Operationalizing hippocampal volume as an enrichment biomarker for amnestic mild cognitive impairment trials: effect of algorithm, test-retest variability, and cut point on trial cost, duration, and sample size

Neurobiol Aging. 2014 Apr;35(4):808-18. doi: 10.1016/j.neurobiolaging.2013.09.039. Epub 2013 Oct 3.


The objective of this study was to evaluate the effect of computational algorithm, measurement variability, and cut point on hippocampal volume (HCV)-based patient selection for clinical trials in mild cognitive impairment (MCI). We used normal control and amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) as normative reference and screening cohorts. We evaluated the enrichment performance of 4 widely used hippocampal segmentation algorithms (FreeSurfer, Hippocampus Multi-Atlas Propagation and Segmentation (HMAPS), Learning Embeddings Atlas Propagation (LEAP), and NeuroQuant) in terms of 2-year changes in Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating Sum of Boxes (CDR-SB). We modeled the implications for sample size, screen fail rates, and trial cost and duration. HCV based patient selection yielded reduced sample sizes (by ∼40%-60%) and lower trial costs (by ∼30%-40%) across a wide range of cut points. These results provide a guide to the choice of HCV cut point for amnestic MCI clinical trials, allowing an informed tradeoff between statistical and practical considerations.

Keywords: Biomarker; Clinical trials; Enrichment; Hippocampal volume; Hippocampus; Inclusion criterion; MRI; Structural MRI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Algorithms*
  • Alzheimer Disease
  • Biomarkers
  • Clinical Trials as Topic
  • Cognitive Dysfunction / diagnosis*
  • Cognitive Dysfunction / pathology*
  • Female
  • Hippocampus / pathology*
  • Humans
  • Male
  • Middle Aged
  • Neuroimaging
  • Neuropsychological Tests
  • Patient Selection
  • Sample Size


  • Biomarkers

Supplementary concepts

  • Alzheimer disease type 1