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Qi R, Sammler E, Gonzalez-Hunt CP, Barraza I, Pena N, Rouanet JP, Naaldijk Y, Goodson S, Fuzzati M, Blandini F, Erickson KI, Weinstein AM, Lutz MW, Kwok JB, Halliday GM, Dzamko N, Padmanabhan S, Alcalay RN, Waters C, Hogarth P, Simuni T, Smith D, Marras C, Tonelli F, Alessi DR, West AB, Shiva S, Hilfiker S, Sanders LH. A blood-based marker of mitochondrial DNA damage in Parkinson's disease. Sci Transl Med. 2023 Aug 30;15(711):eabo1557. PubMed.
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University of California, San Francisco
This is an interesting set of papers. Qi et al. extends these authors’ prior work shedding light on the pathobiology of PD, particularly carriers of pathogenic LRKK2 variants. A blood-based biomarker is critically needed for synucleinopathies, as current modalities involve either procedures, e.g. LP for CSF (SynTap), skin biopsy (SynOne), or expensive imaging (DaT scan). The basic science in this paper appears unimpeachable, and the validation efforts are intriguing.
I would like to see the results independently replicated in larger cohorts that also include other synucleinopathies and atypical presentations such as DLB, MSA, PSP, and CBS. I particularly appreciated the inclusion of AD patients because I wondered how specific this mitochondrial lesion assay is for PD. Regardless, it looks like it provides justification for a trial of mitochondrial agents in prodromal LRRK2 mutation carriers, and the assay itself might be useful to show on-target pathway effects in trials of LRRK2 inhibitors.
Pereira et al. offer a nice validation effort of a biomarker of dopaminergic dysfunction, essentially a fluid biomarker version of a DaT scan (though the plasma results were not as encouraging as CSF). It would be interesting to see how it compares to DaT. Pereira et al. make innovative use of CSF SAA assay to define prodromal LBD.
Campo et al. represents a good proteomic discovery and biomarker validation study. DLB has poor diagnostic accuracy, but this is a known limitation. I appreciate the autopsy validation and also the subgroup analyses with LBD-specific clinical features (e.g., REM).
DLB versus CON is a great comparison, as is inclusion of three PD cohorts. Alas, I’m not sure of the need for a DLB versus AD comparison of diagnostic performance—it makes sense in the discovery to increase specificity of findings but great CSF biomarkers are already available to detect AD so the clinical use is less clear. I would be interested to see the ability to detect LBD co-pathology in AD.
Though the authors focus on a biomarker panel, based on my read of Figure 2c, it appears DDC is the primary driver of difference between DLB and controls. In Fig 5, the AUC is nominally higher for the panel compared to DDC in a few cohorts, but is it significant? Just like in the other study, I’d want to see this replicated, especially compared to DaT including in atypical PD (PSP/CBS). Somewhat less exciting given it’s another CSF assay for LBD and doesn’t have a head-to-head with SAA, but overall very impressive.
View all comments by Lawren VandeVredeParacelsus-Elena-Klinik
This is an exciting time, not only with the robust seed amplification assays showing high sensitivities and specificities in cerebrospinal fluid of neuronal synuclein disorders, but also with emerging blood biomarkers.
DDC indeed has been identified before as a marker, e.g. in the PPMI cohort study. It was thought to be due to a medication effect, but Pereira et al. now show increased values in preclinical LBD, as well, which is interesting. It could well be a compensatory effect before the motor/cognitive disease develops. This is encouraging, as we urgently need biomarkers for identifying candidates for clinical trials in these very early stages of the disease. And we need blood-based biomarkers so we no longer have to rely on cerebrospinal fluid for large population-based screens in the future.
Considering that PD may start in the periphery, there must be a biomarker pattern in peripheral blood that is detectable with newer methods, including mass spectrometry or more sensitive immunoassays.
The mtDNA paper is also a path forward toward a blood panel to identify subjects at risk if developing motor/cognitive disease. It could be used in upcoming clinical trials, with the ultimate goal of preventing the disease.
View all comments by Brit MollenhauerUniversity of California, San Diego
Protein biomarkers for Parkinson’s disease and DLB have been sought extensively, with far fewer hits than in AD. Recent efforts using the O-link multiplex immune-PCR assay system for discovery have yielded interesting results. In a large, multicenter CSF study, the most significantly increased protein in DLB and PD was aromatic amino acid decarboxylase, aka dopa decarboxylase or DDC, which distinguished DLB from AD (Del Campo et al., 2023). Another study noted a similar increase in DDC and a correlation with treatment of PD, which often includes a DDC inhibitor (Paslawski et al., 2023).
