Biomarkers Utilized in the Diagnosis of Synucleinopathies - Key Questions

  • What kind of study design would you want to see for a biomarker evaluation in a neurodegenerative condition? What metrics would constitute statistical significance in the evaluation of diagnostic accuracy?
  • What statistical standards are acceptable given that these are rare disorders?
  • What gold standard should be used with these biomarkers?
  • What demographics should be considered in supporting studies? If only a subset of representative population has been included in the validation, how do we address this demographic evidence gap and whether coverage will be restricted pending more diverse validation studies?
  • When evaluating evidence for outcomes based on diagnosing a neurodegenerative disease with no disease modifying treatment, what metrics do you consider relevant to measure?
  • How do Synucleinopathies present in a patient and how do you evaluate for this category of disorders? Are there any criteria used? Who manages the patients with a diagnosis of Synucleinopathies?
  • When are patients referred for imaging for these disorders? What types of imaging are currently available to evaluate suspected Synucleinopathies? What are the performance characteristics of these imaging modalities in Synucleinopathies including false positive and false negative rates?
  • What role does imaging play in determining different neurodegenerative co-pathologies? What percentage of cases are considered indeterminate after imaging?
  • How are indeterminate cases managed? Which specialty follows them?
  • The definition of Synucleinopathies appears to be complex. There are multiple diseases and a broad array of signs and symptoms that are under this umbrella. Would a biomarker needed to diagnose Synucleinopathies encompass all of them?
  • How do you see these biomarkers tests involved in the detection of Alpha Synuclein being used in the evaluation and management of patients presenting with symptoms suggestive of Synucleinopathy?
  • Are the performance characteristics of these tests considered sufficient to make a diagnosis of Synucleinopathies? Is test interpretation straightforward or are there things to keep in mind while assessing the test report?
    • CSF
    • Skin
  • The relationship between biomarker positivity and clinical diagnosis requires clarification particularly in discordant cases. How is information derived from these tests integrated in determining a clinical diagnosis of Synucleinopathies? 
  • There are several types of Synucleinopathies where the performance of these biomarkers is not as robust such as those with mutations in LRRK2 and PRKN in Hereditary Parkinsons and Multiple System Atrophy. What is the etiology behind this? Is there concern that reliance on biomarkers may lead to missed diagnoses? Is there ongoing research in how best to detect these subtypes?
  • In the workup of a patient, where do you see these biomarkers being utilized? Who should be ordering these tests?
  • In patients diagnosed with dementia would identification of α-synuclein co-pathology influence management decisions? In cases where multiple co-pathologies are suspected, how do multiple biomarker tests impact results and subsequent patient management?
  • Is the evidence mature enough that is, are there longitudinal studies performed to endorse use of biomarkers in risk stratifying patients (e.g. those with Rapid Eye Movement Sleep Behavior Disorder, RBD)? If so, how will risk stratification change clinical management and/or course of patient care?
  • Do these tests have potential uses in monitoring disease progression and treatment success?
  • As a Patient Advocate, how does biomarker testing change a patient’s quality of life given that there is no disease modifying treatment?
  • What barriers to test adoption do you anticipate? CSF SAAs require lumbar puncture, which faces patient aversion and limited availability of experienced practitioners, and skin biopsy is less invasive but requires specialized specimen processing. Should coverage be limited to certain facility types or geographic regions, potentially creating access issues?
  • As long as disease-modifying therapies remain unavailable for Synucleinopathies, what other patient-relevant outcomes should be demonstrated to justify use of these biomarker tests? Asked another way, what constitutes meaningful clinical utility in these biomarkers?
Last Updated Aug 10 , 2026