General characteristics of all study participants are shown in . The sub-group of individuals who received both MRI and CSF measurements was broadly similar to the overall sample of those who received an MRI. As expected, the groups indicate stepwise differences in cognitive measures, HP volume, tau pathology, and CSF amyloid beta, with those in the MCI group displaying higher pathology burden and cognitive impairment compared to the normal group, and the AD group displaying higher pathology burden and cognitive impairment compared to the MCI group. However, the difference in CSF amyloid beta burden between MCI and AD groups was not statistically significant.
Seven independent measures of regional HP atrophy, each of which accounted for greater than 3% of HP structural variability across the population, were derived from our LoCA method. Together, the measures accounted for 46% of the variability in HP surface point positions across the cohort. These 7 measures summarized atrophy to the anterior and posterior portions of the inferior head, the superior portion of the medial head and superior, inferior, and lateral portions of the body (). Of the two measures accounting for atrophy to the lateral body, the first represented focal deficits to only a limited portion of the lateral body, along with slight deformation of the posterior aspect of the body in the superior-inferior direction. The second represented substantial atrophy to a broader extent of the lateral body, along with lesser degrees of reduction to the superior, medial, and inferior aspects of the tail. These measures accounted for 11.5%, 7.9%, 7.5%, 6.9%, 4.6%, 4.2%, 3.2% of hippocampus variability respectively. The magnitudes of Pearson correlations between pairs of the measures were all less than .3. The magnitudes of Pearson correlations between HP volume and the measures summarizing atrophy to the inferior head regions were less than .5, and all other correlations between HP volume and LoCA measures were less than .25. Therefore we concluded that the LoCA measures and total HP volume were not entirely redundant with each other.
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 (more ...)
Associations between LoCA and CSF Measures
The association between HP volume and CSF measures of amyloid beta and tau were highly significant when all subjects were included in the same model. Repeated analyses restricted to individual diagnostic categories, however, revealed that HP volume was not significantly associated with either variable within any diagnostic category.
Conversely, LoCA measures that quantified atrophy to the inferior-anterior HP head and the superior and inferior body were significantly associated with a CSF measure of total amyloid beta 1-42 among cognitively normal individuals (). In these models, each millimeter decrease in local HP thickness was associated with an amyloid beta decrease between 9.9 and 12.4 pg/ml. In addition, the LoCA measure of atrophy to the superior body was also significantly related to CSF amyloid burden among individuals diagnosed with MCI at baseline, but no LoCA measure was associated with CSF amyloid burden among those diagnosed with AD at baseline. In the MCI model, a 1 mm decrease in local superior HP body thickness was associated with a 6.18 pg/ml decrease in CSF amyloid concentration. In each such model relating LoCA measures to CSF amyloid burden, HP volume was an independent predictor that was not statistically significant. No LoCA atrophy measure was significantly associated with total tau burden in any model that was restricted to one of the three baseline diagnostic groups individually. Similar to total hippocampal volume, however, in a model containing individuals from all three groups together, a significant association between CSF tau and a LoCA measure of the superior HP body was observed (p=0.012). HP volume remained a statistically significant independent predictor in this model (p<.001). In this model, a .1 cc decrease in total HP volume was associated with a 3.37 pg/ml increase in CSF tau, and a 1 mm decrease in local superior HP body thickness was associated with a 4.1 pg/ml increase in CSF tau.
Associations between localized hippocampus atrophy and CSF amyloid
, , and provide renderings of the degree of local HP deformation that corresponds to hypothetical participants with varying levels of amyloid and tau. For , we considered a hypothetical male participant in the cognitively normal group whose age (77.0) and total HP volume (2.1 cc) were exactly at the cognitively normal average. Given a prescribed level of amyloid burden, we determined the degree of local HP deformation that is required by the statistical model in combination with the provided age, gender, and total HP volume to predict that level of amyloid burden. We then deformed the population mean HP by the requisite degree of local deformation to generate the rendering. The renderings show the local HP deformations corresponding to the median, first quartile, and third quartile of amyloid values among the normal group. The renderings suggest an increasing degree of atrophy to the medial HP head and body as one moves from right to left in the figure, corresponding to increasing amyloid burden (i.e., decreasing concentration of amyloid in the CSF). For , we generated analogous renderings showing the local HP deformation for a hypothetical average male MCI participant associated with amyloid levels at the MCI median, first quartile, and third quartile. The renderings suggest that in this group, a focal deficit to the medial HP body is associated with increasing amyloid burden (moving from right to left in the figure). For we show the local HP deformation for a hypothetical average participant from the overall sample whose tau burden is at levels corresponding to the mean values of the normal, MCI, and AD groups. The renderings suggest progressive deficits to the medial body in association with increasing levels of tau burden corresponding to typical normal, MCI, and AD levels.
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 (more ...)
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. (more ...)
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 (more ...)
Correlations between LoCA measures and Cognitive Performance
In addition, three LoCA measures were strongly associated with cognitive function across the entire cohort as measured by a battery of standardized neuropsychological test instruments (), in models that simultaneously adjusted for total HP volume. In these models, total HP volume was also independently associated with performance. The magnitudes of effect of .1 cc difference in total HP volume and 1 mm difference in local HP thickness were similar in these models; for example, a .1 cc decrease in total HP volume was associated with a 1.3 point increase in ADAS-Cog total score, while 1 mm decrease in local HP thickness in the superior, lateral, and inferior body were independently associated with ADAS-Cog total score increases of .79,.73, and 1.0 points. Analysis of either total hippocampal volume or the LoCA measures did not show significant associations with cognition when subjects within each diagnostic category were examined separately.
Diagnostic Group Differences in LoCA Measures
In a logistic regression model that also included total HP volume, LoCA measures of atrophy to the superior and lateral body significantly discriminated individuals who were cognitively normal at baseline from those who were MCI at baseline (p=<0.001 and p=.033). In a second model that also included total HP volume, measures of atrophy to the superior and lateral body discriminated those who were diagnosed with MCI at baseline from those diagnosed with AD at baseline (p=0.021 and p=0.043). In these models, total HP volume was also a significant and independent discriminator between the clinical diagnostic groups (p<.001 and p<.001). A decrease of .1 cc in total HP volume was associated with an increase of 1.19 in the odds of receiving a clinical diagnosis of AD relative to MCI. Decreases of 1 mm in local superior body and lateral body thickness were independently associated with increases of 1.19 and 1.22 in odds of diagnosis of AD compared to MCI. A decrease of .1 cc in total HP volume was associated with an increase of 1.41 in the odds of receiving a diagnosis of MCI relative to a lack of clinical diagnosis of either MCI or AD. Decreases of 1 mm in local superior body and lateral body thickness were independently associated with increases of 1.32 and 1.32 in odds of diagnosis of MCI relative to a lack of clinical diagnosis of either MCI or AD.