{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:54:47Z","timestamp":1785840887975,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Open Medicine Foundation Canada"},{"name":"Montreal TransMedTech Institute"},{"id":[{"id":"https:\/\/ror.org\/0595rqt76","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Patient-Led Research Collaborative Funds"},{"id":[{"id":"https:\/\/ror.org\/04f19vj70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Long COVID (LC) is a heterogeneous post-infectious syndrome characterized by persistent symptoms, yet the biological basis underlying its interindividual variability remains poorly understood. Given the clinical overlap between LC and myalgic encephalomyelitis (ME), and prior demonstration that haptoglobin (Hp) phenotypes modulate symptom severity in ME, we investigated whether Hp phenotypes similarly stratify post-exertional cognitive dysfunction in LC. In this longitudinal observational study, 44 individuals with LC and 20 short-course COVID controls, who recovered rapidly from SARS-CoV-2 infection without persistent symptoms or sequelae, underwent Hp phenotyping alongside metabolomic and physiological profiling before and after a standardized 90 min passive post-exertional challenge. Hp phenotypes identified clinically distinct LC subgroups. Compared with Hp1-1 individuals, Hp2 allele carriers exhibited greater fatigue, poorer physical function, and more severe post-exertional symptoms. Immediately following the challenge, Hp2-2 participants with LC showed significant cognitive decline, whereas Hp1-1 individuals demonstrated cognitive resilience and more favorable longitudinal cognitive trajectories. This differential susceptibility was accompanied by higher post-exertional cerebral fractional tissue oxygen extraction in the right hemisphere in Hp1-1 individuals and by distinct metabolic signatures, with Hp2 allele carriers exhibiting lower post-exertional plasma concentrations of citric acid, isethionate, and glucosamine. Lower metabolite levels were associated with poorer cognitive performance. These findings support Hp phenotypes as promising candidate biomarkers for biological stratification in Long COVID, pending validation in larger independent cohorts.<\/jats:p>","DOI":"10.3390\/ijms27157000","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:38:08Z","timestamp":1785839888000},"page":"7000","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Haptoglobin Phenotypes Stratify Post-Exertional Cognitive Dysfunction Associated with Altered Cerebral Oxygenation and Metabolic Signatures in Long COVID"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5549-6603","authenticated-orcid":false,"given":"Atefeh","family":"Moezzi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"},{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3577-3551","authenticated-orcid":false,"given":"Wesam","family":"Elremaly","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Leveau","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"},{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5950-8261","authenticated-orcid":false,"given":"Anita","family":"Franco","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5512-6047","authenticated-orcid":false,"given":"Oleg","family":"Nepotchatykh","sequence":"additional","affiliation":[{"name":"PO-Laboratories, Montreal, QC H4T 2A3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-5618","authenticated-orcid":false,"given":"Christopher W.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1144-6174","authenticated-orcid":false,"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"},{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Stomatology, Faculty of Dentistry, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, April 13). 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