Novel Cerebrospinal Fluid Biomarkers Can Be Used to Distinguish Underlying Pathology in Patients with Specific Form of Dementia

The ratio of the cerebrospinal fluid (CSF) biomarker, p-Tau181, to total t-tau (t-tau)—the p/t ratio—may be useful in distinguishing between frontotemporal lobar degeneration (FTLD) with lesions that are immunoreactive to TDP-43 (FTLD-TDP) and the tau subtype of FTLD (FTLD-tau) in living patients, which should speed research into the pathology, prevention, and treatment of FTLD, according to research presented at the 65^th Annual Meeting of the American Academy of Neurology.

Frontotemporal lobar degeneration, thought to be the fourth most common cause of dementia after Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia, describes a group of heterogeneous disorders that are characterized by lesions in the front and temporal lobes of the brain, but no lesions in the parietal and occipital lobes.

Currently, there is no reliable way to predict the underlying pathology of FTLD in living patients. However, patients with FTLD-TDP have lesions that are found to be immunoreactive to TAR-DNA binding-protein 43 (TDP-43), a protein that regulates messenger RNA and that forms inclusion bodies, called Pick’s bodies, inside neurons. The TDP-43 protein has also been identified in patients with amyotrophic lateral sclerosis (ALS) and in athletes with chronic traumatic encephalopathy. This is in contrast to FTLD-tau, which has nodules of hyperphosphorylated tau protein, the same protein found in Alzheimer’s disease.

Being able to distinguish between these two different underlying pathologies in living patients could be of paramount importance in designing and testing disease-modifying therapies.

William Hu, MD, PhD, of the Emory University School of Medicine ALS Center in Atlanta, Georgia, and colleagues conducted a study involving 69 patients, including 43 patients with a high likelihood of having FTLD-TDP and 26 patients with a high likelihood of FTLD-Tau, to validate five previously identified CSF biomarkers (eotaxin-3, FAS, interleukin-23 [IL-23], agouti-related peptide, and adrenocorticotropic hormone) and measure levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau₁₈₁). Patients with a high likelihood of having FTLD-TDP are those patients with amyotrophic lateral sclerosis or FTD patients with mutations in PGRN or C9ORF72, while those with a high likelihood of FTLD-Tau are those with progressive supranuclear palsy or those with mutations in MAPT.

The researchers validated the group level differences in several CSF markers, including eotaxin-3, Fas, and IL-23. Furthermore, they found that the ratio of p-Tau₁₈₁ to t-Tau (p/t-Tau ratio) was significantly lower in FTLD-TDP cases compared with FTLD-Tau and AD cases. Overall, they found that the p/t-Tau ratio alone is sufficient to distinguish FTLD-TDP from tau-type FTLD with a 86% sensitivity and 76% specificity.

“CSF biomarkers have the potential of accurately identifying FTLD-TDP, and further development of this and other FTLD-TDP biomarkers will significantly accelerate the ante-mortem prediction of FTLD-TDP pathology and design of substrate-specific FTLD clinical trials,” the authors concluded.

Dr. Hu reported no relevant financial conflicts of interests. However, other investigators reported several potential financial conflicts of interest.