Article type: Literature Review
Article title: A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies
Article title: A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies
Journal: Clinics and Practice
Year: 2025
Authors: Jamir Pitton Rissardo, Ana Leticia Fornari Caprara
E-mail: jamirrissardo@gmail.com
Year: 2025
Authors: Jamir Pitton Rissardo, Ana Leticia Fornari Caprara
E-mail: jamirrissardo@gmail.com
ABSTRACT
Alpha-synuclein has been associated with neurodegeneration, especially in Parkinson’s disease (PD). This study aimed to review clinical, biochemical, and neuroimaging markers and management of prodromal synucleinopathies. The prodromal state of synucleinopathies can be better understood with PD pathophysiology, and it can be separated into premotor and pre-diagnostic phases. The incidence of PD in patients with prodromal phase symptoms ranges from 0.07 to 14.30, and the most frequently studied pathology is the REM behavioral disorder (RBD). Neuroimaging markers are related to dopamine denervation, brain perfusion changes, gross anatomy changes, and peripheral abnormalities. α-synuclein assays (SAA) in CSF revealed high sensitivity (up to 97%) and high specificity (up to 92%); in the last decade, there was the development of other matrices (blood, skin, and olfactory mucosa) for obtaining quantitative and qualitative α-synuclein. Other biomarkers are neurofilament light chain, DOPA decarboxylase, and multiplexed mass spectrometry assay. Regarding genetic counseling in α-synucleinopathies, it is an important topic in clinical practice to discuss with patients with high-risk individuals and should involve basic principles of autonomy, beneficence, and non-maleficence. Some of the themes that should be reviewed are the involvement of physical activity, diet (including alcohol, coffee, and vitamin supplementation), smoking, sleep, and stress in the pathophysiology of synucleinopathies. The number of trials related to prodromal symptoms is still scarce, and the number of studies evaluating intervention is even lower.
Keywords: alpha-synuclein; synucleinopathies; biofluid; prodromal; RBD; Parkinson’s disease; prevention.
Alpha-synuclein has been associated with neurodegeneration, especially in Parkinson’s disease (PD). This study aimed to review clinical, biochemical, and neuroimaging markers and management of prodromal synucleinopathies. The prodromal state of synucleinopathies can be better understood with PD pathophysiology, and it can be separated into premotor and pre-diagnostic phases. The incidence of PD in patients with prodromal phase symptoms ranges from 0.07 to 14.30, and the most frequently studied pathology is the REM behavioral disorder (RBD). Neuroimaging markers are related to dopamine denervation, brain perfusion changes, gross anatomy changes, and peripheral abnormalities. α-synuclein assays (SAA) in CSF revealed high sensitivity (up to 97%) and high specificity (up to 92%); in the last decade, there was the development of other matrices (blood, skin, and olfactory mucosa) for obtaining quantitative and qualitative α-synuclein. Other biomarkers are neurofilament light chain, DOPA decarboxylase, and multiplexed mass spectrometry assay. Regarding genetic counseling in α-synucleinopathies, it is an important topic in clinical practice to discuss with patients with high-risk individuals and should involve basic principles of autonomy, beneficence, and non-maleficence. Some of the themes that should be reviewed are the involvement of physical activity, diet (including alcohol, coffee, and vitamin supplementation), smoking, sleep, and stress in the pathophysiology of synucleinopathies. The number of trials related to prodromal symptoms is still scarce, and the number of studies evaluating intervention is even lower.
Keywords: alpha-synuclein; synucleinopathies; biofluid; prodromal; RBD; Parkinson’s disease; prevention.
Citation
Rissardo JP, Caprara ALF. A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies. Clin Pract 2025;15(3):65.
Rissardo JP, Caprara ALF. A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies. Clin Pract 2025;15(3):65.
Figure 1. Stages of Parkinson’s disease with biomarkers. Dopaminergic loss and noradrenergic denervation can be observed. Also, the Braak staging and Lewy body pathology can be linked to the stages.
Figure 2. Movement Disorder Society research criteria for prodromal multiple system atrophy (MSA) and Parkinson’s disease (PD). Abbreviations: DMS, Diagnostic and Statistical Manual of Mental; OH, orthostatic hypotension; PSP, Progressive Supranuclear Palsy; RBD, REM sleep behavior disorder.
Figure 3. Strategic questions of the Parkinson Progression Marker Initiative (PPMI) study.
Figure 4. WHO Exercise recommendation for adults with living disabilities (including PD).
Table 1. Studies about prodromal Parkinson’s disease symptoms.
Table 2. Neuroimaging and prodromal parkinsonian syndromes.
Table 3. α-Synuclein seeding aggregation assays in prodromal populations.
Table 4. Potential matrices biomarkers of α-synucleinopathies.
Table 5. α-Synuclein in L1CAM-enriched extracellular vesicles (L1EVs) in prodromal populations of patients with REM sleep behavior disorder.
Table 6. Lessons learned from Alzheimer’s disease in disclosing amyloid PET results.
Table 7. Mediterranean and MIND diets and Parkinson’s disease risk.
Table 8. Dairy products and Parkinson’s disease risk.
Table 9. Vitamins and Parkinson’s disease risk.
Table 10. Clinical trials with prodromal synucleinopathies registered in the ClinicalTrials.gov Database.
Table 11. Machine learning models for predicting prodromal Parkinson’s disease.