Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease

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Executive function and instrumental activities of daily living in mild cognitive impairment and Alzheimer's disease
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  Executive function and instrumental activities of daily living inMCI and AD Gad A. Marshall, MD a,b,* , Dorene M. Rentz, PsyD a,b , Meghan T. Frey, MA a , Joseph J.Locascio, PhD b , Keith A. Johnson, MD a,b,c , and Reisa A. Sperling, MD a,b   the Alzheimer’sDisease Neuroimaging Initiative a Center for Alzheimer Research and Treatment, Department of Neurology, Brigham andWomen’s Hospital, Harvard Medical School, Boston, MA 02115, USA b Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston,MA 02114, USA c Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston,MA 02114, USA Abstract Background— Impairment in instrumental activities of daily living (IADL) leads to early loss inproductivity and adds significant burden to caregivers. Executive dysfunction is thought to be animportant contributor to functional impairment. The objective of this study was to investigate therelationship between executive function and IADL in a large cohort of well characterized normalolder controls (NC), mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD)patients, 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 DiseaseNeuroimaging Initiative (ADNI) study (228 NC, 387 MCI, 178 AD) were included in theanalyses. A multiple regression model was used to assess the relationship between executivefunction and IADL. Results— A multiple regression model, including diagnosis, global cognitive impairment,memory performance, and other covariates demonstrated a significant relationship betweenexecutive dysfunction and IADL impairment across all subjects (R 2 =0.60, p<0.0001 for model;Digit Symbol, partial β = − 0.044, p=0.005; Trailmaking Test B – A, quadratic relation, p=0.01). Ananalysis using MCI subjects only also yielded a significant relationship (R 2 =0.16, p<0.0001 formodel; Digit Symbol, partial β = − 0.08, p=0.001). Conclusions— These results suggest that executive dysfunction is a key contributor toimpairment in IADL. This relationship was evident even after accounting for degree of memorydeficit across the continuum of cognitive impairment and dementia. © 2010 Elsevier Inc. All rights reserved. * Correspondence to: Gad A. Marshall, MD, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, 221Longwood Avenue, BL-104H, Boston, MA 02115, P: 617-732-8085, F: 617-264-5212, gamarshall@partners.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.None of the authors have a competing interest to disclose. NIH Public Access Author Manuscript  Alzheimers Dement  . Author manuscript; available in PMC 2012 May 1. Published in final edited form as: Alzheimers Dement  . 2011 May ; 7(3): 300308. doi:10.1016/j.jalz.2010.04.005. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    Keywords Alzheimer’s disease; executive function; instrumental activities of daily living; memory; mildcognitive impairment 1. Introduction One of the key clinical features of Alzheimer’s disease (AD) is impairment in dailyfunctioning. Instrumental activities of daily living (IADL) consist of preparing meals,handling the finances, driving or using public transportation, shopping, and many othereveryday activities. IADL impairment leads to early loss of independence and the ability tobe an active member of society, while shifting many daily responsibilities to caregivers andincreasing their burden. IADL impairment in patients with clinical AD has been associatedwith global pathologic changes and frontal and posterior hypometabolism1–3.As AD progresses, executive dysfunction becomes more prominent. Executive functionconsists of complex attention, working memory, verbal and visual organization, planning, judgment, and reasoning. Executive dysfunction and IADL impairment have been shown topredict progression from amnestic mild cognitive impairment (MCI) to clinical AD and arethought to be associated with each other and prefrontal dysfunction4–7. Most studiesexploring the relationship between executive function and IADL have focused on eithernormal aging8, 9 or dementia4, 10. However, only a few studies with small numbers of subjects have explored the relationship between executive function and IADL across thecontinuum from normal aging to MCI and mild AD11, 12. MCI subjects are aheterogeneous group with variable pathology. Therefore, investigating the relationshipbetween executive function and IADL more