Contributed Commentary by Peter Schueler
October 1, 2021 | Accurate diagnosis and monitoring of neurodegenerative diseases are complicated by a patient’s delayed clinical symptoms, which often appear decades after molecular disease onset. Biomarkers that detect the molecular changes preceding the clinical symptoms of neurodegenerative disease are critical for clinical trials at pre-symptomatic stages, effective diagnostics and the subsequent development of preventive therapies.
Clinical trials for neurodegenerative diseases use biomarkers to characterize and select target populations and track drug efficacy against natural disease progression, instead of gross symptomatology. While clinical trials have relied on imaging biomarkers for decades, their utility has been limited by accessibility and cost. The ongoing development of fluid (such as blood or spinal fluid) biomarkers may offer a promising alternative. Moving forward, innovations in the design and optimization of biomarkers will be pivotal for future treatments of presently incurable and devastating neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
The twenty-year window of opportunity
Biomarkers that are sensitive to early stages of a neurodegenerative disease are essential for early clinical intervention and research. For instance, typical Alzheimer’s patients have elevated levels of beta-amyloid up to twenty years before noticeable cognitive decline spurs them to see a specialist. By that point, their Alzheimer’s is easy to diagnose—they perform poorly in cognitive exams, and brain scans show their hippocampus and entorhinal cortex are shrunken—but their Alzheimer’s has progressed beyond where clinical intervention will do much good.
However, if these patients know they have a family history or other risk factors of Alzheimer’s, they may proactively request a PET scan to determine the concentrations of beta-amyloid and tau in their brains, Alzheimer’s primary imaging biomarkers. A positive test might qualify them to enroll in an early-intervention clinical trial, which would monitor and possibly slow the progression of their disease. Long-established imaging biomarkers, such as those for Alzheimer’s, reliably detect pre-symptomatic disease and can even predict future progression. A biomarker’s ability to select for patients and monitor treatment efficacy, all before clinical symptoms arise, makes them an essential component of early stage clinical trials.
Unfortunately, the benefits of imaging biomarkers are counteracted by their expense and inaccessibility, which are barriers for early diagnosis and drive up the cost of trials. Fluid biomarkers may provide a sensitive and accessible alternative to biomarker imaging. But most fluid biomarkers for neurodegenerative diseases remain experimental. Currently, only the Alzheimer’s fluid biomarkers amyloid-beta 42 and p-tau 181 have calibrated cut-off concentrations in plasma for prognosis based on clinical trial data. Future work in validating fluid biomarkers and correlating biomarker changes with disease progression would help scientists understand early pathological mechanisms of neurodegenerative disease, and help clinical trials capitalize on a long, but understudied, period of pre-symptomatic disease progression.
Better together than alone
For most neurodegenerative diseases a combination of imaging and/or a set of various fluid biomarkers may be required for accurate diagnosis and monitoring throughout the disease progression. Parkinson's Disease (PD) is emblematic of this. As with Alzheimer's, early molecular indications of PD—an accumulation of the misfolded protein α-synuclein—may begin up to twenty years before declines in motor function. However, clinical PD symptoms are difficult to distinguish from other Parkinson’s-like disorders, making the development of PD specific biomarkers, especially for early stages of disease progression, very challenging.
Currently, motor symptoms inform most initial PD diagnoses, despite a misdiagnosis rate of nearly 20%. The imaging biomarker dopamine transporter single-photon emission computed tomography (DAT-SPECT) is able to accurately diagnose ambiguous cases of PD such as essential tremor. However, it is not sufficiently sensitive to disease progression, especially early on.
There remains an urgent need for biomarkers that can detect PD early and quantify disease progression. Fluid biomarkers for α-synuclein may fulfill this need. But these biomarkers are not yet validated for use in clinical trials. A range of other PD biomarkers are also under development, including skin biopsies, smell tests, sleep analyses and microbiome linkages. Identifying the optimal combination of biomarkers, especially for neurodegenerative disorders with ambiguous symptoms, will be pivotal in the development of effective therapies. Eventually, clinical trials will rely on these markers to enroll their target participants, and accurately monitor their responses to treatment.
Biomarkers have demonstrated utility in neurodegenerative clinical trials. Yet, substantial work still needs to be done to make them more standardized, specific, sensitive and accessible. Of existing biomarkers, imaging biomarkers are the most validated and established for routine clinical use. However, imaging biomarkers are often prohibitively expensive and inaccessible. Conversely, fluid biomarkers can be collected with less effort and cost, which allows for the analysis of multiple markers simultaneously. Despite their advantages, fluid biomarkers have primarily been used experimentally, with few validated clinical applications. Most fluid-based biomarkers require further research to develop standard and scalable methods for analysis and interpretation.
Clinical trials are also ongoing to assess optimal use of fluid biomarkers in parallel with imaging biomarkers and clinical assessments for diagnosis, monitoring, and prediction of degenerative neurological disease, especially those with ambiguous clinical symptomatology. Informed by this research, clinical trials may one day be able to use a combination of these biomarkers and clinical symptoms to optimize their screening process for high-risk patients in early stages of their disorder, interpret patient data with higher precision, and shorten the duration of clinical trials.
Peter Schueler, MD, is board certified in Neurology and in Pharmaceutical Medicine (Swiss Medical Association). After his medical education he worked in the pharmaceutical industry and since 2000 in the CRO world, being with ICON since 2007. He issued over 40 publications as first author on drug development and drug safety. In 2015 his book “Re-engineering clinical trials” was published by Elsevier. He continues to lecture in Pharmaceutical Medicine at the University of Duisburg-Essen and at the European Center Pharmaceutical Medicine (ECPM), Basel, Switzerland. He can be reached at Peter.Schueler@iconplc.com.