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Therefore, reliable blood-based biomarkers reflecting mitochondrial alterations are needed. Emerging evidence suggests that somatic changes to mitochondrial DNA (mtDNA) may reflect early disease-associated processes relevant to PD conversion and clinical manifestation.<\/jats:p>\n                  <jats:p>In this study, we analysed somatic mtDNA major arc deletions as a measure of mitochondrial genome integrity and evaluated 7S DNA abundance as well as copy number as complementary readouts in whole blood (n = 776) from a large cohort, including idiopathic and genetic PD patients, individuals at risk, PD converters, patients with primary mitochondrial disease and healthy controls. This work was complemented by analyses in CSF samples (n = 72). Finally, mtDNA measures were integrated with genetic, protein and clinical data, including mitochondrial polygenic risk scores, \u03b1-synuclein seeding assays and serum neurofilament light chain levels.<\/jats:p>\n                  <jats:p>In blood, the strongest effects occurred in PINK1\/PRKN-PD (deletions: P &amp;lt; 0.0001; 7S DNA: P &amp;lt; 0.0001) and early-onset idiopathic PD (7S DNA: P = 0.0009\u20130.0030). Individuals with prodromal signs conferring a high risk for PD also showed increased mtDNA deletions (P = 0.0045) and reduced 7S DNA (P = 0.0046). In PD converters, these alterations were detectable prior to clinical diagnosis (deletions: P = 0.0024; 7S DNA: P = 0.0091). In CSF-derived extracellular vesicles, we observed an age-associated increase in mtDNA copy number in healthy controls (R2 = 0.121, P = 0.035) that was absent in idiopathic PD (R2 = 0.014, P = 0.548).<\/jats:p>\n                  <jats:p>Across all patients with PD, those with the highest mtDNA deletion burden and lowest 7S DNA exhibited a higher risk of developing cognitive impairment and depression, while also showing a longer time to postural instability (deletions: P = 0.0187; 7S DNA: P = 0.0281).<\/jats:p>\n                  <jats:p>Integration of mtDNA readouts, mitochondrial polygenic risk scores, \u03b1-synuclein seeding and serum neurofilament light chain levels revealed complementary contributions to biological heterogeneity in PD, with receiver operating characteristic analyses showing moderate group-level discrimination using mtDNA measures alone [area under the curve (AUC) = 0.66] and substantially improved discrimination when combined with \u03b1-synuclein and neurodegeneration markers (AUC up to 0.96). \u03b1-Synuclein seeding activity was associated with later age at onset, whereas mtDNA deletion burden showed an inverse association, indicating that these biomarkers capture distinct biological dimensions of PD.<\/jats:p>\n                  <jats:p>MtDNA damage markers, particularly deletion burden, capture mitochondrial dysfunction arising from both genetic and environmental influences and are detectable across early clinical stages of PD. While not serving as stand-alone diagnostic biomarkers, mtDNA measures provide complementary biological information within a multimodal framework and may support patient stratification based on mitochondrial involvement using a minimally invasive approach.<\/jats:p>","DOI":"10.1093\/brain\/awag135","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T11:43:17Z","timestamp":1776253397000},"source":"Crossref","is-referenced-by-count":8,"title":["Blood mtDNA markers of mitochondrial subtype and early-onset Parkinson\u2019s disease biology"],"prefix":"10.1093","author":[{"given":"Anne","family":"Gr\u00fcnewald","sequence":"first","affiliation":[{"name":"Luxembourg Centre for Systems Biology (LCSB), University of Luxembourg , Esch-sur-Alzette 4362 ,","place":["Luxembourg"]},{"name":"Institute of Neurogenetics, University of L\u00fcbeck , L\u00fcbeck 23538 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Knab","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Centre for Neurology, University Clinic T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zied","family":"Landoulsi","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biology (LCSB), University of Luxembourg , Esch-sur-Alzette 4362 ,","place":["Luxembourg"]},{"name":"Transversal Translational Medicine, Luxembourg Institute of Health , Esch-sur-Alzette 88270 ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Ghelfi","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biology (LCSB), University of Luxembourg , Esch-sur-Alzette 4362 ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soraya","family":"Hezzaz","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biology (LCSB), University of Luxembourg , Esch-sur-Alzette 4362 ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Delcambre","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biology (LCSB), University of Luxembourg , Esch-sur-Alzette 4362 ,","place":["Luxembourg"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Zarani","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radu-Gabriel","family":"Copie","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"R\u00f6ben","sequence":"additional","affiliation":[{"name":"Centre for Neurology, University Clinic T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karan","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen , T\u00fcbingen 72076 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,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"S\u00fcnkel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Hospital T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]},{"name":"Partner Site T\u00fcbingen, German Center for Mental Health (DZPG) , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Schulte","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen , T\u00fcbingen 72076 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Kathrin","family":"Hauser","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen , T\u00fcbingen 72076 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