closely may be important for identifyingsubjects with MCI who are likely to progress to clinical AD. Early identification of thoseMCI subjects who are at risk for AD will allow them to take advantage of early treatmentopportunities as they arise. Moreover, it is important to determine what the additionalcontribution of executive dysfunction is to impairment in IADL, when accounting formemory deficits and global cognitive impairment, as treatments specifically targetingexecutive dysfunction may also be beneficial in maintaining patient independence.The objective of this study was to investigate the relationship between executive functionand IADL in a large cohort of well characterized subjects, including normal older controls(NC), MCI, and mild AD patients. In particular, we sought to determine the influence of executive function on functional capacity both across the continuum of aging to earlydementia, and specifically within the MCI group. We used novel statistical analyses tocarefully tease apart the complex relations between IADL and measures of executivefunction. Moreover, we investigated the influence of several factors that were not allconsidered in the previous literature, including diagnostic group, age, education, memoryperformance, global cognitive impairment, depression, and apathy. 2. Methods 2.1. Subjects from ADNI database Data used in the preparation of this article were obtained from the Alzheimer’s DiseaseNeuroimaging Initiative (ADNI) database (www.loni.ucla.edu\ADNI)13. ADNI is a largemulti-center, longitudinal, observational trial taking place across North America, in whichsubjects with normal cognition, amnestic MCI, and mild AD are followed with periodicneuropsychological testing, multiple imaging techniques, and fluid biomarkers. The goals of ADNI are to standardize brain imaging across multiple sites, obtain a large longitudinal Marshall et al.Page 2  Alzheimers Dement  . Author manuscript; available in PMC 2012 May 1. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    dataset for future research, and develop reliable biomarker surrogates for treatment trials.ADNI is the result of efforts of many co-investigators from a broad range of academicinstitutions and private corporations, and subjects have been recruited from over 50 sitesacross the U.S. and Canada.Subjects with complete baseline clinical datasets (n=793) from the ADNI study (228 NC,387 MCI, 178 AD) were included in the current analysis. Subjects were ages 55–91(inclusive), in general good health or had stable medical problems at the time of screening,and had a study partner/caregiver able to provide an independent evaluation of the subject’scognitive, behavioral, and functional status. Subjects had a Modified Hachinski IschemicScore14   4 and a Geriatric Depression Scale15 (GDS, short form) < 6. Subjects did nothave other significant neurological conditions, significant active psychiatric disorders, oralcohol or substance abuse within two years of screening. 6 subjects who did not meet thespecific ADNI diagnostic classification criteria stated below, but who were still listed in theADNI database, were excluded from the current analyses.Subjects were assigned to a diagnostic group (NC, MCI, or AD) by the site investigators atthe screening visit and again at the baseline visit. Baseline diagnoses were used in thecurrent analyses because at the end of the baseline visit, the site investigators had theadvantage of reviewing the comprehensive neuropsychological testing (assessing memory,attention, executive function, language, and visuospatial function) and additional studypartner questionnaires about behavior and daily functioning. In accordance with the ADNIprotocol, both quantitative cut-off scores and qualitative clinical assessments were used bysite investigators to determine the diagnosis of each subject. Diagnoses were ultimatelybased on the clinical judgment of the site investigator. The criteria for each diagnostic groupare described below.NC subjects had a global Clinical Dementia Rating scale16 (CDR) score = 0, CDR MemoryBox score = 0, Mini-Mental State Examination17 (MMSE) of 25–30 (inclusive), andperformance 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-Revised18(WMS-R) (subjects who had   16 years of education, required a LM-IIa score > 8; 8–15years, LM-IIa > 4; 0–7 years, LM-IIa > 2). Moreover, NC subjects had to be deemedcognitively normal based on an absence of significant impairment in cognitive functions orIADL following review of the screening and baseline data by the site investigator.MCI subjects fulfilled criteria for