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Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment

From the Departments of Neurology (L.A.v.d.P., W.M.v.d.F., E.S.C.K., N.C.F., P.S.) and Radiology (F.B.), Alzheimer Centre, VU Medical Centre, Amsterdam, the Netherlands; and Dementia Research Centre (N.C.F.), Institute of Neurology, University College London, UK.

Address correspondence and reprint requests to Dr van de Pol, Department of Neurology, VUMC, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands L.vandepol{at}vumc.nl

Objective: A large cohort of subjects with mild cognitive impairment (MCI) was categorized into tertiles based on hippocampal atrophy rates, as a proxy for Alzheimer-type pathology. We compared baseline clinical, neuropsychological, and MRI measures to characterize these MCI subgroups.

Methods: Serial MRI data of 323 subjects with MCI (49% men; mean ± SD age: 69 ± 9 years), followed for 2 years in a clinical trial, were available. Baseline hippocampal and whole brain volumes (WBV) were measured, and hippocampal volume change was assessed. Baseline medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), and lacunes were rated visually. The cohort was categorized into tertiles based on hippocampal atrophy rates (absent, moderate, and severe).

Results: Rates of hippocampal atrophy (%/year) were 0.0 ± 0.8 in the absent, 1.7 ± 0.4 in the moderate, and 3.6 ± 1.0 in the severe (mean ± SD) tertile. Older age and the APOE 4 allele were associated with higher hippocampal atrophy rates (p < 0.0001 and p = 0.015). General cognition deteriorated over the MCI groups (p < 0.0001), whereas, after adjustment for age and sex, episodic memory and executive function did not. Baseline hippocampal atrophy was associated with increasing atrophy rates (hippocampal volume: p = 0.025; MTA score: p = 0.008); in contrast, WBV, WMH, and lacunes, adjusted for age and sex, were not significantly associated with hippocampal atrophy rates.

Conclusions: In mild cognitive impairment (MCI), older age, poorer general cognition, hippocampal atrophy, and APOE 4 predict subsequent accelerated rates of hippocampal atrophy, suggestive of the accumulation of Alzheimer-type pathology, which may become clinically manifest in the future. These markers may improve identification of subjects with MCI at risk for Alzheimer disease.

GLOSSARY: AD = Alzheimer disease; ADAS-cog = Alzheimer's Disease Assessment Scale, cognition part; ARWMC = Age-Related White Matter Changes Scale; CDR = Clinical Dementia Rating Scale; FLAIR = fluid-attenuated inversion recovery; Gal-Int-11 = Galantamine-International-11 trial; MCI = mild cognitive impairment; MTA = medial temporal lobe atrophy; WBV = whole brain volume; WMH = white matter hyperintensity.

L.A. van de Pol received funding from the Image Analysis Centre at the VU Medical Centre. Additional funding was supplied by the Stichting Alzheimer and Neuropsychiatric Foundation. The Alzheimer Center is supported by the VUMC Fonds. N.C. Fox holds an MRC (UK) Senior Fellowship.

Disclosure: The Image Analysis Center and the Dementia Research Centre received fees for analyzing scans and for consultancy services from the Janssen Research Foundation.

Received November 1, 2006. Accepted in final form April 23, 2007.

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