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.

Background: The frontal assessment battery (FAB) is commonly applied in elderly subjects for assessing frontal dysfunction. The FAB was originally developed to assess frontal lobe function easily and quickly at the bedside and consists of six subtests that explore the different aspects of frontal lobe function. However, there were few studies on the functional neuroanatomical substrates of the FAB performance in Alzheimer's disease patients. This study aimed to identify the functional neuroanatomical correlates of FAB scores in patients with Alzheimer's disease. Methods: The FAB was administered to 177 patients with very mild to moderate AD and 30 cognitively normal (CN) elderly individuals, and regional cerebral glucose metabolism (rCMglc) was measured by a [18 F] fluorodeoxyglucose (FDG) PET scan. Correlations between FAB scores and rCMglc were analyzed on a voxel-by-voxel basis using statistical parametric mapping 8 (SPM8).Results: For overall AD group, significant positive correlations between FAB scores and rCMglc were found in the bilateral middle temporal, bilateral middle frontal, left inferior parietal, right supramarginal, and right angular gyrus regions, independently of age, gender, education. After controlling the effect of global cognitive decline with MMSE score, significant positive correlation between FAB scores and rCMglc were found only in the bilateral middle frontal and right superior frontal gyri. Conclusions: This is the first FDG-PET study on the functional neuroanatomical correlates of FAB performances in AD. The results support that, regardless of the degree of global cognitive impairment, FAB performance in AD patients depends mainly on the functional integrity of the prefrontal cortical regions. Figure. Statistical parametric mapping showing brain areas with significant positive correlations between regional cerebral glucose metabolism and FAB score in AD group (uncorrected p < 0.005, k>20, age, gender, education, MMSE score as covariate)

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