Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study

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Abstract

Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aβ<sub>42</sub>, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.

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Subjective Memory Complaints and Cognitive Impairment in Older People

Louise M. Reid, Alasdair MacLullich (2006)

Subjective memory complaints (SMCs) are common in older people and are often thought to indicate cognitive impairment. We reviewed research on the relationship between SMCs and (a) current cognitive function, (b) risk of future cognitive decline, and (c) depression and personality. SMCs were found to be inconsistently related to current cognitive impairment but were more strongly related to risk of future cognitive decline. However, SMCs were consistently related to depression and some personality traits, e.g. neuroticism. In conclusion, the determinants of SMCs are complex. The utility of SMCs in the diagnosis of pre-dementia states (e.g. mild cognitive impairment) is uncertain and requires further evaluation.

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Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment.

D. P. Devanand, M. Jay Goodkind, Jennifer Manly … (2006)

The likelihood of conversion to Alzheimer disease (AD) in mild cognitive impairment (MCI) and the "optimal" early markers of conversion need to be established. To evaluate conversion rates to AD in subtypes of MCI and to identify neuropsychological measures most predictive of the time to conversion. Patients were followed up semiannually and controls annually. Subtypes of MCI were determined by using demographically adjusted regression norms on neuropsychological tests. Survival analysis was used to identify the most predictive neuropsychological measures. Memory disorders clinic. One hundred forty-eight patients reporting memory problems and 63 group-matched controls. A consensus diagnosis of probable AD. At baseline, 108 patients met criteria for amnestic MCI: 87 had memory plus other cognitive domain deficits and 21 had pure memory deficits. The mean duration of follow-up for the 148 patients was 46.6 +/- 24.6 months. In 3 years, 32 (50.0%) of 64 amnestic-"plus" and 2 (10.0%) of 20 "pure" amnestic patients converted to AD (P = .001). In 148 patients, of 5 a priori predictors, the percent savings from immediate to delayed recall on the Selective Reminding Test and the Wechsler Adult Intelligence Scale-Revised Digit Symbol Test were the strongest predictors of time to conversion. From the entire neuropsychological test battery, a stepwise selection procedure retained 2 measures in the final model: total immediate recall on the Selective Reminding Test (odds ratio per 1-point decrease, 1.10; 95% confidence interval, 1.05-1.14; P < .0001) and Digit Symbol Test coding (odds ratio, 1.06; 95% confidence interval, 1.01-1.11; P = .01). The combined predictive accuracy of these 2 measures for conversion by 3 years was 86%. Mild cognitively impaired patients with memory plus other cognitive domain deficits, rather than those with pure amnestic MCI, constituted the high-risk group. Deficits in verbal memory and psychomotor speed/executive function abilities strongly predicted conversion to AD.

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Utility of combinations of biomarkers, cognitive markers, and risk factors to predict conversion from mild cognitive impairment to Alzheimer disease in patients in the Alzheimer's disease neuroimaging initiative.

Jesús Gomar, Maria T Bobes-Bascaran, Concepcion Conejero-Goldberg … (2011)

Biomarkers have become increasingly important in understanding neurodegenerative processes associated with Alzheimer disease. Markers include regional brain volumes, cerebrospinal fluid measures of pathological Aβ1-42 and total tau, cognitive measures, and individual risk factors. To determine the discriminative utility of different classes of biomarkers and cognitive markers by examining their ability to predict a change in diagnostic status from mild cognitive impairment to Alzheimer disease. Longitudinal study. We analyzed the Alzheimer's Disease Neuroimaging Initiative database to study patients with mild cognitive impairment who converted to Alzheimer disease (n = 116) and those who did not convert (n = 204) within a 2-year period. We determined the predictive utility of 25 variables from all classes of markers, biomarkers, and risk factors in a series of logistic regression models and effect size analyses. The Alzheimer's Disease Neuroimaging Initiative public database. Primary outcome measures were odds ratios, pseudo- R(2)s, and effect sizes. In comprehensive stepwise logistic regression models that thus included variables from all classes of markers, the following baseline variables predicted conversion within a 2-year period: 2 measures of delayed verbal memory and middle temporal lobe cortical thickness. In an effect size analysis that examined rates of decline, change scores for biomarkers were modest for 2 years, but a change in an everyday functional activities measure (Functional Assessment Questionnaire) was considerably larger. Decline in scores on the Functional Assessment Questionnaire and Trail Making Test, part B, accounted for approximately 50% of the predictive variance in conversion from mild cognitive impairment to Alzheimer disease. Cognitive markers at baseline were more robust predictors of conversion than most biomarkers. Longitudinal analyses suggested that conversion appeared to be driven less by changes in the neurobiologic trajectory of the disease than by a sharp decline in functional ability and, to a lesser extent, by declines in executive function.

