Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer’s Disease

Abstract

We aimed to identify and characterize subtypes of Alzheimer’s disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer's Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the “both impaired” subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: “hippocampal atrophy only” (19.0%), “cortical atrophy only” (11.7%), and “both spared” (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-β1–42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Aβ neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients.

Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer’s disease

“…Among AD dementia patients, the cortical factor was associated with the worst baseline executive function, whereas the temporal factor was associated with the worst baseline memory. This result is consistent with previous work showing that thinning of frontoparietal cortical regions was associated with nonamnestic presentations and dysexecutive phenotypes (9) and that the "cortical atrophy-only" subtype had worse baseline executive function than the "hippocampal atrophy-only" subtype (16). Thus, our data-driven approach provides additional evidence that distinct atrophy patterns among AD patients impact different cognitive domains.…”

“…Our analyses suggested that the cortical factor was associated with faster decline in both memory and executive function than the temporal factor at the dementia stage, which is consistent with the hippocampalsparing subtype exhibiting faster MMSE decline than the limbicpredominant subtype among AD dementia patients (3). Similarly, our finding that the cortical factor was associated with the most rapid memory and executive function decline among AD dementia patients was also consistent with the work by Byun et al (16). Among AD dementia patients, the cortical factor was associated with the worst baseline executive function, whereas the temporal factor was associated with the worst baseline memory.…”

“…S2). It is noteworthy that the atrophy patterns extracted using K = 3 were similar to results from other groups investigating AD subtypes (7,15,16), although notable differences did emerge. Specifically, our three-factor model revealed a temporal factor associated with atrophy in the temporal cortex, hippocampus, and amygdala; a cortical pattern associated with atrophy in the frontal, parietal, lateral temporal, and lateral occipital cerebral cortices; and a subcortical factor associated with atrophy in the cerebellum, striatum, and thalamus (Fig.…”

“…In our analyses, 50%, 40%, and 10% of the patient's atrophy map would contribute to the estimation of the probabilistic atrophy maps of the subcortical, temporal, and cortical factors, respectively. This method extends previous approaches (7,15,16) that classified each patient into one single subtype and then, performed group comparisons to obtain differential atrophy patterns, despite the fact that each patient might express multiple latent atrophy factors. Thus, more information about each participant is retained by treating factor compositions continuously rather than assigning participants to a single group.…”

“…Most studies investigating the heterogeneity of AD have examined patients soon after AD onset or at advanced AD stages (3,7,(15)(16)(17). However, the pathophysiological processes of AD begin at least a decade before clinical diagnosis (18), suggesting that the emergence of this heterogeneity may occur before the onset of clinical dementia.…”