Subtypes based on cerebrospinal fluid and magnetic resonance imaging markers in normal elderly predict cognitive decline

Abstract

Cerebrospinal fluid (CSF) and structural magnetic resonance imaging (MRI) show patterns of change in Alzheimer's disease (AD) that precede dementia. The Alzheimer's Disease Neuroimaging Initiative (ADNI) studied normal controls (NC), subjects with mild cognitive impairment (MCI), and subjects with AD to identify patterns of biomarkers to aid in early diagnosis and effective treatment of AD. Two hundred twenty-two NC underwent baseline MRI and clinical examination at baseline and at least one follow-up. One hundred twelve also provided CSF at baseline. Unsupervised clustering based on initial CSF and MRI measures was used to identify clusters of participants with similar profiles. Repeated measures regression modeling assessed the relationship of individual measures, and of cluster membership, to cognitive change over 3 years. Most individuals showed little cognitive change. Individual biomarkers had limited predictive value for cognitive decline, but membership in the cluster with the most extreme profile was associated with more rapid decline in ADAS-cog. Subtypes among NC based on multiple biomarkers may represent the earliest stages of subclinical cognitive decline and AD.

Figure 1

Longitudinal trajectories of ADAS-COG scores for a random sample of 50 ADNI normal controls. The average longitudinal trajectory for each of the three clusters is also presented.

Figure 2

Longitudinal trajectories of RAVLT scores for a random sample of 50 ADNI normal controls. The average longitudinal trajectory for each of the three clusters is also presented.

Figure 3

Three-dimensional representation of cluster assignments for 96 ADNI normal controls, based on unsupervised clustering using eleven baseline MRI and CSF markers and serum homocysteine, without use of clinical data to define clusters. This representation is shown on three axes of the original 11-dimensional data space, chosen to maximize separation of cluster centers for clearest visualization on paper of the cluster locations.

Figure 4

Difference for each biomarker of cluster means from the mean for all ADNI normal controls, standardized by normal control standard deviation, compared to distances for ADNI MCI and AD groups. Sign of standardized differences was reversed for all variables except Aβ_1–42 and ventricular volume so that high values (top of figure) represent worse biomarker measurements.