Functional Brain Imaging May Spot Alzheimer's Early

Megan Brooks

August 21, 2013

Two hallmark cerebrospinal fluid (CSF) biomarkers of early Alzheimer's disease (AD) correlate with decay in the default mode network (DMN) seen on resting-state functional connectivity MRI (rs-fcMRI), a new study suggests.

Beau M. Ances, MD, PhD, and colleagues from the Knight Alzheimer's Disease Research Center at Washington University, St. Louis, Missouri, say rs-fcMRI may be an effective noninvasive way to detect early asymptomatic AD.

Earlier research by Dr. Ances and others has shown that AD disrupts connections in the DMN and other brain networks, as reported at that time by Medscape Medical News. "Our study is one the first that links resting-state functional connectivity and CSF biomarkers," Dr. Ances told Medscape Medical News.

"We are excited about this work," Dr. Ances said. "We hope in the future that resting-state functional connectivity markers will be added to our arsenal for evaluation of early AD. While these results are only cross-sectional in nature they help place changes in resting-state functional connectivity in context with other measures."

Still, he added, "we do not advocate for using this technique yet at the individual patient level, but our work creates a stepping stone for helping justify the use of this method. We think that resting-state functional connectivity will provide additional spatial information for areas involved in early AD."

The study was published online August 19 in JAMA Neurology.

Best Chance of Success

The ability to diagnose AD early is crucial as many researchers now believe that treating patients before symptoms of dementia appear offers the best chances of success.

Dr. Beau M. Ances

Patients with symptomatic AD typically have reduced amyloid β42 (Aβ42) and increased phosphorylated tau181 (ptau) in CSF. Cognitively healthy individuals can also exhibit these CSF biomarkers of AD pathology.

Emerging evidence, Dr. Ances and colleagues note, suggests that functional scans of brain networks involved in AD has "great potential" for characterizing pathophysiologic changes during the preclinical phase of AD.

They note that rs-fcMRI abnormalities have been "consistently" observed in the DMN in patients with symptomatic AD. More recent rs-fcMRI investigations have detected DMN changes in asymptomatic individuals.

For their latest study, Dr. Ances and colleagues examined changes in the DMN in relation to CSF Aβ42 and ptau in a cross-sectional longitudinal cohort of 207 older adults with normal cognition (Clinical Dementia Rating, 0).

They found that decreased CSF Aβ42 and increased CSF ptau were each independently associated with reduced DMN integrity, with the most prominent decreases in functional connectivity observed in the posterior cingulate cortex (PCC) and medial temporal lobe (MTL).

These are "2 key hubs that are often affected by AD" and are associated with memory, Dr. Ances said. Memory impairment in the early phases of AD may be attributable to the "convergent effects of both amyloid and tau pathology," the researchers note in their paper.

They also note that the effects of CSF Aβ42 and ptau on DMN functional connectivity were not due to age or structural atrophy in the PCC and MTL.

Caveats "Substantial"

In an accompanying editorial in JAMA Neurology, William Jagust, MD, from the Helen Wills Neuroscience Institute and School of Public Health at University of California, Berkeley, agrees that this technique has potential but that more study is needed.

"From a clinical perspective," he writes, "the results suggest that a relatively simple magnetic resonance imaging measure might be a reasonable biomarker for early AD. The caveats, however, are substantial."

For example, he notes that "technical factors in assessing resting state networks are crucial: small amounts of head motion can produce artifacts that are difficult to detect, there are multiple approaches to data analysis, and reliability over time and across centers has not been extensively established."

Dr. Jagust also says validating this approach as a biomarker requires much stronger links to disease phenotypes that include the progression to AD dementia. "Nevertheless, the appeal of this technique is that it can be performed on available clinical instruments, requires no particular cognitive task, and can be obtained in a few minutes," Dr. Jagust writes.

Targeting the PCC and the MTL "could be a simple and widely applicable data-analytic approach to track early disease if the difficult technical issues, predictive value, sensitivity, and specificity can be worked out," he concludes.

Funding for the study was provided by the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the American Roentgen Ray Society, the Charles F. and Joanne Knight Alzheimer's Disease Research Center, the National Institute of Nursing Research, and the Alzheimer's Association. Dr. Ances and Dr. Jagust have disclosed no relevant financial relationships. A complete list of author disclosures is listed with the original article.

JAMA Neurol. Published online August 19, 2013. Abstract Editorial

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