Letters to the Editor: What About Biomarkers for Parkinson’s Disease?

| January 1, 2021

Dear Editor:

Parkinson’s disease (PD) affects over 600,000 patients in the United States; these numbers might double by 2040, as the population of older people increases.1 Diagnostic clues include the signs of resting tremor, bradykinesia, muscle rigidity, and postural imbalance. However, these clinical indicators might be inaccurate much of the time. A low rate of diagnostic precision emphasizes a need for early recognition of PD to minimize patients being untreated. Biomarkers are an aid to prompt, correct diagnoses.

Early diagnosis. Biomarkers could shorten the time to neuroprotective treatment to mitigate irreversible brain damage early in the PD prodrome.2 They might also help monitor disease progression and response to therapy. Biomarkers are divided into clinical, biochemical, genetic, and imaging classifications.

Clinical markers. Motor and nonmotor signs of PD can assist at diagnosis; however, tremors and rigidity are not well-correlated with disease level and/or progression. Nonmotor aspects of constipation, hyposmia, rapid eye movement sleep, behavior change, and depression might predate motor findings and are better diagnostically.3

Biochemical markers. The gene, alpha-synuclein (SYNA), evidences correlation in plasma to patients with PD as a potential biomarker for synucleinopathies.4 SYNA-oligomers accumulation is associated with PD neurodegeneration, detection of at-risk individuals, monitoring progression, and intervention response. Elevated SYNA-oligomers levels evidence diagnostic specificity and sensitivity at 85 and 53 percent, respectively.4 

Genetic markers. Although PD derives from an interplay of lifestyle, environmental, and genetic factors, genetic mutations are linked with familial cases. These include the leucine-rich repeat kinase 2 (LRRK 2), SYNA, Parkin (PARK-2), 1 phosphatase and tensin homolog (PTEN-induced kinase), and DJ-1 genes.5 LRRK2 genes are common among individuals with PD, in a pattern similar to the idiopathic and sporadic cases. They are also frequently noted in late-onset disease, which allows it for utilization as screening instruments, in contrast to DJ-1 genes.6 Genetic mutations can increase oligomeric SYNA, which induces oxidative stress, mitochondrial dysfunction, and abnormal processing of proteins.7

Imaging markers. Dopamine transporter is a presynaptic protein involved in the reuptake of dopamine. It is frequently employed at imaging with positron emission tomography and/or single-photon emission tomography using tracers like 6-(18F) fluorodopa, 11-C dihydrotetrabenazine or 2β-[11C]carbomethoxy-3β-4-fluorophenyltropane.8 Reduction in striatal binding evidences diagnostic accuracy, with a sensitivity near 100 and specificity at 89 percent.9

The International Parkinson and Movement Disorder Society has reviewed the accuracy of automated segmentation and quantification of SN (substantia nigra) and locus coeruleus volumes by neuromelanin-sensitive magnetic resonance imaging. Reportedly, there is iron overload in the SN region and imaging changes at various stages of PD.10



Biofluids, genetic techniques, and neuroimaging are developing PD biomarkers. Using a combination of them improves early diagnoses. Dopamine transporter imaging is widely utilized and supplemented by imaging techniques. Although diagnosis is mainly based on clinical signs and symptoms, biochemical biomarkers might be incorporated into diagnosing and staging of PD. Genetic and imaging markers can help at recognizing and monitoring patients with Parkinson’s disease.


  1. Kowal SL, Dall TM, Chakrabarti R, et al. The current and projected economic burden of Parkinson’s disease in the United States. Mov Disord. 2013;28(3):311–318.
  2. Wu Y, Le W, Jankovic J. Preclinical biomarkers of Parkinson disease. Arch Neurol. 2011;68(1):22–30.
  3. Newman EJ, Breen K, Patterson J, et al. Accuracy of Parkinson’s disease diagnosis in 610 general practice patients in the West of Scotland. Mov Disord. 2009;24(16):2379–2385.
  4. El-Agnaf OM, Salem SA, Paleologou KE, et al. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 2006;20(3):419–425.
  5. Klein C, Schlossmacher MG. Parkinson disease, 10 years after its genetic revolution: multiple clues to a complex disorder. Neurology. 2007;69(22):
  6. Mollenhauer B, Zhang J. Biochemical premotor biomarkers for Parkinson’s disease. Mov disord. 2012;27(5):644–650.
  7. Parnetti L, Castrioto A, Chiasserini D, et al. Cerebrospinal fluid biomarkers in Parkinson disease. Nat Rev Neurol. 2013;9(3):131–140.
  8. Ravina B, Marek K, Eberly S, et al. Dopamine transporter imaging is associated with long‐term outcomes in Parkinson’s disease. Mov Disord.
  9. Bor-Seng-Shu E, Felicio AC, Braga-Neto P, et al. Dopamine transporter imaging using 99mTc-TRODAT-1 SPECT in Parkinson’s disease. Med Sci Mon Int Med J Exp Clin Res. 2014;20:1413–1418.
  10. Berg D, Roggendorf W, Schröder U, et al. Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol. 2002;59(6):999–1005.
  11. With regards,

Naga Krishnakanth Madireddy, MD; Dheeraj Kumar Posa, MBBS; Shivani Naik, MD; Steven Lippmann, MD

Department of Neurology at the University of Louisville in Louisville, Kentucky.

Funding/financial disclosures. The authors have no conflict of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

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Category: Biomarkers, Current Issue, Letters to the Editor, Neurodegenerative Disease, Neurology, Parkinson's disease

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