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Here, single\u2010molecule fluorescence microscopy is applied to post\u2010mortem brain extracts to quantitatively characterize aggregates containing TDP\u201043 at the individual particle level. The resulting aggregate fingerprints, consisting of morphological and compositional profiles, are sufficient to distinguish MND donors from neurologically normal controls and further discriminate between clinically distinct MND subgroups. Comparative proteomic analysis confirms and extends these findings, revealing convergent and complementary molecular signatures. These results demonstrate, for the first time, that single\u2010molecule aggregate profiling can stratify MND cases using patient\u2010derived tissues, paving the way for the development of sensitive minimally invasive diagnostics and mechanistically informed disease monitoring tools.<\/jats:p>","DOI":"10.1002\/advs.202505484","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T08:54:50Z","timestamp":1758617690000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Quantitative Profiling of Nanoscopic Protein Aggregates Reveals Specific Fingerprint of TDP\u201043\u2010Positive Assemblies in Motor Neuron Disease"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5345-8360","authenticated-orcid":false,"given":"Dezerae","family":"Cox","sequence":"first","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge Cambridge CB2 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