Brain regions vulnerable and resistant to aging without Alzheimer's disease.

Xinyang Feng,Hannah C Sigmon,Adam M Brickman,Jia Guo,Scott A Small,Frank A Provenzano,Richard P Sloan,Stephen D Ginsberg

doi:10.1371/journal.pone.0234255

Xinyang Feng, Hannah C Sigmon + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0234255

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Abstract

‘Normal aging’ in the brain refers to age-related changes that occur independent of disease, in particular Alzheimer’s disease. A major barrier to mapping normal brain aging has been the difficulty in excluding the earliest preclinical stages of Alzheimer’s disease. Here, before addressing this issue we first imaged a mouse model and learn that the best MRI measure of dendritic spine loss, a known pathophysiological driver of normal aging, is one that relies on the combined use of functional and structural MRI. In the primary study, we then deployed the combined functional-structural MRI measure to investigate over 100 cognitively-normal people from 20–72 years of age. Next, to cover the tail end of aging, in secondary analyses we investigated structural MRI acquired from cognitively-normal people, 60–84 years of age, who were Alzheimer’s-free via biomarkers. Collectively, the results from the primary functional-structural study, and the secondary structural studies revealed that the dentate gyrus is a hippocampal region differentially affected by aging, and that the entorhinal cortex is a region most resistant to aging. Across the cortex, the primary functional-structural study revealed and that the inferior frontal gyrus is differentially affected by aging, however, the secondary structural studies implicated other frontal cortex regions. Together, the results clarify how normal aging may affect the brain and has possible mechanistic and therapeutic implications.

Highlights

Concordant changes in functional and structural MRI reflect dendritic spine loss We have developed a series of new tools for processing and analyzing mouse MRI, including cortical surface reconstruction, thickness estimation, layer parcellation and image visualization (See Methods), and have combined them with previously-developed applications
In anticipation of our human aging studies, we first performed an MRI study in mice using a paradigm that is known to induce dendritic spine loss in specific cortical layers. From these mouse studies we learned that while both cerebral blood volume (CBV)-fMRI and structural MRI are sensitive to spine loss, a concordant change in both enhances this sensitivity
We learned that for CBV-fMRI mapping, a derived total CBV (tCBV) is a better parameter than derived %CBV

Summary

Introduction

‘Normal aging’ refers to age-related changes in the brain that occur independent of brain disorders. Structural imaging is the second approach that should be sensitive to spine loss, and can generate images with submillimeter resolution from which precise measures of volume and thickness can be derived This expectation has been validated in recent studies, showing that variables derivable from structural MRI are sensitive to dendritic spine loss [21, 22]. While both functional and structural imaging might be sensitive to spine loss, they are not necessarily specific, a concern relevant to the latter since many brain elements can contribute to volume independent of spine density. Both the functional-structural study and the secondary structural studies suggest the entorhinal cortex, a region most vulnerable to AD, turned out to be the region most resistant to normal aging

Results

Discussion

Methods