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

Proximity to Parent Reduces Anxious Youth Stress Response

Functional magnetic resonance imaging provides a powerful tool for understanding anxiety in children as well as adults.

This technique does not use any form of radiation and presents minimal risk for research participants.  We are beginning to better understand important mechanisms of childhood anxiety.

An innovative study of neural stress markers in children examined an important variable in childhood anxiety.  When children are studied in an fMRI scanner, they may or may not have a parent accompany them into the scanner room.  It is important to understand how parental proximity affects the anxiety tasks used in children.

Conner and colleagues from the University of Pittsburgh, Cal-Berkeley and the University of Virginia recently published a study related to this topic in the journal PLOS One. 

In their study, children with clinical anxiety underwent an anxiety task in the fMRI scanner.  Children were allowed to request that their accompanying parent stay with them in the scanner room.  If they did not request this, their parents waited in a external room during the period of the scanning. 

Children in the scanner were presented a series of words that included words with a cognitive element of physical danger, i.e. ghost, social anxiety, positive emotions and neutral words.  Children rated each word as positive, negative or neutral using a three-button glove.

The key findings from the study comparing 10 anxious children with parents in the scanning room, 10 anxious children with parents in the waiting room and 10 non-anxious control children with parents in the waiting room:

• Anxious children with parents in the waiting room showed increased brain response compared to control children to anxiety words in three areas known to be related to stress response: hypothalamus, the ventromedial prefrontal cortex and the left ventrolateral prefrontal cortex
• This stress response was attenuated in anxious children with parents in the scanning room.  Their level of response was very similar to control children.

The figure at the right highlights the medial frontal cortex.  This area was found to be important in the child stress response in the current study and is sensitive to parental proximity.

The authors of this study concluded that for anxious youth, "caregivers may act as emotion regulators".  They note that treatments that facilitate transfer of emotional regulation of anxiety from parental support to an internal self-mechanism may play a key role in advancing  anxiety disorder treatment in children.

Another important implication in this study is the potential role of parental proximity in comparing imaging studies across research centers.  Disparate results may be related to differing rates of parental proximity between research centers.

It is important to note this study did not use a randomized design as children were allowed to self-select whether they had a parent in the scanning room.  Nevertheless, this study proposes a brain mechanism related to a parental role in anxiety regulation for children who suffer from an anxiety disorder.  Interested readers can access the free full text of this manuscript by clicking on the link in the citation below.

Photo of blue curaco from San Diego Zoo from the author's files.

Image of prefrontal cortex is a screenshot from the iPad app 3D Brain.

Conner OL, Siegle GJ, McFarland AM, Silk JS, Ladouceur CD, Dahl RE, Coan JA, & Ryan ND (2012). Mom-It Helps When You're Right Here! Attenuation of Neural Stress Markers in Anxious Youths Whose Caregivers Are Present during fMRI. PloS one, 7 (12) PMID: 23236383

Early Brain Inflammation in Lupus (SLE)

I previously reviewed a brain research imaging study of patients with systemic lupus erythematosis (SLE).  This study found evidence of disruption of brain connectivity markers even before any clinical brain symptoms.

SLE is a multi-organ disease known to produce significant neuropsychiatric symptoms.  These symptoms do not affect all patients with SLE as the brain effects are highly variable in this disorder.  Studying patients with early SLE without brain-related symptoms provides insight into the timing, course and prevalence of brain pathophysiology.

A second study from the University of Texas Health Sciences Center at San Antonio, School of Medicine, Research Imaging Institute lends support to the early effect of SLE on the brain.

In this study, 85 subjects with SLE underwent brain positron emission tomography (PET).  PET imaging is a sensitive tool to assess brain glucose metabolism and brain inflammation.

The key elements of the design of this study included:

• Case identification: Newly diagnosed SLE (within 9 months of initial diagnosis) with SLE disease severity measured by the SLE Disease Activity Index (SLEDAI)
• Clinical presentation: Potential subjects with stroke were eliminated, 19 of the remaining sample had neuropsychiatric symptoms (anxiety, depression, psychosis, mononeuropathy or headache symptoms) and 17 had abnormal white matter hyperintensities or atrophy on magnetic resonance imaging (MRI).
• Imaging parameters: Fluoro-deoxy-glucose (FDG) PET imaging analysis by visual inspection and statistical analysis by SLEDIA severity scores

The key findings from the study included:

• 36 of 85 subjects (42%) showed abnormal PET images (decreased glucose uptake) on visual ratings localized to the frontal and parietal brain cortex
• Disease activity ratings correlated with white matter increases in FDG uptake in multiple brain regions including: frontal, parietal and occipital regions, subcortical temporal regions, limbic regions, cerebellar white matter and brain stem areas
• Subjects with neuropsychiatric symptoms showed hypermetabolism in frontal regions and subcortical white matter regions most notably in the corpus callosum regions
• Subjects without neuropsychiatric symptoms showed hypermetabolism that was limited to frontal lobe, anterior cingulate and corpus callosum regions

It is interesting that the study was able to identify specific brain regions (corpus callosum noted in figure to the right) of white matter inflammation in those with anxiety, depression and other neuropsychiatric symptoms.  This supports a specific regional effect of the SLE disease process on production of psychiatric symptoms commonly found in the disorder. 

