Longitudinal pattern of regional brain volume change differentiates normal aging from MCI

Abstract

Background: Neuroimaging measures have potential as surrogate markers of disease through identification of consistent features that occur prior to clinical symptoms. Despite numerous investigations, especially in relation to the transition to clinical impairment, the regional pattern of brain changes in clinically normal older adults has not been established. We predict that the regions that show early pathologic changes in association with Alzheimer disease will show accelerated volume loss in mild cognitive impairment (MCI) compared to normal aging.

Methods: Through the Baltimore Longitudinal Study of Aging, we prospectively evaluated 138 nondemented individuals (age 64-86 years) annually for up to 10 consecutive years. Eighteen participants were diagnosed with MCI over the course of the study. Mixed-effects regression was used to compare regional brain volume trajectories of clinically normal individuals to those with MCI based on a total of 1,017 observations.

Results: All investigated volumes declined with normal aging (p < 0.05). Accelerated change with age was observed for ventricular CSF (vCSF), frontal gray matter, superior, middle, and medial frontal, and superior parietal regions (p < or = 0.04). The MCI group showed accelerated changes compared to normal controls in whole brain volume, vCSF, temporal gray matter, and orbitofrontal and temporal association cortices, including the hippocampus (p < or = 0.04).

Conclusion: Although age-related regional volume loss is apparent and widespread in nondemented individuals, mild cognitive impairment is associated with a unique pattern of structural vulnerability reflected in differential volume loss in specific regions. Early identification of patterns of abnormality is of fundamental importance for detecting disease onset and tracking progression.

Figure 1 Trajectories of select brain volume changes (cm³) Age-related changes in (A) whole brain volume, (B) ventricular CSF (vCSF), (C) total white matter, (D) total gray matter, (E) hippocampus, and (F) orbitofrontal cortex. Thin red (mild cognitive impairment [MCI]) and blue (normal) lines represent individual volumes over time for a random sample of participants; thick red and blue lines indicate respective estimated average volumes for each group. Increase in vCSF accelerates with age. The hippocampus and orbitofrontal cortex decline linearly with increasing age and at a steeper rate in the MCI group. Males show steeper changes in whole brain and vCSF volume decline.

Figure 2 Patterns of gray matter volume loss in MCI and normal aging Average slopes of RAVENS maps for normal (A) and MCI (B) groups. The red-yellow color indicates greater volume loss. Bottom row: Difference between the two groups: blue/green are regions in which MCI subjects showed higher rate of gray matter decrease. (C) Red/yellow colors reflect an increase of periventricular small vessel disease, which appears gray in T1-weighted images and is segmented as gray matter. The color bars display estimated regression coefficients and are defined by the following numbers, all in mm³/year (per voxel in the template space): a = −0.020, b = −0.0053, c = 0.026, d = 0.0053, e = −0.0053, f = −0.023. MCI = mild cognitive impairment.