A study published in the journal Alzheimer’s & Dementia evaluates the ability of a novel protein assay to detect and analyze blood-based biomarkers of dementias, including FTD.

Blood Biomarkers as a Path for Early, Accurate Diagnosis

Clinically usable biomarkers are essential to early and accurate diagnosis, especially as potentially disease-modifying FTD treatments progress through clinical trials. Biomarkers are measurable aspects of biology which can give clues as to the presence or progression of disease. No approved biomarkers currently exist that are specific for FTD. Blood biomarkers, in comparison to biomarkers detected in the cerebrospinal fluid (CSF), are easier to measure, with blood draws being less invasive and accessible to more clinicians than lumbar punctures.

As the authors of the study note, blood-based protein biomarkers have the potential to support diagnosis by capturing the presence of a molecular pathology or process occurring during disease, such as neuroinflammation. Blood biomarker development research has advanced significantly, with recently developed assays able to survey many blood-based proteins simultaneously with high sensitivity. One such blood biomarker tool being tested in research settings is the nucleic acid–linked immuno-sandwich assay (NULISA), which features separate tests for central nervous system (CNS) disease and inflammation.

The researchers set out to test NULISA’s ability to detect biomarkers and evaluate whether it could detect biomarkers within and between several neurodegenerative disorders, including FTD. The authors took a two-stage approach to the study. They first compared NULISA assays of conventional biomarkers against another assay (Simoa), which has high sensitivity but captures fewer targets. The authors then reviewed the CNS and inflammation panels to evaluate the feasibility of using NULISA to identify potential diagnostic and prognostic biomarkers.

Of the 142 study participants, 18 had FTD with behavior variant FTD (bvFTD), 15 had FTD with primary progressive aphasia (PPA), 36 had progressive supranuclear palsy (PSP), 34 had Lewy body dementia (LBD), 20 had Alzheimer’s disease, and 20 had mild cognitive impairment (MCI) with measurable amyloids (a common biomarker of Alzheimer’s). Blood samples were collected through a standard phlebotomy and were processed for analysis using NULISA.

NULISA Reliably Detects Protein Panel in Blood

The authors write that NULISA could detect proteins with high sensitivity in both the CNS and inflammation panels, though not all samples passed quality control checks. In comparing blood-serum biomarkers measured by NULISA with plasma biomarkers detected by Simoa, a significant correlation in protein levels was observed between the two assays.

The NULISA CNS panel revealed considerable differences between disorders when comparing the different groups of participants. For FTD and PSP, increased protein neurofilament light (NfL) levels were the most significant biomarker that distinguished participants with either disorder from healthy controls. Additionally, compared to controls, a specific pair of enzymes was found to be elevated in people with bvFTD. Higher levels of certain proteins in the CNS panel differentiated people with PSP from those with bvFTD, and vice versa. When reviewing the CNS panel for potentially prognostic biomarkers, the authors found that heightened NfL levels were significantly associated with disease progression and severity, as well as low levels of the hormone CRH.

It is important to note that NfL is not specific to FTD and can be elevated in a variety of conditions which cause damage to the brain, or in cases of systemic inflammation. The power of these large exploratory studies is to identify new candidate biomarkers, and/or validate use of existing candidates in certain instances.

The inflammation panel revealed that the proteins amphiregulin and CD276 were raised in people with bvFTD, PSP, and LBD. People with bvFTD and PSP had higher levels of multiple inflammation markers, helping them to stand apart from people with AD, MCI, and LBD, who had a more limited set of markers. However, unlike the CNS panel, the authors found no markers that significantly differentiated bvFTD and PSP. In checking the inflammation panel for prognostic markers, the authors found that 25 were statistically significant predictors of disease progression, including CD276 and amphiregulin.

Overall, NULISA proved highly sensitive to changes in serum protein levels across disorders. The CNS panel demonstrated high reliability and was capable of differential protein detection, while the inflammation panel demonstrated the complexity of changes caused by different disorders. The study showed that complex assays like NULISA can provide consistent results (like the established Simoa tests) while providing  a broader range of information.

These types of studies can help identify new protein candidates which could serve as biomarkers which distinguish disorders. More research will be needed to follow-up on the identified candidates to assess their specificity to a certain disorder or stage of disease. Are you interested in contributing to FTD research? The FTD Disorders Registry can connect you to studies recruiting participants and help you share your lived experiences with researchers to guide research.