The author note their study is the first study that demonstrates a "strong association between SLE disease activity and increased FDG uptake indicating inflammation of white matter of newly diagnosed SLE patients".  They argue that this finding suggest that primary brain pathology in SLE is inflammation targeting white matter vascular and microglial structures. 

This is an important study using brain imaging to better understand the mechanisms related to the neuropathology of SLE.  The study supports an early onset of brain inflammation in SLE, often before any neuropsychiatric symptoms.  

For interested readers the complete text article can be accessed by selecting the PMID link below.

Photo of eclectus parrot from the author's files. 

Ramage, A., Fox, P., Brey, R., Narayana, S., Cykowski, M., Naqibuddin, M., Sampedro, M., Holliday, S., Franklin, C., Wallace, D., Weisman, M., & Petri, M. (2011). Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus Arthritis & Rheumatism, 63 (10), 3048-3057 DOI: 10.1002/art.30458

What We Know About Obesity and Mortality

To begin 2013 I would like to do a series of posts related to weight, overweight and obesity on mortality and brain disorders.

This morning a new meta-analysis was published in JAMA examining the relationship between weight category and all cause mortality.  This study is receiving a significant degree of attention as it challenges a commonly held belief that even mild obesity is linked to earlier death.

The study was conducted by a research team at the Centers for Disease Control, the University of Ottawa in Canada and the National Institutes of Health.  A key focus in this analysis of all relevant published research is examining the effect of the lowest level of obesity (those with a BMI between 30 and 35).  Normal weight is considered to be in the 20 to 25 BMI range, overweight between 25 and 30.  BMI rates above 35 are considered severe obesity.

So for perspective, let's look at the cutoffs for a BMI of 25, 30 and 35 for two heights (5 foot 6 inches and 5 foot 10 inches)

• BMI 25- 155 pounds/175 pounds
• BMI 30- 185 pounds/210 pounds
• BMI 35- 215 pounds/245 pounds

So and individual who is 5 feet six inches tall would be in the overweight category from 155 to 185 pounds, mildly obese between 185 and 215 pounds and moderately to severely obese over 215.  Likewise you can substitute the relevant weight for a person 5 foot 10 inches tall by using the second weights in the above table.

I have summarized the hazard ratio estimates from the current study in the chart below.  The hazard ratio is set a 1.0 for those in the normal weight range and relevant category mortality hazard ratios are compared by BMI.  The hazard ratios are estimated from combining all relevant data of published research studies on this topic.

 The mortality hazard estimates actually are lower for the overweight and mildly obese categories in this meta-analysis.  However, only the 25-30 BMI overweight category reaches statistical significance compared to normal weight categories.  The hazard ratios suggest that for me at 5 foot 10 inches, I would need to be over 245 (BMI of 35) pounds to significantly increase my mortality risk.

This study suggests we might want to dial back a bit the public health concerns about milder amounts of obesity.  There is  no doubt that greater levels of obesity (BMI over 35) contribute significantly to earlier risk of death.  For those with lower levels of obesity, weight loss may be less important than regular aerobic exercise, eating a healthy diet and not smoking in promoting a longer life.

For those interested in calculating their own BMI, I recommend this easy web-based calculator provided by the National Heart Lung and Blood Institute.

Photo of great blue heron in flight is from the author's files.

Data from the chart comes from the original manuscript cited below.  Interested readers can access the JAMA free full manuscript by clicking here. 

Flegal KM, Kit BK, Orpana H, Graubard BI (2013). Association of All-Cause Mortality With Overweight and Obesity Using Standard Body Mass Index Categories JAMA, 309 (1), 71-82

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. 

Top Ten Brain Posts 2012: #2 Cannabis Neurosis

The number two rated Brain Post for 2012 looked at a study of the risk factors associated with the development of cannabis dependence.

This study examined genetic and psychological factors found in a group of 50 individuals with DSM-IV cannabis dependence compared to a control group without a diagnosis of cannabis dependence.

The study found two factors appeared to increase the risk for cannabis dependence.

One factor was a genetic factor involving the proenkephalin gene.  A second factor was high score on a psychological measure of neurosis.  Neurosis is a psychological factor related to risk for a variety of anxiety conditions.

The study found a particularly elevated interaction risk for individuals who had both the high risk proenkephalin genotype as well as high scores on neuroticism.  When both factors were present, risk for cannabis dependence was estimated to be about ten times higher compared to individuals without the high risk gene and with low neuroticism scores.

Legalization of marijuana in some states in the U.S. will provide a natural experiment to look at rates of problems with cannabis use.  Although limited cannabis may be used without major complications in some individuals, others may find increased access leading to development of dependence and related social, medical and behavioral complications.

Photo of Christmas ornament angel from the author's files. 

Top Ten Brain Posts 2012: #3 Brain and Fatigue

Fatigue plays a key role in limiting athletic performance.  Athletes with superior control of the physiology of fatigue have a competitive advantage.

Fatigue with exertion has been felt to be primarily a peripheral phenomenon.  As muscles fatigue, peripheral lactic acid appears to limit continued exertion.

However, in the #3 rated Brain Post of 2012, I reviewed a summary of research showing the brain plays a key role in assessment of fatigue. 

This review found evidence for the brain insula playing a key role in the central assessment of fatigue.  The insula appears to be a key connection between motor and limbic brain areas of function including assess of fatigue.

The review suggests athletes with better brain control of fatigue may be able to better finish the final stages of competition.

Photo of Christmas ornament angel from the author's files.