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Author and article information

Journal

Journal ID (publisher-id): DEM

Journal ID (nlm-ta): Dement Geriatr Cogn Disord

Journal ID (doi): 10.1159/issn.1420-8008

Title: Dementia and Geriatric Cognitive Disorders

Publisher: S. Karger AG

ISSN (Print): 1420-8008

ISSN (Electronic): 1421-9824

Publication date Subscription-year: 2013

Publication date (Print): August 2013

Publication date (Electronic): 03 May 2013

Volume: 36

Issue: 1-2

Pages: 1-19

Affiliations

^aDepartment of Geriatric Psychiatry, Clinic of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, ^bNetwork Aging Research (NAR), Heidelberg University, Heidelberg, ^cAlzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian University, Munich, and ^dDepartment of Psychiatry, Goethe University of Frankfurt, Frankfurt, Germany; ^eDepartment of Psychology, Stockholm University, ^fKI-Alzheimer Disease Research Center (KI-ADRC), Karolinska Institutet, and ^gSection for Clinical Geriatrics, NVS Department, Karolinska Institutet, Karolinska University Hospital, Stockholm, and ^hClinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; ⁱFundació ACE, Barcelona, Spain; ^jKingshill Research Centre, Swindon, ^kThe Research Institute for the Care of Older People (RICE), Bath, and ^lDementia Research Group, John James Laboratories and ^mDepartment of Care of Elderly, Frenchay Hospital, University of Bristol, Bristol, UK; ⁿInstitute Born Bunge, Laboratory of Neurochemistry and Behavior, University of Antwerp and Memory Clinic ZNA, Antwerp, Belgium; ^oLENITEM, IRCCS Fatebenefratelli, Brescia, and ^pClinical Neurophysiology Service Unit, Department of Endocrinological and Metabolic Sciences, University of Genoa, Genoa, Italy; ^qDepartment of Geriatrics, Hopital Broca, Paris, ^rInstitute National de la Santé et de la Recherche Medicinale INSERM U 888, Montpellier, and ^sDepartment of Internal Medicine and Clinical Gerontology, Toulouse University Hospital, Toulouse, France; ^tDepartment of Geriatrics and Radboud Alzheimer Centre, Radboud University Medical Centre, Nijmegen, ^uDepartment of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, and ^vDepartment of Psychiatry and Neuropsychology, Alzheimer Centre Limburg, Institute of Brain and Cognition, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands; ^wDepartment of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; ^wMemory Clinic and Geriatric-Alzheimer Unit Clinical Department, ‘Carol Davila' University of Medicine and Pharmacy, Bucharest, Romania; ^yAristotle University of Thessaloniki Memory and Dementia Centre, 3rd Department of Neurology, G. Papanicolaore General Hospital, Thessaloniki, Greece

Author notes

*Marinella Damian, PhD, Zentralinstitut für Seelische Gesundheit, J5, DE-68159 Mannheim (Germany), E-Mail marinella.damian@zi-mannheim.de

Article

Publisher ID: 348354 Other ID: Dement Geriatr Cogn Disord 2013;36:1-19

DOI: 10.1159/000348354

PubMed ID: 23651945

SO-VID: 67a1d8a7-c66b-4039-8b14-19d96a3c6535

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Date accepted : 08 January 2013

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Figures: 3, Tables: 7, Pages: 19

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Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study

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Abstract

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Karger: Neurology and Neuroscience

Most cited references 19

Subjective Memory Complaints and Cognitive Impairment in Older People

Neuropsychological prediction of conversion to Alzheimer disease in patients with mild cognitive impairment.

Utility of combinations of biomarkers, cognitive markers, and risk factors to predict conversion from mild cognitive impairment to Alzheimer disease in patients in the Alzheimer's disease neuroimaging initiative.

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Cited by 16

Most referenced authors 925