Friday, January 11, 2013

Brain MRI and Enhanced Alzheimer's Drug Trials

Clinical research trials in Alzheimer's disease are hampered by insensitive outcome measures.

This effect results in the need for very expensive large sample sizes trial protocols.

Current state-of-the-art Alzheimer's trials frequently use the Minimental Status Exam (MMSE) or the cognitive subscale of the Alzheimers disease assessment scale (ADAS Cog).  These measures are imperfect and imprecise, often requiring a minimum of 200 to 300 subjects to be enrolled.

One strategy to improve Alzheimer's disease clinical trial methodology is to use more sensitive brain imaging markers to measure therapeutic response.

Ai-Ling Lin and colleagues from the University of Texas Health Science Center at San Antonio have recently reviewed the clinical research literature on this topic (citation below).  They reviewed research studies on cognitive decline using a number of brain imaging techniques including:

  • High-resolution magnetic resonance imaging (MRI)
  • Diffusion tensor imaging (DTI)
  • Functional MRI (fMRI)
  • Cerebral blood flow estimation using arterial spin labeling MRI (ASL-MRI)
  • Single-photon emission computed tomography (SPECT)
  • Magnetic resonance imaging spectroscopy
  • Positron emission tomography (PET)

Obviously, there are many imaging tools available as potential biomarkers in Alzheimer's disease.  A key research issue is to find the most sensitive tool (or set of tools) that is valid and financially feasible.

The review covers research findings related to brain imaging markers in cognitively normal adults with genetic markers for Alzheimer's disease (APOE gene), mild cognitive impairment, the conversion of mild cognitive impairment to Alzheimer's disease and those diagnosed with Alzheimer's disease.  For the purpose of this post I will focus on their findings in those who have Alzheimer's disease.

Alzheimer's disease produces a marked increase in the volume of global and focal brain atrophy.  They note in their study the relative magnitude of yearly brain volume reduction in the 70 to 80 year age group in Alzheimer's disease compared to those without Alzheimer's disease (controls).  The data from high-resolution MRI studies show:
  • Yearly global atrophy rate: 2 to 3% in Alzheimer's disease, 0.3% to 0.5% controls
  • Yearly hippocampus atrophy rate: 3.0 to 5.9% in Alzheimer's disease, 1.0% to 1.7% in controls
  • Yearly entorhinal cortex: 7.2% to 8.4% in Alzheimer's disease, 1.4% to 2.9% in controls

The entorhinal cortex region is a key region in assessing Alzheimer's disease related brain atrophy.  The entorhinal cortex region is highlighted in the figure on the left in blue.

Brain changes in Alzheimer's disease are also found in the default mode network assessed by MRI functional connectivity imaging and in cerebral blood flow using ASL-MRI.

The authors conclude that multimodal MRI (high-resolution MRI, functional connectivity MRI and arterial spin labeling MRI) holds promise as a powerful strategy to measure therapeutic effects in experimental drug study clinical trials for Alzheimer's disease.  They note these techniques will require validation against currently used primary outcome measures.  

However, because of the sensitivity of multimodal MRI, clinical trials may be able to reduce sample sizes to only about 20 to 25 subjects.  

This enhancement would be a big leap in Alzheimer's drug research and development.  It holds the promise of speeding up the clinical trial process and allowing for the study of more potential therapeutic compounds.

Photo of fire-tufted barbet from the San Diego Zoo is from the author's files.

Entorhinal cortex figure is a screen shot from the iPad app 3D Brain.

Lin AL, Laird AR, Fox PT, & Gao JH (2012). Multimodal MRI neuroimaging biomarkers for cognitive normal adults, amnestic mild cognitive impairment, and Alzheimer's disease. Neurology research international, 2012 PMID: 21949904

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