safdieh, A. Lunde, A. Luo, M. Kramps, M. McInnis, C. Ochner
BACKGROUND Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. OBJECTIVES Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). DESIGN Observational. SETTING Online. PARTICIPANTS Men/Women, aged 25+, recruited via facebook.com. INTERVENTION Alzheimer's Universe (www.AlzU.org) education research platform. MEASUREMENTS Pre/post-test performance, self-reported Likert-scale ratings, completion rates. RESULTS Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. CONCLUSIONS Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.
{"title":"Alzheimer's Prevention Education: If We Build It, Will They Come? www.AlzU.org.","authors":"Richard S. Isaacson, N. Haynes, A. Seifan, D. Larsen, S. Christiansen, J. C. Berger, Joseph Safdieh, A. Lunde, A. Luo, M. Kramps, M. McInnis, C. Ochner","doi":"10.14283/jpad.2014.4","DOIUrl":"https://doi.org/10.14283/jpad.2014.4","url":null,"abstract":"BACKGROUND Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. OBJECTIVES Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). DESIGN Observational. SETTING Online. PARTICIPANTS Men/Women, aged 25+, recruited via facebook.com. INTERVENTION Alzheimer's Universe (www.AlzU.org) education research platform. MEASUREMENTS Pre/post-test performance, self-reported Likert-scale ratings, completion rates. RESULTS Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. CONCLUSIONS Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25 interactive webinar-based vs. blog-post style lessons on learning and patient outcomes, in a randomized, within-subjects design trial.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 2 1","pages":"91-98"},"PeriodicalIF":6.4,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66892855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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