The exciting study by Pereira et al. expands on these efforts by using the Swedish BioFINDER cohort, in which CSF and plasma are available and CSF samples were analyzed for α-synuclein seeding via RT-QuIC. They found that DDC was increased in SAA+ cases, including DLB, PD, and cases of preclinical PD, i.e., the changes occurred early in the course of disease. Changes were present whether patients were taking L-dopa/carbidopa or not. CSF levels also were increased in patients with atypical Parkinsonism, including MSA, PSP and CBS (unlike Paslawski et al.), but not in AD. In plasma, levels of DDC were also increased in SAA+ DLB in a separate cohort. The power of having concomitant SAA+ data allowed Pereira et al. to identify CSF DDC as a strong marker of PD and DLB, but the findings of an increase in atypical PSP suggests that DDC is a "damage" marker related to dopaminergic and possibly other aminergic nerves.
The ability to detect increase DDC in plasma raises the possibility of early screening and detection, and potentially of differential diagnosis of PD versus atypical Parkinsonism if CSF is also obtained for SAA.
Replicating these findings and developing a different assay for DDC will be important steps in translation. Staging systems for PD are being proposed, e.g. Neuronal Synuclein Disorder, which includes DaTscan as a marker of dopaminergic neurodegeneration. It will be interesting to see how CSF or plasma DDC might fit into those proposed schemes.
A different approach to PD biomarkers was taken by Qi et al., who adapted PCR to amplify mitochondrial DNA in peripheral leukocyte pellets. The elegant concept is that if mitoDNA damage is present, amplification will be less efficient. This strategy gets around many of the difficulties of analyzing mitochondrial function, and allowed frozen cell pellets to be studied. Qi et al. found that mitochondrial damage was present in cells from patients with idiopathic PD and LRKK2 mutation carriers, with very good sensitivity and specificity in discovery and replication cohorts. The test was semiquantitative, and further iterations to develop a quantitative test raise the possibility of identifying patients with greater or lesser degrees of mitochondrial damage. This could allow patient selection for personalized approaches to treatment.
Combining mitochondrial biomarker analyses with biomarkers such as SAA and DDC may help to further characterize heterogeneity of disease mechanisms in PD.
References:
Del Campo M, Vermunt L, Peeters CF, Sieben A, Hok-A-Hin YS, Lleó A, Alcolea D, van Nee M, Engelborghs S, van Alphen JL, Arezoumandan S, Chen-Plotkin A, Irwin DJ, van der Flier WM, Lemstra AW, Teunissen CE. CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease. Nat Commun. 2023 Sep 13;14(1):5635. PubMed.
Paslawski W, Khosousi S, Hertz E, Markaki I, Boxer A, Svenningsson P. Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson's disease. Transl Neurodegener. 2023 Sep 4;12(1):42. PubMed.
View all comments by Douglas GalaskoUniversity of Pennsylvania, Veterans Affairs Medical Center
Two recent publications have identified novel biomarkers for PD based on pathways that have long been known to be associated with its pathogenesis (Qi et al., 2023). Interestingly, these biomarkers also reflect changes in blood that are concurrently reported in the central nervous system (CNS).
Pereira et al. utilize an unbiased proteomics approach using Olink technology to identify elevation of dopa decarboxylase in individuals with PD and atypical parkinsonism in the Swedish BIOFINDER study (Cui et al., 2022; The Swedish BioFINDER study. Accessed September 19, 2023). DDC is highly relevant because it is the enzyme that converts levodopa, the diagnosis-defining PD medication, to dopamine, the neurotransmitter whose levels are reduced in the CNS due to neuronal cell death in the midbrain of individuals with PD. With high reliability, CSF levels of DDC differentiate healthy controls from individuals with PD or atypical parkinsonism.
DDC CSF levels may also be a potential prodromal biomarker, as it reliably differentiated individuals without PD who were positive for a novel α-synuclein biomarker, the seed aggregation assay (SAA). Moreover, plasma elevation in DDC also demonstrated similar ability to discriminate individuals with parkinsonism from healthy controls, which again reflects the systemic nature of PD.
The directionality of this effect, whether CNS to periphery or vice versa, requires further investigation. The result that DDC levels do not differentiate PD from atypical parkinsonism suggest that this biomarker may reflect dopaminergic dysfunction rather than PD-specific pathology.
