Brain Advance Access originally published online on May 23, 2007
Brain 2007 130(7):1767-1776; doi:10.1093/brain/awm102
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations
1Alzheimer's Disease Research Center, UCLA Department of Neurology, Los Angeles, CA,2Psychiatry and Biobehavioral Science, UCLA, Los Angeles, CA, USA,3Laboratory of Experimental Psychology, National Institute of Neurology and Neurosurgery, Mexico City, Mexico,4Department of Neurology, Keck School of Medicine, USC, Rancho Los Amigos National Rehabilitation Center, Downey, CA,5Ahmanson-Lovelace Brain Mapping Center, UCLA, Los Angeles, CA,6Neuropsychiatry Research Memory Clinic, Olive View-UCLA Medical Center, Sylmar, CA, USA,7Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda Campus and8Department of Psychiatry, VA Greater Los Angeles Healthcare System, West Los Angeles, California, USA
Correspondence to: John M. Ringman, MD, Assistant Professor, UCLA Department of Neurology, Alzheimer's Disease Research Center, 10911 Weyburn Ave, Suite 200, Los Angeles, CA 90095-7226, USA E-mail: jringman{at}mednet.ucla.edu
Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.
Key Words: familial Alzheimer's disease; presymptomatic; diffusion tensor imaging; fractional anisotropy; Presenilin-1; amyloid precursor protein; white matter; fornix; biomarker
Abbreviations: APP, amyloid precursor protein; CDR, clinical dementia rating; DTI, diffusion tensor imaging; DWI, diffusion-weighted imaging; FAD, familial Alzheimer's disease; MCI, mild cognitive impairment
Received December 15, 2006. Revised March 26, 2007. Accepted April 5, 2007.