Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease
TL;DR: Investigating the relationship between executive function and IADL in a large cohort of well‐characterized normal older controls, mild cognitive impairment (MCI), and patients with mild Alzheimer's disease, separately as well as across the entire sample, while accounting for demographic, cognitive, and behavioral factors.
Abstract: Background Impairment in instrumental activities of daily living (IADL) leads to early loss in productivity and adds significant burden to caregivers. Executive dysfunction is thought to be an important contributor to functional impairment. The objective of this study was to investigate the relationship between executive function and IADL in a large cohort of well-characterized normal older controls, mild cognitive impairment (MCI), and patients with mild Alzheimer's disease, separately as well as across the entire sample, while accounting for demographic, cognitive, and behavioral factors. Methods Subjects with baseline clinical datasets (n = 793) from the Alzheimer's Disease Neuroimaging Initiative study (228 normal older controls, 387 MCI, 178 Alzheimer's disease) were included in the analysis. A multiple regression model was used to assess the relationship between executive function and IADL. Results A multiple regression model, including diagnosis, global cognitive impairment, memory performance, and other covariates demonstrated a significant relationship between executive dysfunction and IADL impairment across all subjects ( R 2 = .60, P s = −.044, P = .005; Trailmaking Test B–A, quadratic relation, P = .01). Similarly, an analysis using MCI subjects only yielded a significant relationship ( R 2 = .16, P s = −.08, P = .001). Conclusions These results suggest that executive dysfunction is a key contributor to impairment in IADL. This relationship was evident even after accounting for degree of memory deficit across the continuum of cognitive impairment and dementia.
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University of California, San Francisco1, Veterans Health Administration2, United States Department of Veterans Affairs3, University of California, San Diego4, University of California, Davis5, Washington University in St. Louis6, Brigham and Women's Hospital7, Mayo Clinic8, Helen Wills Neuroscience Institute9, Janssen Pharmaceutica10, Indiana University11, University of Pennsylvania12, Foundation for the National Institutes of Health13, Bristol-Myers Squibb14, University of California, Los Angeles15
TL;DR: The major accomplishments of ADNI have been the development of standardized methods for clinical tests, magnetic resonance imaging, positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting, and the improvement of clinical trial efficiency.
Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.
906 citations
Cites background from "Executive function and instrumental..."
...A companion paper by the same group [277] examined the relationship between functional impairment and executive function in a longitudinal study of the ADNI cohort....
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TL;DR: This intervention warrants longer-term and larger-scale trials to examine effects on conversion to dementia, as evidence for efficacy in people with dementia is weak and limited to trials of immersive technologies.
Abstract: Objective:Previous meta-analyses indicate that computerized cognitive training (CCT) is a safe and efficacious intervention for cognition in older adults. However, efficacy varies across populations and cognitive domains, and little is known about the efficacy of CCT in people with mild cognitive impairment or dementia.Method:The authors searched Medline, Embase, PsychINFO, CINAHL, and CENTRAL through July 1, 2016, for randomized controlled trials of CCT in older adults with mild cognitive impairment or dementia. Overall cognition, individual cognitive domains, psychosocial function, and activities of daily living were pooled separately for mild cognitive impairment and dementia trials.Results:The overall effect on cognition in mild cognitive impairment across 17 trials was moderate (Hedges’ g=0.35, 95% CI=0.20–0.51). There was no evidence of publication bias or difference between active- and passive-controlled trials. Small to moderate effects were found for global cognition, attention, working memory, l...
421 citations
Cites result from "Executive function and instrumental..."
...On theotherhand, consistentwith findings of previous meta-analyses of CCT (13, 15), we report lack of efficacy on executive function, a key predictor of functional decline (61)....
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TL;DR: This is the first meta‐analysis of active video games (‘exergames’) for cognition and domain‐specific analyses found exergames improved executive functions, attentional processing and visuospatial skills, presenting the firstMeta‐analytic evidence for effects of exergame on cognition.