Limitations of this work include lack of validation with protein detection methods besides Olink, lack of use of a non-parkinsonism neurologic disease group, and use of a relatively genetically and ethnically homogenous population. Since this biomarker does not differentiate PD from other forms of parkinsonism, DDC could be developed for use in a similar manner to how DAT scans are used or for use in individuals who have barriers to imaging.
Qi et al. developed a novel method to measure mitochondrial DNA damage in a high-throughput method, termed mito DNADX (Qi et al., 2023). Mitochondrial dysfunction is a well-known phenomenon in PD; it has been demonstrated in selective brain regions as well as peripheral blood cells (Legati et al., 2023). Outside of assessing its role as a biomarker, the development and validation of a quantitative, sensitive, and reproducible method to assess mitochondrial DNA quality is impressive in itself.
This study validates that mitochondrial DNA damage in peripheral blood mononuclear cells can be used as a biomarker to reliably differentiate individuals with PD from healthy controls (AUC = 0.8-1.0) in multiple cohorts. Notably, this difference was seen in individuals with PD regardless of whether they carry the known G2019S risk mutation in LRRK2 and was also seen in LRRK2 mutation carriers without PD. Despite use of a LRRK2 inhibitor improving mitochondrial DNA quality in immortalized lymphocytes from individuals with PD, there were no identified differences in phosphorylation of known LRRK2 substrates.
Even if identified mitochondrial DNA changes are not specific to LRRK2, this manuscript certainly provides a new peripheral biomarker for in vivo mitochondrial damage in PD (and likely other disorders). Whether this biomarker can be used in prodromal populations, and how it relates to SAA, was not definitively examined in this study. Furthermore, while mitochondrial DNA changes were not seen in AD, the ability to differentiate PD from atypical parkinsonism was not tested. The sensitivity of measured mitochondrial DNA quality to sample processing and storage, as well as the relatively highly technical nature of the mito DNADX assay, are significant roadblocks for development into a readily accessible clinical assay.
Both these biomarkers will require further validation in other cohorts on a larger scale to determine feasibility of use in a clinical setting. Regardless, these findings certainly raise mechanistic questions in PD pathogenesis, particularly with respect to the interplay of central and peripheral mechanisms in dopamine metabolism and mitochondrial function. These studies increase our hope that reproducible blood-based biomarkers for PD and other neurodegenerative disorders are on the horizon.
References:
Qi R, Sammler E, Gonzalez-Hunt CP, Barraza I, Pena N, Rouanet JP, Naaldijk Y, Goodson S, Fuzzati M, Blandini F, Erickson KI, Weinstein AM, Lutz MW, Kwok JB, Halliday GM, Dzamko N, Padmanabhan S, Alcalay RN, Waters C, Hogarth P, Simuni T, Smith D, Marras C, Tonelli F, Alessi DR, West AB, Shiva S, Hilfiker S, Sanders LH. A blood-based marker of mitochondrial DNA damage in Parkinson's disease. Sci Transl Med. 2023 Aug 30;15(711):eabo1557. PubMed.
Cui M, Cheng C, Zhang L. High-throughput proteomics: a methodological mini-review. Lab Invest. 2022 Nov;102(11):1170-1181. Epub 2022 Aug 3 PubMed.
Legati A, Ghezzi D. Parkinson's Disease, Parkinsonisms, and Mitochondria: the Role of Nuclear and Mitochondrial DNA. Curr Neurol Neurosci Rep. 2023 Apr;23(4):131-147. Epub 2023 Mar 7 PubMed.
View all comments by George KannarkatBarcelonaBeta Brain Research Center
VU University Medical Center
It is amazing to see three papers with complementary information indicating that CSF Dopa decarboxylase (DDC) is a novel biomarker that might be useful to identify disorders characterized by dopamine deficiency in their very early stages. More studies are probably needed to validate plasma findings and its potential implementation, taking medication status into consideration, since treatment can increase the activity of DDC in the serum (van Rumund et al., 2021). We expect that the new immunoassay for DDC that has been developed and validated by the Teunissen lab will help to answer remaining questions and advance the implementation of this biofluid marker.
References:
van Rumund A, Pavelka L, Esselink RA, Geurtz BP, Wevers RA, Mollenhauer B, Krüger R, Bloem BR, Verbeek MM. Peripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase. NPJ Parkinsons Dis. 2021 Mar 19;7(1):29. PubMed.
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