New Biomarker Identifies FTLD Subtype in Living Patients

Caroline Cassels

April 16, 2013

San Diego, California — A newly identified cerebrospinal fluid (CSF) biomarker can accurately distinguish between 2 major subtypes of frontotemporal lobar degeneration (FTLD) in living patients, a finding investigators believe will pave the way for more intelligent treatment trials for this disease.

Research conducted by investigators at Investigators at Emory University in Atlanta, Georgia, showed that the ratio of phosphorylated tau and total tau (p/t-tau) could discriminate not only between FTLD-TDP and FTLD-tau but also between FTLD-TDP and other disorders, such as Alzheimer's disease (AD).

"We found that the folks with the TDP type of frontotemporal lobar degeneration uniformly had decreased p-tau to t-tau ratios not only compared to the FTD-tau group but also to individuals with Alzheimer's disease, controls and so forth. So we really believe this is a strong and very promising biomarker," principal investigator William T. Hu, MD, PhD, told Medscape Medical News.

Dr. Hu presented the findings here at the American Academy of Neurology (AAN) 65th Annual Meeting.

Treatment Hindered

According to Dr. Hu, FTLD strikes patients earlier in life than AD does and, depending on the subtype, is characterized by behavioral symptoms or loss of language functions.

Currently, he said, there is no reliable way of distinguishing between FTLD-TDP and FTLD-tau in most living patients because the conditions can result in the same behavioral or language impairments. In addition, few biomarker studies have used pathology or well-characterized cases to identify or validate CSF biomarkers.

Furthermore, treatment choices are few, said Dr. Hu, who noted that no disease-modifying treatments are available and that antipsychotics and anxiolytics are the mainstay of care for individuals with neuropsychiatric symptoms. Patients with language disturbances have almost no therapeutic options, he said.

Given this background, he noted that it is imperative to accurately identify the underlying neuropathology of FTLD subtypes.

"Treatment trials in FTLD have been entirely hindered by the fact that we don't know what [FTLD subtypes] patients have," said Dr. Hu.

Previous preliminary research by Dr. Hu and colleagues identified 5 potential CSF biomarkers in a small series of 23 patients with known FTLD-TDP pathology. These included adrenocorticotropin hormone, agouti-related peptide, eotaxin-3, Fas, and interleukin (IL)-17 and -23.

High Sensitivity, Specificity

The aim of the current study was to validate these previously identified CSF biomarkers and also to report a new CSF FTLD-TDP biomarker in patients with a high likelihood of 1 of the 2 FTLD subtypes, said Dr. Hu.

The investigators recruited 2 independent cohorts of patients with FTD from 2 centers to undergo CSF analysis. These included individuals with a high likelihood of FTLD-TDP (FTD patients with amyotrophic lateral sclerosis or FTD patients with mutations in PGRN or C9ORF72) and those with a high likelihood of FTLD-tau (FTD patients with progressive supranuclear palsy or FTD patients with mutations in MAPT), as well as FTD patients who donated CSF and had subsequent autopsy confirmation of FTLD-TDP or FTLD-tau.

Dr. Hu and colleagues then tested the original 5 biomarkers in a "training" group of 30 patients: 19 with FTLD-TDP and 11 with FTLD-tau. Results from this phase of the study validated 2 of the original 5 — Fas and IL-23 — in distinguishing FTLD-TDP. However, the findings also suggested the p/t-tau ratio could independently distinguish between the 2 subtypes.

The investigators then attempted to validate these results in a "test" group of 86 participants: 31 with FTLD-TDP, 19 with FTLD-tau, 10 healthy controls, 21 with AD, and 5 with peripheral neuropathy.

Results in the test cohort revealed that the p/t-tau ratio was able to identify FTLD-TDP with a sensitivity and specificity of 86% and 76%, respectively.

These findings, said Dr. Hu, are quite exciting and represent an opportunity for treatment advances in this patient population.

"We hope to put this biomarker to the test in a practical fashion and see whether we can enrich a clinical trial for FTLD," said Dr. Hu.

The study received research support from AAN, Alzheimer's Drug Discovery Foundation/Association for Frontotemporal Degeneration, Bristol-Myers Squibb, and Pfizer. Dr. Hu reports he has consulted for Sanofi, National Parkinson's Foundation, the State of New Jersey, and the Province of Alberta.

American Academy of Neurology (AAN) 65th Annual Meeting. Presented March 15, 2013.