Abstract
Several advances in fluid and tissue-based biomarkers for use in Parkinson’s disease (PD) and other synucleinopathies have been made in the last several years. While work continues on species of alpha-synuclein (aSyn) and other proteins which can be measured from spinal fluid and plasma samples, immunohistochemistry and immunofluorescence from peripheral tissue biopsies and alpha-synuclein seeding amplification assays (aSyn-SAA: including real-time quaking induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA)) now offer a crucial advancement in their ability to identify aSyn species in PD patients in a categorical fashion (i.e., of aSyn + vs aSyn −); to augment clinical diagnosis however, aSyn-specific assays that have quantitative relevance to pathological burden remain an unmet need. Alzheimer’s disease (AD) co-pathology is commonly found postmortem in PD, especially in those who develop dementia, and dementia with Lewy bodies (DLB). Biofluid biomarkers for tau and amyloid beta species can detect AD co-pathology in PD and DLB, which does have relevance for prognosis, but further work is needed to understand the interplay of aSyn tau, amyloid beta, and other pathological changes to generate comprehensive biomarker profiles for patients in a manner translatable to clinical trial design and individualized therapies.
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Introduction
Parkinson’s disease (PD) is pathologically characterized by inclusions of alpha-synuclein (aSyn) that compose Lewy bodies and Lewy neurites [1]. These inclusions are found in fairly stereotyped patterns that progress from brainstem nuclei, to limbic regions and lastly to neocortical areas [2]. At this time, a definitive diagnosis of PD can only be rendered after neuropathological assessments are performed, with levels of clinically established and clinically probable certainties being attainable during life [3]. Clinical diagnostic accuracy for PD has varied among studies over the last several decades and ranges from 50% to greater than 90% [4,5,6,7,8,9]. Factors that tend to relate to lower diagnostic accuracy are an older age at onset and a shorter degree of disease duration at time of assessment or a lower amount of clinical follow-up time [4, 9]. Thus, the diagnostic standard remains postmortem neuropathological diagnosis until a method to reliably detect aSyn in vivo is developed. Most biomarker studies rely on patients who have been clinically diagnosed with PD who do not go on to have autopsy validation. While this creates some uncertainty regarding the accuracy of diagnosis and this may be problematic in develo** novel biomarkers, the current clinical criteria for PD are felt to have high specificity [9]. Furthermore, because there is no currently accepted quantitative aSyn biomarker, studies of these candidate biomarkers are compared to clinical metrics like motor severity or cognition which can be influenced by many factors and are fundamentally indirect measures of disease activity. While aSyn-specific biomarkers remain a critical unmet need for the field, they are especially needed for application in early disease when clinical diagnostic accuracy is at its lowest and also when disease-modifying interventions may have the greater utility.
Over the last decade, there has been considerable advancements in fluid and tissue-based assays in PD. Early work focused on CSF aSyn species including total aSyn, phosphorylated aSyn, and oligomeric aSyn species using immunoassays [10,11,12]. Plasma aSyn assays are under development as well [13, 14]. More recently, aSyn deposits have been noted in a variety of peripheral tissues of PD patients, including skin, submandibular glad, colon, and nasal mucosa and these observations have led to the development of methods to detect these deposits through immunohistochemistry or immunofluorescence methods [15, 16]. Additionally, the observations that pathologically misfolded aSyn species may induce sequential templating of normal monomeric aSyn in a prion-like fashion, has led to the development of aSyn-seeding amplification assays (aSyn-SAAs), which use these properties to identify patients who harbor pathogenic aSyn seeds in spinal fluid and peripheral tissues [17,18,19,20,21]. While some of these assays are still under development in the research setting, others are reaching levels of standardization and interlaboratory variability rapidly approaching possible acceptable levels for clinical use.
aSyn aggregates in Lewy bodies and Lewy neurites are the primary neuropathology and gold-standard for diagnosis of PD and their burden is roughly related to severity of disease and certain disease features like dementia [22,23,24,25,26]. However, multiple biological factors, even sex, can influence phenotypic expression of pathological burden [27, 28]. Additionally, it is exceedingly common in autopsy studies that other co-pathologies aside from aSyn are found; approximately 35–50% of PD patients with dementia with have moderate to high levels of AD neuropathologic change [29,30,31,200]. Still, understanding the interplay of aSyn, Aβ, and tau pathology in PD and DLB is of interest as it will inform the interpretation of AD biomarkers in these populations as these assays become more widely available and stratifying clinical trials by the presence or absence of AD co-pathology may be of interest [201].
