Susceptibility of the conventional criteria for mild cognitive impairment to false‐positive diagnostic errors

Abstract

Background We assessed whether MCI subtypes could be empirically derived within the Alzheimer’s Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes. Methods Cluster analysis was performed on neuropsychological data from 825 MCI ADNI participants. Results Four subtypes emerged: 1) Dysnomic (n=153), 2) Dysexecutive (n=102), 3) Amnestic (n=288), and 4) Cluster-Derived Normal (n=282) who performed within normal limits on cognitive testing. The Cluster-Derived Normal group had significantly fewer APOE-ε4 carriers and fewer who progressed to dementia compared to the other subtypes; they also evidenced cerebrospinal fluid AD biomarker profiles that did not differ from the normative reference group. Conclusions Identification of empirically-derived MCI subtypes demonstrates heterogeneity in MCI cognitive profiles that is not captured by conventional criteria. The large Cluster-Derived Normal group suggests that conventional diagnostic criteria are susceptible to false positive errors, with the result that prior MCI studies may be diluting important biomarker relationships.

Heterogeneous cortical atrophy patterns in MCI not captured by conventional diagnostic criteria

“…Previous research has identified considerable heterogeneity beyond the amnestic/nonamnestic distinction with respect to neuropsychological performance in MCI samples. [4][5][6][7] In a recent study, 7 cluster analysis was performed on 825 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Although nearly all participants (99.8%) were originally classified simply as amnestic MCI by conventional criteria, 2,8 results showed 4 cognitive phenotypes.…”

“…This cluster-derived normal (CDN) group performed within normal limits on all neuropsychological measures examined, despite other performances on screening measures that led to their MCI diagnosis. The existence of this group, which comprises over one-third of the ADNI MCI cohort, indicates that the conventional diagnostic criteria for MCI may be highly susceptible to falsepositive errors, especially in light of this group's normal CSF Alzheimer disease (AD) biomarker profiles 7 and normal amyloid imaging scans using florbetapir PET. 9 In addition, longitudinal data over an average of roughly 2 years showed that the CDN group demonstrated a lower rate of progression to AD (10.7%) and a higher rate of reversion to cognitively normal (9.2%) relative to the impaired MCI groups (progression rate 35%-56%; reversion rate 1%-2%).…”

“…9 In addition, longitudinal data over an average of roughly 2 years showed that the CDN group demonstrated a lower rate of progression to AD (10.7%) and a higher rate of reversion to cognitively normal (9.2%) relative to the impaired MCI groups (progression rate 35%-56%; reversion rate 1%-2%). 7 It has been proposed that individuals with nonamnestic subtypes of MCI will progress to non-AD forms of dementia, such as vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. 2 In the MCI subtypes identified in the ADNI sample, 7 all 3 impaired subtypes demonstrated memory impairment (i.e., there was no nonamnestic group).…”

“…7 It has been proposed that individuals with nonamnestic subtypes of MCI will progress to non-AD forms of dementia, such as vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. 2 In the MCI subtypes identified in the ADNI sample, 7 all 3 impaired subtypes demonstrated memory impairment (i.e., there was no nonamnestic group). Of those who progressed to dementia, nearly all received a diagnosis of AD as opposed to another form of dementia.…”

“…The current study aimed to investigate regional cortical thickness patterns among the empirically derived MCI subtypes. 7 METHODS Data were obtained from the ADNI database (adni.loni.usc.edu). ADNI is the result of efforts of many coinvestigators from a range of academic institutions and private corporations.…”