amnestic MCI (single and multiple domain)19: Non-demented subjects with memory complaint (global CDR score = 0.5, with a Memory Boxscore   0.5), MMSE of 24–30 (inclusive), and essentially preserved IADL (there was nospecified score on a test of IADL to determine this criterion; it was a qualitative clinicaldetermination made by the investigator at each site). Subjects performed at an objective cut-off of 1.5 standard deviations below education-adjusted norms on the LM-IIa of the WMS-R(subjects who had   16 years of education, required a LM-IIa score   8; 8–15 years, LM-IIa   4; 0–7 years, LM-IIa   2).AD subjects met the National Institute of Neurologic and Communicative Disorders andStroke and the AD and Related Disorders Association Work Group (NINCDS-ADRDA)criteria for probable AD20 with mild dementia severity (global CDR score = 0.5 or 1),MMSE of 20–26 (inclusive), and the same objective cut-off scores on the LM-IIa of theWMS-R as MCI subjects.The study was approved by the local Institutional Review Boards (IRB) of each participatingsite. Written informed consent was obtained from all subjects and study partners after all Marshall et al.Page 3  Alzheimers Dement  . Author manuscript; available in PMC 2012 May 1. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    study procedures and risks were thoroughly explained in accordance with local IRBguidelines. 2.2. Clinical assessments The Functional Activities Questionnaire21 (FAQ) was used to assess IADL impairment(higher scores indicate greater impairment, range 0–30). In one study FAQ scores of   6were reported as consistent with functional impairment22; other studies do not provide anestablished cut-off score for the FAQ.Trailmaking Test A23 (TMT-A, higher scores indicate greater impairment; range 17–150seconds; 17 seconds was the lowest score obtained in this analysis; if subjects were not ableto complete the task after 150 seconds, it was discontinued, and they were assigned a scoreof 150 seconds), Trailmaking Test B23 (TMT-B, higher scores indicate greater impairment;range 34–300 seconds; 34 seconds was the lowest score obtained in this analysis; if subjectswere not able to complete the task after 300 seconds, it was discontinued, and they wereassigned a score of 300 seconds), and the Wechsler Adult Intelligence Scale-Revised(WAIS-R) Digit Symbol24 (DSym, lower scores indicate greater impairment, possible range0–110; in the current sample the highest score was 80) were used to assess executivefunction. TMT-A and TMT-B both depend on processing speed and visuomotor andperceptual-scanning skills, but TMT-B also requires considerable cognitive flexibility inshifting from number to letter sets under time pressure. DSym depends on multiple cognitiveabilities including attention, psychomotor speed, complex scanning, visual tracking, andimmediate memory. These tests were selected from the ADNI neuropsychological batterybecause they have been well-validated and have a wide range of scores across the continuumof normal aging to mild AD. Prior studies have used these tests, as well as other tests toassess the relationship between executive function and IADL8, 10, 12, 25, 26. For theanalyses of the current study we used DSym and a difference score between TMT-B andTMT-A (TMT-B minus TMT-A, TMT-B-A), which corrects for processing speed andvisuomotor scanning, resulting in a purer executive function measure of set shifting27.Other assessments relevant to this analysis included the MMSE (a measure of globalcognitive function; range 20–30 in the current analysis, but 0–30 in general; lower scoresindicate greater impairment), the Rey Auditory Verbal Learning Test28 (RAVLT) 30 minutedelayed recall task (a measure of memory performance; range 0–15; lower scores indicategreater impairment), GDS short form (a measure of depression; range 0–5 in the currentanalysis, but 0–15 in general; higher scores indicate greater impairment), theNeuropsychiatric Inventory brief questionnaire form29 (NPI-Q) Depression item (a measureof depression; range 0–3; higher scores indicate greater impairment), and the NPI-Q Apathyitem (a measure of apathy; range 0–3; higher scores indicate greater impairment). 