Localized hippocampus measures are associated with Alzheimer pathology and cognition independent of total hippocampal volume

Abstract

Hippocampal injury in the Alzheimer's disease (AD) pathological process is region-specific and magnetic resonance imaging (MRI)-based measures of localized hippocampus (HP) atrophy are known to detect region-specific changes associated with clinical AD, but it is unclear whether these measures provide information that is independent of that already provided by measures of total HP volume. Therefore, this study assessed the strength of association between localized HP atrophy measures and AD-related measures including cerebrospinal fluid (CSF) amyloid beta and tau concentrations, and cognitive performance, in statistical models that also included total HP volume as a covariate. A computational technique termed localized components analysis (LoCA) was used to identify 7 independent patterns of HP atrophy among 390 semiautomatically delineated HP from baseline magnetic resonance imaging of participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Among cognitively normal participants, multiple measures of localized HP atrophy were significantly associated with CSF amyloid concentration, while total HP volume was not. In addition, among all participants, localized HP atrophy measures and total HP volume were both independently and additively associated with CSF tau concentration, performance on numerous neuropsychological tests, and discrimination between normal, mild cognitive impairment (MCI), and AD clinical diagnostic groups. Together, these results suggest that regional measures of hippocampal atrophy provided by localized components analysis may be more sensitive than total HP volume to the effects of AD pathology burden among cognitively normal individuals and may provide information about HP regions whose deficits may have especially profound cognitive consequences throughout the AD clinical course.

Figure 1

Graphical depiction of the seven local hippocampus structural measures provided by LoCA. Each row depicts a LoCA measure that describes atrophy to the hippocampal region shown in blue. The first two oblique viewpoints show the inferior and superior aspects of the population average hippocampus, with anterior (posterior) oriented toward the bottom (top) of the image. The second two viewpoints show the medial-superior and lateral-inferior aspects with anterior (posterior) oriented toward the top (bottom) of the image.

Figure 2

Local hippocampus atrophy corresponding to a hypothetical cognitively-normal male subject whose age and total hippocampus volume were set to the cognitively-normal mean, and whose amyloid burden was set to the first quartile, median, and third quartile of cognitively normal participant values. See Results text for details. Red, yellow, and green axes correspond to medial, anterior, and superior directions respectively.

Figure 3

Local hippocampus atrophy corresponding to a hypothetical male subject with MCI whose age and total hippocampus volume were set to the MCI mean, and whose amyloid burden was set to the first quartile, median, and third quartile of MCI participant values. See Results text for details. Red, yellow, and green axes correspond to medial, anterior, and superior directions respectively.

Figure 4

Local hippocampus atrophy corresponding to a hypothetical male subject whose age and total hippocampus volume were set to the mean of the overall study population and whose tau burden was set to the mean values for normal, MCI, and AD participants. See Results text for details. Red, yellow, and green axes correspond to medial, anterior, and superior directions respectively.