Donna J. Cross PhD, Presenter: Nothing to Disclose

Jennifer A. Flexman BEng, Abstract Co-Author: Nothing to Disclose

Yoshimi Anzai MD, Abstract Co-Author: Nothing to Disclose

Jeff Stevenson, Abstract Co-Author: Nothing to Disclose

Kenneth R. Maravilla MD, Abstract Co-Author: Nothing to Disclose

Satoshi Minoshima MD, PhD, Abstract Co-Author: Nothing to Disclose

New biomarkers for Alzheimer’s disease (AD) have been investigated extensively. Cortical projection neurons with long axons are selectively vulnerable in AD, and impairment of axonal transport suggested. Using in vivo manganese-enhanced MR imaging (Mn-MRI) and novel tracer kinetic modeling, we hypothesized that axonal transport rate would decrease with aging, which would be accelerated in AD transgenic mice.

Serial T1-weighted images were obtained at pre- and post-injection of MnCl2 on a 1.5T MR scanner (3D-SPGR pulse sequence; TE=6.8 ms; TR=15 ms; FA=45 deg; 4 NEX). Rats were scanned longitudinally and in a separate aged group. APPswe/PS1 transgenic mice (Aß deposits 4–6 mos.) and age-matched controls (young, 8-12 wks, and old, 43-45 wks) were scanned with the same parameters. Images were coregistered, stereotactically aligned, and normalized (NEUROSTAT). Pixel-wise subtraction was performed for group-wise statistical comparison. Time-intensity changes were examined for the olfactory bulb and tract. Tracer kinetic estimation based on a mass transport model was applied using bulb intensity as input function for subsequent tract changes. Time to peak of Mn2+ flow was estimated in anterior and posterior tract.

Age-related decreases in axonal transport rate were indicated in the olfactory tract of living rat brains. Longitudinally scanned, mid-age group was decreased by 58% and aged group by 71% of young rate (transport = 4.07±1.24 mm/hr, 1.72±0.89 mm/hr, and 1.16±0.18 mm/hr for young, mid-age, and aged respectively). Rat neuronal transport rate decline correlated with increased age. Aged control mice were decreased by 43% and aged transgenic by 60% of young controls.

Results indicated age-associated axonal transport deficits in living brains as well as increased deficits in AD transgenic mice. Kinetic analysis of dynamic Mn-MRI provides a unique method to study this critical neuronal function. This study unveils an early pathophysiology of AD and potential new treatment target.

Future application of this non-invasive technique to humans could provide a new method and critical biomarker for study of aging and AD.

Cross, D, Flexman, J, Anzai, Y, Stevenson, J, Maravilla, K, Minoshima, S, Quantitative Mn-MRI Analysis of Axonal Transport Rate in Aging and in Brains with Alzheimer’s Pathology.  Radiological Society of North America 2007 Scientific Assembly and Annual Meeting, November 25 - November 30, 2007 ,Chicago IL. http://archive.rsna.org/2007/5011818.html