Inferring changepoint times of medial temporal lobe morphometric change in preclinical Alzheimer's disease

Laurent Younes, Marilyn Albert, Michael I. Miller

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


This paper uses diffeomorphometry methods to quantify the order in which statistically significant morphometric change occurs in three medial temporal lobe regions, the amygdala, entorhinal cortex (ERC), and hippocampus among subjects with symptomatic and preclinical Alzheimer's disease (AD). Magnetic resonance imaging scans were examined in subjects who were cognitively normal at baseline, some of whom subsequently developed clinical symptoms of AD. The images were mapped to a common template, using shape-based diffeomorphometry. The multidimensional shape markers indexed through the temporal lobe structures were modeled using a changepoint model with explicit parameters, specifying the number of years preceding clinical symptom onset. Our model assumes that the atrophy rate of a considered brain structure increases years before detectable symptoms. The results demonstrate that the atrophy changepoint in the ERC occurs first, indicating significant change 8-10 years prior to onset, followed by the hippocampus, 2-4 years prior to onset, followed by the amygdala, 3 years prior to onset. The ERC is significant bilaterally, in both our local and global measures, with estimates of ERC surface area loss of 2.4% (left side) and 1.6% (right side) annually. The same changepoint model for ERC volume gives 3.0% and 2.7% on the left and right sides, respectively. Understanding the order in which changes in the brain occur during preclinical AD may assist in the design of intervention trials aimed at slowing the evolution of the disease.

Original languageEnglish (US)
Pages (from-to)178-187
Number of pages10
JournalNeuroImage: Clinical
StatePublished - 2014


  • AD
  • Abbreviations
  • Alzheimer's disease
  • CDR
  • Clinical Center of the National Institutes of Health
  • ERC
  • FWER
  • GPB
  • Geriatric Psychiatry Branch
  • MCI
  • MMSE
  • NIA
  • NIH
  • NIMH
  • National Institute for Mental Health
  • National Institute on Aging
  • RSS
  • SPGR
  • clinical dementia rating
  • diffeomorphometry
  • entorhinal cortex
  • family-wise error rate
  • mild cognitive impairment
  • mini-mental state exam
  • region-of-interest large deformation diffeomorphic metric mapping
  • residual sum of squares
  • spoiled gradient echo
  • study of shape using a metric on the diffeomorphic connections between structures

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience


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