PD and DLB patients tend to have lower levels of CSF Aβ42 and tau species than normal controls in groupwise comparisons early in the disease [45, 46, 49, 73, 202,203,204]. In PD, lower levels of CSF Aβ42 is related to worse cognition cross-sectionally, longitudinally, and is related to higher likelihood of AD co-pathology at death [44, 46, 47, 64, 73, 202, 204, 205]. Interestingly, one study showed an increase in CSF Aβ42 in PD patients with freezing of gait compared to PD patients who did not [206]; thus, clinical heterogeneity of PD may influence biomarker interpretation as well. While total and p-tau 181 is on average lower than controls in early PD, levels may increase later in the disease in some patients which is also associated with a greater likelihood of dementia [207,208,209,210]. While optimal cut-offs for these Aβ42, t-tau, and p-tau 181 and their ratios have been well established in Alzheimer’s disease, it is not clear if the same cutoffs apply in PD and other Lewy body disorders [211, 212]. Indeed, in rare autopsy-confirmed work, there is data to suggest CSF Aβ42 may be associated with increasing aSyn pathology independent of plaque burden in LBD [47].
More recently, plasma assays (Aβ1-42, t-tau, p-tau 181, p-tau 217, and p-tau 231) are being developed for use in AD but are already being studied in PD as well [213,214,215,216]. Plasma Aβ42 may be related to more severe gait impairment and severity of akinetic rigid symptoms [217, 218]. Plasma p-tau 181 and p-tau 217 levels correlate with degree of tau PET and Aβ PET status [219]. In studies of DLB, where tau co-pathology is more likely, plasma p-tau 181 and 231 have been associated with faster cognitive declines [219, 220]. Higher levels of plasma p-tau 181 are reported in PD patients when compared to healthy controls and these levels correlate with plasma aSyn markers [221]. However, in some studies plasma p-tau 181 has not clearly been linked to cognitive decline in PD and plasma t-tau and neurofilament light chain measurements have had stronger correlations with cognitive dysfunction [95, 105, 222]. In DLB, in particular, where rates of AD co-pathology are often quite high, stratification by the presence of these AD biomarkers may prove especially important for clinical trial enrollment of more biologically homogenous patients or those who may benefit from combination therapies [201].
Conclusion
aSyn-specific biomarkers have long been an unmet need in the field of neurodegenerative medicine. While the search for biomarkers with strong associations with disease pathology continues, several new fluid and tissue based biomarkers are being developed which offer the ability to detect aSyn species in patients with PD, DLB, and also in prodromal states, which is critical for therapeutic trials targeting aSyn mechanisms. CSF aSyn and plasma aSyn species detected by current assays may be limited but further development with newer second-generation immunoassays or other methods of detection may provide additional opportunities for biomarker development. Please see Table 3 for a summary of CSF (Table 1), plasma (Table 2), and aSyn-SAA and immunofluorescence (Table 4) biomarker data findings in PD. aSyn immunofluorescence from skin samples and aSyn-SAA assays both from CSF and peripheral tissues appear promising and will likely be of imminent use in clinic and research settings which will likely provide accurate methods of categorically assessing for the presence of aSyn deposits and aSyn seeds [138]. More work will be needed to determine of more labor-intensive methods like calculating SD50 will provide quantitative readouts of aSyn seeding that have relevance for disease activity, but initial studies suggest some significant correlations with disease duration and pathological burden. Most studies of aSyn-SAA to date have been done in clinically defined cohorts of PD and other synucleinopathies, some with autopsy validation [164, 167, 168]. However, given the sensitivity of some of these assays in detecting aSyn seeds or clinicians may have to grapple shortly interpretation of a positive result in patients without a defined synucleinopathy syndrome, and it is not entirely clear if these patients are universally destined to phenoconvert. The integration of other biomarkers like hyposmia, polysomnograms for RBD, and DAT scans will likely further be of use to stratify those aSyn positive cases who are more likely to develop a parkinsonian syndrome. When combined with CSF or plasma biomarkers for AD, a more comprehensive picture of both primary and commonly occurring AD co-pathologies can be constructed for PD patients. These assays will likely prove useful in augmenting enrollment of homogenous populations into clinical trials. Focuses for future work to bring these skin immunofluorescence and aSyn-SAAs to clinical use include assay standardization and research in autopsy-confirmed cohorts to clarify the complex relationships between pathology in the brain and those detected from peripheral tissues and biofluids. aSyn assays that have quantitative value for disease activity remain a major unmet need, but the exciting development of these assays will allow for clinical assessments to be augmented by aSyn-specific biomarkers in a manner which has not been previously available for living patients.
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Coughlin, D.G., Irwin, D.J. Fluid and Biopsy Based Biomarkers in Parkinson’s Disease. Neurotherapeutics 20, 932–954 (2023). https://doi.org/10.1007/s13311-023-01379-z
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DOI: https://doi.org/10.1007/s13311-023-01379-z