Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates

Article type: Research Article

Authors: Bondi, Mark W.^{a; b; *} | Edmonds, Emily C.^b | Jak, Amy J.^{a; b} | Clark, Lindsay R.^d | Delano-Wood, Lisa^{a; b} | McDonald, Carrie R.^b | Nation, Daniel A.^e | Libon, David J.^f | Au, Rhoda^g | Galasko, Douglas^{a; c} | Salmon, David P.^c | for the Alzheimer's Disease Neuroimaging Initiative¹

Affiliations: [a] Veterans Affairs San Diego Healthcare System, San Diego, CA, USA | [b] Department of Psychiatry, University of California San Diego, School of Medicine, La Jolla, CA, USA | [c] Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA | [d] San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology, San Diego, CA, USA | [e] Department of Psychology, University of Southern California, Los Angeles, CA, USA | [f] Department of Neurology, Drexel University, College of Medicine, Philadelphia, PA, USA | [g] Department of Neurology and the Framingham Heart Study, Boston University, School of Medicine, Boston, MA, USA

Correspondence: [*] Correspondence to: Mark W. Bondi, PhD, Psychology Service (116B), VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. E-mail: mbondi@ucsd.edu.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of the ADNI and/or provided data but did not participate in analysis or writing of this article. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Abstract: We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method's susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of ‘true positive’ cases and removal of ‘false positive’ cases.

Keywords: Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative, biomarker, cluster analysis, dementia, mild cognitive impairment, neuropsychology, progression

DOI: 10.3233/JAD-140276

Journal: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 275-289, 2014