Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study

Abstract

Background: Three subtypes of Alzheimer's disease (AD) have been pathologically defined on the basis of the distribution of neurofibrillary tangles: typical AD, hippocampal-sparing AD, and limbic-predominant AD. Compared with typical AD, hippocampal-sparing AD has more neurofibrillary tangles in the cortex and fewer in the hippocampus, whereas the opposite pattern is seen in limbic-predominant AD. We aimed to determine whether MRI patterns of atrophy differ between these subtypes and whether structural neuroimaging could be a useful predictor of pathological subtype at autopsy.

Methods: We identified patients who had been followed up in the Mayo Clinic Alzheimer's Disease Research Center (Rochester, MN, USA) or in the Alzheimer's Disease Patient Registry (Rochester, MN, USA) between 1992 and 2005. To be eligible for inclusion, participants had to have had dementia, AD pathology at autopsy (Braak stage ≥IV and intermediate to high probability of AD), and an ante-mortem MRI. Cases were assigned to one of three pathological subtypes--hippocampal-sparing, limbic-predominant, and typical AD--on the basis of neurofibrillary tangle counts in hippocampus and cortex and ratio of hippocampal to cortical burden, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss between groups and with age-matched control individuals. Neuroimaging was obtained at the time of first presentation. To summarise pair-wise group differences, we report the area under the receiver operator characteristic curve (AUROC).

Findings: Of 177 eligible patients, 125 (71%) were classified as having typical AD, 33 (19%) as having limbic-predominant AD, and 19 (11%) as having hippocampal-sparing AD. Most patients with typical (98 [78%]) and limbic-predominant AD (31 [94%]) initially presented with an amnestic syndrome, but fewer patients with hippocampal-sparing AD (eight [42%]) did. The most severe medial temporal atrophy was recorded in patients with limbic-predominant AD, followed by those with typical disease, and then those with hippocampal-sparing AD. Conversely, the most severe cortical atrophy was noted in patients with hippocampal-sparing AD, followed by those with typical disease, and then limbic-predominant AD. The ratio of hippocampal to cortical volumes allowed the best discrimination between subtypes (p<0·0001; three-way AUROC 0·52 [95% CI 0·47-0·52]; ratio of AUROC to chance classification 3·1 [2·8-3·1]). Patients with typical AD and non-amnesic initial presentation had a significantly higher ratio of hippocampal to cortical volumes (median 0·045 [IQR 0·035-0·056]) than did those with an amnesic presentation (0·041 [0·031-0·057]; p=0·001).

Interpretation: Patterns of atrophy on MRI differ across the pathological subtypes of AD. MRI regional volumetric analysis can reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype of AD at autopsy.

Funding: US National Institutes of Health (National Institute on Aging).

Figure 1

Group comparisons of grey matter volume using voxel-based morphometry. Rows 1-3 show patterns of loss in each pathological subtype compared to specific age-matched control groups. Rows 4-5 show differences between the pathological subtypes. Results are shown on three dimensional renderings of the brain after correction for multiple comparisons using the family wise error correction at p<0.05.

Figure 2

Unthresholded effect size maps showing all group comparisons of grey matter volume using voxel-based morphometry.

Figure 3

Box plots of gray matter findings by AD dementia group for 14 regions of interest. The set of box plots at the top left show the hippocampus-to-cortex volume ratio. Otherwise the value shown is the gray matter volume expressed as a percentage of TIV. Each box indicates the lower quartile (25th percentile), the median, and the upper quartile (75th percentile) of the distribution. By convention the “whiskers” of the box extend to the point furthest from the box yet still within 1.5 times the width of the box (the inter-quartile range). Points beyond the whiskers are individually indicated. As indicated in the key in the lower-right corner of the figure, the boxes are color coded. Box height on the vertical axis is related to sample size. The p-value for the one-way ANOVA test is shown in parenthesis at the top of each plot.

Figure 4

Estimates and 95% confidence intervals for the difference in gray matter volume scaled by TIV expressed as an approximate percentage difference. The numbers to the right of each confidence interval indicate the P-value for the group-wise comparison from the ANOVA model placed above the estimated AUROC for the two groups. At the right of the figure is the three-way AUROC, with a 95% confidence interval, placed above the ratio of the three-way AUROC to chance classification of 1/6 (95% confidence interval).

Figure 5

Box plots of the hippocampus-to-cortex gray matter volume for each AD dementia group. The typical AD group has been divided into those with a predominantly memory domain of impairment versus others. Two subjects from the typical AD group are not shown due to insufficient clinical information. Each box indicates the lower quartile (25th percentile), the median, and the upper quartile (75th percentile) of the distribution. By convention the “whiskers” of the box extend to the point furthest from the box yet still within 1.5 times the width of the box (the inter-quartile range). Points beyond the whiskers are individually indicated. Box height on the vertical axis is related to sample size. At the top left is the p-value for the one-way ANOVA test.