Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults - PubMed (original) (raw)

Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults

B C Dickerson et al. Neurology. 2011.

Abstract

Objective: Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the "disease signature" of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up.

Methods: We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals.

Results: AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (> 1). Of the 11 CN individuals with baseline low AD-signature thickness (≥ 1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥ 1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4.

Conclusions: By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

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Figures

Figure 1

Figure 1. Baseline and longitudinal clinical characteristics of the 2 samples

(A, B) Baseline and follow-up episodic memory Z scores from the 2 samples, illustrating the stability (or even slight improvement in sample 2) of performance in the cognitively normal (CN)-stable groups over nearly a decade of follow-up. In contrast, the CN-Alzheimer disease (AD) converters performed normally at baseline but declined substantially over nearly a decade of follow-up by the time of diagnosis of AD dementia. (C, D) Detailed illustration of cognitive decline in each of the CN-AD converter individuals. (C) Annual Clinical Dementia Rating (CDR)–sum of boxes scores increased from normal (0) at baseline to mild dementia in each of the 8 individuals in the Massachusetts General Hospital sample. (D) Annual episodic memory Z scores declined from normal to substantially impaired in each of the 7 individuals in the Rush sample. Breaks in lines indicate years for which data were not available.

Figure 2

Figure 2. Thinner cortex in regions associated with Alzheimer disease (AD) in asymptomatic adults who eventually develop dementia

(A) For each of the 2 samples, the average cortical thickness of the AD-signature regions was slightly thinner in the cognitively normal (CN)-AD converter group than the CN-stable group at the time of the baseline MRI scan. The absolute difference in the means of the groups for each sample is less than ¼ mm, but because variance is small the Cohen d effect size between the groups is very large for each sample (>1.2). Inset illustrates AD-signature regions of interest. (B) Illustration of the risk of AD dementia as a function of AD-signature thickness from baseline MRI scans in the pooled group of all participants in this study. For the group of 9 individuals with high AD-signature thickness, none developed AD dementia in the follow-up period, while for the group of 45 individuals with average AD-signature thickness, 20% developed AD dementia in the follow-up period. A striking 55% of the 11 individuals with low AD-signature thickness developed AD dementia in the follow-up period.

Figure 3

Figure 3. Alzheimer disease (AD)-signature MRI biomarker predicts time to dementia in people who were cognitively normal when scanned

Univariate survival plot of predicted time to AD dementia for hypothetical average study participants with AD-signature cortical thickness in the lowest (smallest) tertile, middle tertile, and highest tertile. The displayed survival curves are therefore model predictions and do not directly represent subject results. AD-signature thickness was predictive of progression from normal cognition to AD dementia (hazard ratio 3.5 for 1 SD decrease in thickness; 95% confidence interval 2.0–6.4; p < 0.00005) in the model. The mean thickness of the lowest tertile was 1.1 standard deviations thinner than the mean of the entire group of all participants, the mean of the middle tertile was at approximately the mean of the entire group, and the mean of the highest tertile was 1.1 standard deviations thicker than the mean.

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