2.3. Data analysis For our primary analysis, a linear and curvilinear (quadratic) multiple regression analysis(general linear model) was conducted using all subjects with FAQ as the dependent variableand the following predictors: diagnostic group, linear and quadratic terms for the measuresof executive function (TMT-B-A (a difference score between TMT-B and TMT-A), DSym),for age, for education, for global cognitive impairment (MMSE), for memory performance(RAVLT delayed recall), for measures of depression (GDS, NPI-Q Depression), and forapathy (NPI-Q Apathy), and also the interaction of diagnosis with the linear/quadratic termsfor these predictors. Starting with a saturated model with all predictive terms, the most non-significant terms were progressively removed, one at a time, in a backward eliminationstrategy until only individually significant predictors remained in the model. (Non-significant lower order counterparts of significant higher order terms were allowed to Marshall et al.Page 4  Alzheimers Dement  . Author manuscript; available in PMC 2012 May 1. N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t  N I  H -P A A  u t  h  or M an u s  c r i   p t    remain, e.g., a non-significant linear term corresponding to a significant quadratic predictorwas retained.)Two analyses with MCI subjects only were then performed. In the first analysis, a linearmultiple regression analysis was conducted across MCI subjects with FAQ as the dependentvariable and the following simultaneous predictors: executive function (TMT-B-A, DSym),age, education, MMSE, RAVLT delayed recall, GDS, NPI-Q Depression, and NPI-QApathy.The second analysis was performed using a clinically relevant dichotomy between MCIsubjects considered to be with and without executive dysfunction. All ADNI MCI subjectswere required to meet amnestic MCI criteria. For this analysis, MCI subjects were thendivided into subjects with impaired memory and executive dysfunction (MCI Executive) andsubjects with impaired memory and no executive dysfunction (MCI Non-Executive). MCIExecutive subjects performed at an objective cut-off of 1.5 standard deviations belowreported normative means for TMT-B and DSym. The norms used were from the UniformData Set of the Alzheimer’s Disease Centers30, which has a similar population to ADNI.The relationship between FAQ and MCI Executive and MCI Non-Executive subjects wasdetermined using independent samples t-test. Finally, a linear multiple regression analysiswas conducted with FAQ as the dependent variable and the following simultaneouspredictors: MCI Executive vs. MCI Non-Executive status, age, education, MMSE, RAVLTdelayed recall, GDS, NPI-Q Depression, and NPI-Q Apathy. 3. Results Table 1 provides the demographics for all subjects as a combined group, as well as the threediagnostic groups separately. As expected, there were significant differences in MMSE,RAVLT delayed recall, NPI-Q Depression item, NPI-Q Apathy item, FAQ, TMT-A, TMT-B, TMT-B-A, and DSym between NC, MCI, and AD groups. Additionally, age was greaterin NC compared to MCI subjects (t=2.13, p=0.03). There was a significantly greaterproportion of male subjects in the MCI group when compared to the NC and AD groups(omnibus chi-square test p=0.002; MCI vs. NC: p=0.003; MCI vs. AD: p=0.007). Meanyears of education were less in the AD group when compared to the NC and MCI groups(AD vs. NC: t=4.62, p<0.0001; AD vs. MCI: t=3.89, p=0.0001). Table 2 providescorrelations between FAQ (the dependent variable) and each of the predictors in the modelacross the entire sample and within each diagnostic group.Across the sample as a whole, there were significant negative correlations between TMT-Band DSym (r= − 0.71, p<0.0001) and TMT-B-A and DSym (r= − 0.60, p<0.0001), consistentwith greater executive dysfunction being represented by higher scores on TMT-B and TMT-B-A and lower scores on DSym.In the regression model for all subjects, after backward elimination, a significant (p<0.0001)overall regression model emerged, accounting for 60% of the variance of FAQ. Individuallysignificant (p  0.05) terms retained in this model showed relations generally consistent withpredictions: (1) an expected main effect for diagnosis in which the AD group had overallmore highly elevated FAQ scores (greater IADL impairment) than the MCI group, which inturn had higher scores than those for the NC group; (2) a negative linear relation for DSymwithin each diagnostic group (unstandardized partial regression coefficient ( β )= − 0.044,p=0.005, 95% confidence interval (CI) for β = − 0.075, − 0.013), i.e., lower DSym scores(greater executive dysfunction) were associated with higher FAQ scores (greater IADLimpairment) (see Figure 1); (3) a quadratic relation for TMT-B-A within diagnosis in whichFAQ scores increased (greater IADL impairment) with increasing TMT-B-A scores (greater Marshall et al.Page 5  Alzheimers Dement  . Author manuscript; available in PMC 2012 May 1. 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