Volumetric MRI and Neuropathology in the Elderly: a Key Bridging Study

In the October 17^th issue of PLoS One, Robert Dawe and colleagues, from the Illinois Institute of Technology and the Rush Alzheimer’s Disease Center, present the results of a key bridging study of volumetric MRI correlation with normal aging, Alzheimer’s disease (AD), and additional neuropathologies frequently associated with aging (link).

As mentioned in an earlier post (Biomarker Qualification Consortia: The ADNI Success Story), in vivo volumetric MRI of specific region of the brain (i.e. medial temporal lobe à hippocampus) has been shown to be a valuable biomarker of disease progression in AD and mild cognitive impairment (MCI).  While the correlation between reduction in hippocampal volume and histopathologically confirmed AD has been conclusively demonstrated, the effect of other neuropathologies generally associated with aging on hippocampal volume remained ill-defined.

In order to address this gap in knowledge, the authors combined antemortem imaging studies, antemortem cognitive testing, postmortem MRI on isolated brain hemisphere, and histopathology on the brains of 100 elderly subjects from the Rush Memory and Aging Project, and the Religious Order Study (two longitudinal clinical-pathologic studies of aging).  The authors confirmed the strong association between reduced hippocampal volume and the diagnostic of AD (determined prior to death based on cognition test and determined postmortem based on histopathology).  In addition, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory.  Other pathologies such as Lewy bodies, moderate amyloid angiopathy, gross infarcts, and micro infarcts were not significantly associated with reduced hippocampal volume.  In contrast, hippocampal sclerosis (HS) was strongly associated with significant reduction in hippocampal volume independently of the presence or absence of co-occurring AD pathology (of 13 individuals with HS, 9 had also AD pathology and 4 had not other pathology).  In fact, the association of HS and reduced hippocampal volume was more pronounced than that observed in AD.  Shape analysis of the hippocampal surface confirmed prior knowledge namely that hippocampal volume reduction in AD is more pronounced in the head and tail of the hippocampus, and that these changes tend to be more homogeneously distributed in HS.  The authors did not discuss whether shape analysis of the hippocampal surface could be used to distinguish between AD and HS.

Despite some minor limitations: the postmortem MRI performed on isolated brain hemispheres precluded the measurement of cranial volume, this study provides a highly valuable bridge between in vivo volumetric MRI measurements and underlying neuropathology.  


Thierry Sornasse for Integrated Biomarker Strategy