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Trajectories of brain loss in aging and the development of cognitive impairment

From the Departments of Neurology (M.M.M., A.D., D.H., L.E.S., J.F.Q., J.A.K.), Public Health and Preventive Medicine (N.E.C.), and Biomedical Engineering (J.A.K.), Oregon Health and Science University, and Portland Veteran Affairs Medical Center (L.E.S., J.F.Q., J.A.K.), Portland, OR.

Address correspondence and reprint requests to Dr Carlson, Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Mail Code CB669 Portland, OR 97239 carlsoni{at}ohsu.edu

Background: The use of volumetric MRI as a biomarker for assessing transitions to dementia presumes that more rapid brain loss marks the clinical transition from benign aging to mild cognitive impairment (MCI). The trajectory of this volume loss relative to the timing of the clinical transition to dementia has not been established.

Methods: The authors annually evaluated 79 healthy elderly subjects for up to 15 consecutive years with standardized clinical examinations and volumetric brain MRI assessments of ventricular volume. During the study period, 37 subjects developed MCI. A mixed effects model with a change point modeled the pattern of brain volume loss in healthy aging compared with subjects diagnosed with MCI.

Results: The brain loss trajectory of subjects developing MCI during follow-up differed from healthy aging in a two-phase process. First, the annual rate of expansion of ventricular volume decreased with age; however, the annual rates of expansion were greater in those who developed cognitive impairment during follow-up compared with those who did not. Further, subjects who developed MCI had an acceleration of ventricular volume expansion approximately 2.3 years prior to clinical diagnosis of MCI.

Conclusions: Ventricular expansion is faster in those developing mild cognitive impairment years prior to clinical symptoms, and eventually a more rapid expansion occurs approximately 24 months prior to the emergence of clinical symptoms. These differential rates of preclinical atrophy suggest that there are specific windows for optimal timing of introduction of dementia prevention therapies in the future.

GLOSSARY: AD = Alzheimer disease; BMI = body mass index; CDR = Clinical Dementia Rating Scale; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination.

Supplemental data at www.neurology.org

Editorial, page 824

e-Pub ahead of print on November 28, 2007, at www.neurology.org.

Supported by National Center for Research Resources (grant UL1 RR024140 01), National Institute on Aging (grant AG08017), Department of Veterans Affairs.

Disclosure: The authors report no conflicts of interest

Received September 27, 2006. Accepted in final form July 5, 2007.

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