Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures

Abstract

Objective: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls.

Methods: We included 64 patients with AD (67 +/- 9 years; F/M 38/26), 44 patients with MCI (71 +/- 6 years; 21/23), and 34 controls (67 +/- 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 +/- 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools.

Results: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5-22.2]), hippocampal atrophy rate (5.2 [1.9-14.3]), and whole brain atrophy rate (2.8 [1.1-7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1-606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression.

Conclusion: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD.

Figure 1 Mean volumes and atrophy rates Box plots of (A) baseline hippocampal volume, (B) hippocampal atrophy rate, (C) baseline whole brain volume, and (D) whole brain atrophy rate per diagnostic group (controls, mild cognitive impairment [MCI], and Alzheimer disease [AD]), and box plots of patients with MCI who remained stable and those who progressed to AD for (E) hippocampal atrophy rate and (F) whole brain atrophy rate. Lines represent median; boxes, interquartile range; and whiskers, range; o = outliers. *p < 0.005.

Figure 2 Regional fluid registration Individual examples of color overlay, representing contraction (green and blue) and expansion (yellow and red) within the right hippocampal regions of interest of (A) a control who remained stable, (B) a control who had progressed to Alzheimer disease (AD) at follow-up, (C) a patient with mild cognitive impairment (MCI) who remained stable, and (D) a patient with MCI who progressed to AD during follow-up.

Figure 3 Kaplan-Meier curves of time to conversion within all subjects without dementia at baseline MRI markers were dichotomized based on the median value: (A) baseline hippocampal volume, (B) hippocampal atrophy rate, (C) baseline whole brain volume, and (D) whole brain atrophy rate. On the X-axis: follow-up duration (years); on the Y-axis: proportion of subjects who remained stable. Blue line: highest baseline volume (A; C) or lowest atrophy rate (B; D). Red line: lowest baseline volume (A; C) or highest atrophy rate (B; D). Tables represent the number of patients exposed to risk at the intervals of 0, 1, 2, and 3 years.