Multiple markers contribute to risk of progression from normal to mild cognitive impairment.
OBJECTIVE
To identify a parsimonious set of markers that optimally predicts subsequent clinical progression from normal to mild cognitive impairment (MCI).


METHODS
250 clinically normal adults (mean age = 73.6 years, SD = 6.0) from the Harvard Aging Brain Study were assessed at baseline on a wide set of markers, including magnetic resonance imaging markers of gray matter thickness and volume, white matter lesions, fractional anisotropy, resting state functional connectivity, positron emission tomography markers of glucose metabolism and β-amyloid (Aβ) burden, and a measure of vascular risk. Participants were also tested annually on a battery of clinical and cognitive tests (median follow-up = 5.0 years, SD = 1.66). We applied least absolute shrinkage and selection operator (LASSO) Cox models to determine the minimum set of non-redundant markers that predicts subsequent clinical progression from normal to MCI, adjusting for age, sex, and education.


RESULTS
23 participants (9.2%) progressed to MCI over the study period (mean years of follow-up to diagnosis = 3.96, SD = 1.89). Progression was predicted by several brain markers, including reduced entorhinal thickness (hazard ratio, HR = 1.73), greater Aβ burden (HR = 1.58), lower default network connectivity (HR = 1.42), and smaller hippocampal volume (HR = 1.30). When cognitive test scores were added to the model, the aforementioned neuroimaging markers remained significant and lower striatum volume as well as lower scores on baseline memory and processing speed tests additionally contributed to progression.


CONCLUSION
Among a large set of brain, vascular and cognitive markers, a subset of markers independently predicted progression from normal to MCI. These markers may enhance risk stratification by identifying clinically normal individuals who are most likely to develop clinical symptoms and would likely benefit most from therapeutic intervention.
['Rabin|Jennifer S|JS|', 'Neal|Taylor E|TE|', 'Nierle|Hannah E|HE|', 'Sikkes|Sietske A M|SAM|', 'Buckley|Rachel F|RF|', 'Amariglio|Rebecca E|RE|', 'Papp|Kathryn V|KV|', 'Rentz|Dorene M|DM|', 'Schultz|Aaron P|AP|', 'Johnson|Keith A|KA|', 'Sperling|Reisa A|RA|', 'Hedden|Trey|T|']
D000368:Aged D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D001921:Brain D060825:Cognitive Dysfunction D018450:Disease Progression D006801:Humans D008279:Magnetic Resonance Imaging D009483:Neuropsychological Tests D049268:Positron-Emission Tomography D014057:Tomography, X-Ray Computed
Mild cognitive impairment Aging Neuroimaging Memory Alzheimer's disease Amyloid Clinical Dementia Rating Survival