250 citations
United States Department of Veterans Affairs1, University of California, San Diego2, University of California, Davis3, Washington University in St. Louis4, Biogen Idec5, Brigham and Women's Hospital6, Mayo Clinic7, Helen Wills Neuroscience Institute8, Eisai9, Indiana University10, University of Pennsylvania11, Eli Lilly and Company12, University of Southern California13
TL;DR: The major accomplishments of ADNI have been the development of standardized methods for clinical tests, magnetic resonance imaging, positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting, and the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes.
Abstract: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [ 18 F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU , and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.
249 citations
Cites background from "Executive function and instrumental..."
...A companion paper by the same group [277] examined the relationship between functional impairment and executive function in a longitudinal study of the ADNI cohort....
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TL;DR: Combined cognitive and exercise training can be effective for improving the cognitive functions and functional status of older adults with and without cognitive impairment, but limited evidence can be found in populations with cognitive impairment when the evaluation included an active control group comparison.
246 citations
References
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01 Dec 1969TL;DR: The concepts of power analysis are discussed in this paper, where Chi-square Tests for Goodness of Fit and Contingency Tables, t-Test for Means, and Sign Test are used.
Abstract: Contents: Prefaces. The Concepts of Power Analysis. The t-Test for Means. The Significance of a Product Moment rs (subscript s). Differences Between Correlation Coefficients. The Test That a Proportion is .50 and the Sign Test. Differences Between Proportions. Chi-Square Tests for Goodness of Fit and Contingency Tables. The Analysis of Variance and Covariance. Multiple Regression and Correlation Analysis. Set Correlation and Multivariate Methods. Some Issues in Power Analysis. Computational Procedures.
115,069 citations
Additional excerpts
...45; effect size (Cohen’s ‘‘d’’ [31]) 5 0....
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TL;DR: A simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
76,181 citations
"Executive function and instrumental..." refers background in this paper
...NC subjects had a global Clinical Dementia Rating scale [16] (CDR) score 5 0, CDR Memory Box score 5 0, Mini-Mental State Examination [17] (MMSE) score of 25 to 30 (inclusive), and performance at an objective cut-off of 1.5 standard deviations above education-adjusted cut-off scores on the Logical Memory IIa (LM-IIa) of the Weschler Memory Scale-Revised [18] (WMS-R) (subjects who had R16 years of education, required a LM-IIa score ....
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...NC subjects had a global Clinical Dementia Rating scale [16] (CDR) score 5 0, CDR Memory Box score 5 0, Mini-Mental State Examination [17] (MMSE) score of 25 to 30 (inclusive), and performance at an objective cut-off of 1....
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01 Jan 2002
TL;DR: The Mini-Mental State (MMS) as mentioned in this paper is a simplified version of the standard WAIS with eleven questions and requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
Abstract: EXAMINATION of the mental state is essential in evaluating psychiatric patients.1 Many investigators have added quantitative assessment of cognitive performance to the standard examination, and have documented reliability and validity of the several “clinical tests of the sensorium”.2*3 The available batteries are lengthy. For example, WITHERS and HINTON’S test includes 33 questions and requires about 30 min to administer and score. The standard WAIS requires even more time. However, elderly patients, particularly those with delirium or dementia syndromes, cooperate well only for short periods.4 Therefore, we devised a simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely. It is “mini” because it concentrates only on the cognitive aspects of mental functions, and excludes questions concerning mood, abnormal mental experiences and the form of thinking. But within the cognitive realm it is thorough. We have documented the validity and reliability of the MMS when given to 206 patients with dementia syndromes, affective disorder, affective disorder with cognitive impairment “pseudodementia”5T6), mania, schizophrenia, personality disorders, and in 63 normal subjects.
70,887 citations
TL;DR: The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information becomes available.
Abstract: Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
26,847 citations
TL;DR: Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD, and appear to constitute a clinical entity that can be characterized for treatment interventions.
Abstract: Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
8,255 citations
"Executive function and instrumental..." refers background in this paper
...Furthermore, in amnestic MCI subjects with or without executive dysfunction, the annual conversion rate to clinical AD is already 10% to 15% (compared to 1%–2% for normal elderly controls) [37]....
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