Subregional neuroanatomical change as a biomarker for Alzheimer's disease

Abstract

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.

Fig. 1.

Tissue segmentation, with 6- and 12-month volume change fields for an MCI subject. (A) Segmentation of the baseline MRI scan, with different brain structures represented in different colors. (B) Corresponding coronal slice overlain with a heat map representation of the voxelwise estimates of volumetric change at 6 months and (C) 12 months. (D) Left hemisphere cortical parcellation of the baseline MRI scan. (E) Cortical surface overlain with a heat map representation of the estimates of cortical volumetric change at 6 months and (F) 12 months. Region-specific estimates were obtained by averaging the voxelwise change within each region of interest. In this subject, the left middle-temporal gyrus has decreased in volume by 4.7% at 6 months and by 8.2% at 12 months; the left temporal-horn lateral ventricle has increased by 17.4% at 6 months and by 35.3% at 12 months.

Fig. 2.

Sample size estimates for AD from a linear mixed-effects model with random slopes. The bars, with 95% confidence intervals, indicate the expected number of subjects needed per arm to detect a 25% reduction in rate of change at the P < 0.05 level with 80% power, assuming a 24-month trial with scans every 6 months. Results for Model T are in blue and results for Model D are in red; numerical values are shown in Table 1.

Fig. 3.

Sample size estimates for MCI (see Fig. 2 for description). Numerical values are in Table 2. Note that the Model D (red) upper bound on the 95% confidence interval for ventricles is 2,421.