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

Top Ten Brain Posts 2012: #1 ADHD and IQ

The most highly viewed Brain Post of 2012 examined a study of brain development, IQ and ADHD.

ADHD rates are increased in lower IQ children but can be found in those with normal and above normal IQ performance.  

This study looked at a sensitive measure of brain development and compared the structural brain patterns of children with ADHD with low IQ and children with ADHD with normal IQ.

The study found two distinct patterns related to brain development in these two groups:
Low IQ children with ADHD showed delay brain gray matter development in the prefrontal cortex region compared to control children
High IQ children with ADHD had reduced gray matter volume throughout the brain but no focal developmental abnormality patterns

These results suggest more than one brain developmental abnormality in ADHD.  Future studies of brain structure, brain function and genetic risk factors will need to consider controlling for IQ performance.

Photo of blue heron and snowy egret hunting together is from the author's files. 

Can Exercise Reduce Stroke Damage?

This is the fourth and final post is a series focusing on exercise and the brain.  In the first post, I reviewed research documenting the brain's role in exercise fatigue.  The second post examined the hypothesis that aerobic physical activity had a key evolutionary role in the growth of brain size in humans.  The third post focused on animal study research supporting a role for exercise in reducing vulnerability to anxiety by changes in the 5-HT2C serotonin receptor.

In this post, I will review a provocative study suggesting that physical fitness and it's effect on brain vascular health, may limit the brain damage produced by stroke.

Dunn and colleagues at the University of Calgary in Canada conducted an experiment in rats that has recently been published in the journal PLOS ONE.  They noted that in the mammalian brain a chemical called hypoxia inducible factor, or HIF-1alpha, exists that improves "the capacity of tissue to survive low oxygen conditions".   They hypothesized that manipulation of environmental factors that increase HIF-1alpha may serve as a potential mechanism to reduce the brain damage associated with hypoxic events.

In their study, rather than exercise, they exposed rats to hypoxia by placing them in a 1/2 atmosphere environment for three weeks.  This results in brain changes that can also be seen with aerobic exercise including:

• Increase in capillary density by up to 30%
• Increase in brain oxygen partial pressure by up to 40%

The hypoxia-exposed experimental rat group was then compared to a group of control rats following stroke simulation by occlusion of the middle cerebral artery for one hour.  They then compared the stroke outcome of the case and control groups and noted the following key findings:

• Case rats had an increase in total hemoglobin, total hematocrit, capillary density and brain tissue oxygen level prior to the stroke simulation
• Absolute brain volume of stroke damage assessed by magnetic resonance imaging was reduced by 52% in the case group compared to controls
• Case rats showed no motor behavioral deficits 48 hours after the stroke simulation while control rats showed continued motor deficits
• Case rats showed a reduction in brain inflammation post stroke simulation measured by levels of lymphocyte infiltration and number of macrophages

The authors note in their discussion, that one clinical implication from their study relates to humans living in high altitudes under chronic acclimation to hypoxia.  They note there is limited study of stroke in these populations.  There is some human research showing that chronic high-altitude hypoxia with increased hemoglobin and hematocrit might actually lead to a higher incidence of stroke.  However, individuals living at high-altitude might be expected to have a better stroke outcome due to other adaptive brain mechanisms associated with acclimation to hypoxia.

The authors also note their study supports additional research in humans for ways to increase brain neuroplasticity through stimulation of HIF-1alpha.  This might be accomplished by a high baseline rate of aerobic exercise or use of pharmacological agents such as desferoxamine.

Such interventions in high-risk stroke populations (i.e. those who have had a transient ischemic attack) may lead to reduction in brain damage related to future stroke events. 

For the general population, this study suggests one benefit of aerobic exercise might include reduction in both the risk for stroke and a better outcome if one occurs.

For free access to this study, select the PMID link from the reference below. 

Photo of blue jay is from the author's files.

Dunn JF, Wu Y, Zhao Z, Srinivasan S, & Natah SS (2012). Training the brain to survive stroke. PloS one, 7 (9) PMID: 23028788