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The relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegenerative effects is not fully understood. This study investigates neurodegeneration patterns across CSF Alzheimer's disease biomarker groups, the association of brain volumes with CSF amyloid and tau status and sex differences in these relationships in a clinical neurology sample. MRI and CSF Alzheimer's disease biomarkers data were analysed in 306 patients of the Mass General Brigham healthcare system aged 50+ (mean age = 68.4 ± 8.8 years; 43.1% female), who had lumbar punctures within 1 year of clinical MRI scans. We first analysed neurodegeneration patterns across four biomarker groups: 60 controls (A-T- amyloid negative, tau negative, cognitively unimpaired), 25 A+T- (amyloid positive, tau negative), 121 A+T+ (amyloid positive, tau positive) and 100 other dementia (A-T- amyloid negative, tau negative, cognitively impaired). Second, we examined volumetric associations with amyloid (amyloid positive, tau negative versus control) and tau in the presence of amyloid (amyloid positive, tau positive versus amyloid positive, tau negative) across 52 brain areas. Third, we examined sex differences in these relationships. Finally, we validated core analyses across three independent datasets - NACC (National Alzheimer's Coordinating Center), ADNI (Alzheimer's Disease Neuroimaging Initiative) and EPAD (European Prevention of Alzheimer's Dementia) - totalling 3137 participants, and performed meta-analyses to obtain more robust estimates. We observed distinct neurodegeneration patterns across biomarker groups, with disrupted connectivity (brain volume covariance networks) in amyloid positive and other dementia groups, while amyloid and tau negative, cognitively unimpaired controls exhibited the most connected network. Amyloid was associated with subcortical, cerebellar and brainstem atrophy, with consistent association observations in the thalamus and amygdala across all four datasets. Tau in the presence of amyloid demonstrated general brain shrinkage through enlargement of extracerebral CSF, alongside unexpected ventricle shrinkages. Sex-based analyses revealed that A+T+ (amyloid positive, tau positive) had lower sex differences in connectivity patterns compared with other groups. Sex differences were also noted in amyloid-related ventricular volume changes. This study reveals how amyloid and tau affect brain connectivity and volume across sex and CSF biomarker groups, emphasizing global brain changes and sex differences. By leveraging automated pipelines and advanced MRI and biomarker analyses, we extracted meaningful and replicable findings from heterogeneous clinical samples from real-world data. The meta-analyses across four datasets enhance the generalizability of our results.
Brain MRI signatures across sex and CSF Alzheimer's disease biomarkers / Cheng, Y.; He, Y.; Gopinath, K.; Billot, B.; Iglesias, J. E.; Wu, C. -Y.; Dodge, H.; Wills, A. -M.; Carlyle, B.; Kivisakk, P.; Hyman, B. T.; Arnold, S. E.; Das, S.; Tennigkeit, F.; Pfeifer, A.; Vincenzetti, C.; Monin, F.; Maitra, G.; O'Sullivan, J.; Teligladas, A.; Diaz, A.; Bintener, C.; Birck, C.; Gove, D.; Georges, J.; Ellis, K.; Peulen, S.; Danasi, E.; Vlachos, G.; Scarmeas, N.; Mencik, A.; Ng, C.; Picard, H. J.; Ericson, M.; Gaunt, M.; Pourbaix, N.; Lenz, R.; Eyraud, R.; Mcgarrity, R.; Chauvet, V.; Allouche, A. -E.; Le Balanger, B.; Dubois, B.; Benmansour, E.; Nyasse, F.; Filali, H.; Youssef, I.; Ameil, L.; Dubois, M.; Lajaail, N.; Nyasse, N.; Younsi, N.; Talla, P. F.; Benadjaoud, S.; Lehericy, S.; Beshelemu, T. A.; Alonso, B. G.; Molina, B.; Sherriff, I.; Pesini, P.; Tirado, P.; Perez, V.; Mcneill, A.; Gibson, A.; Fox, A.; Overduin, B.; Lee, C.; Allan, D.; Taylor, D.; Mcdonald, E.; Peaker, H.; O'Hanlon, K.; Thornton, K.; Harper, L.; Brankin, P.; Bryce, R.; Barnes, R.; Callado, A. B.; Radoi, A.; Beteta, A.; Navarro, A.; Blasco, B.; Herrero, C.; Minguillon, C.; Arenaza, E.; Nebot, E.; Huesa, G.; Blasco, G. S.; Oliver, G.; Benavides, G. S.; Operto, G.; Knezevic, I.; Cami, J.; Molinuevo, J. L.; Gispert, J. D.; Pereda, J.; Fauria, K.; Tenas, L.; Shekari, M.; Buongiorno, M. T.; Escriva, M.; Mila, M.; Santos, M.; Montserrat, M.; Alegret, M.; Cadevall, N.; Carranza, N.; Rivera, O. G.; Marne, P.; Petrone, P.; Cacciaglia, R.; Menezes-Cabral, S.; Wendelberger, B.; Fitzgerald, M.; Quintana, M.; Berry, S.; Andersson, S.; Berry, T.; Bolan, A.; Sperling, B.; Walsh, D.; Ratti, E.; Smyth, E.; Lawson, F.; Tsvang, I.; Sevigny, J.; Brandao, J. P.; Ogorman, J.; Unternarer, M.; Jankovich, M. V.; Pan, M.; Mitelman, O.; Liston-Kraft, P.; Von Rosenstiel, P.; Buddhaeberlein, S.; Knox, S.; Olsson, T.; Goerke, B.; Debove, C.; Harder, D.; Schwall-Rudolph, D.; Plaue, G.; Wunderlich, G.; Ghazvini, J.; Meyer-Kleinmann, J.; Huber, K.; Hattemer, L.; Gordon, M.; Eckes, M.; Potter, M.; Nusser, M.; Garcia, M.; Drake, P.; Mcginty, P.; Goeggel, R.; Jones, R.; Rau, S.; Scanlon, S.; Pollentier, S.; Sommer, S.; Flaherty, S.; Dieminger, W.; Savina, D.; Hanseeuw, B.; Bortolotti, M.; Demonet, J. -F.; Warszawa, A. A. A.; Biel-Czarnecka, M.; Czarnecki, M.; Incesoy, E. I.; Menne, F.; Lindner, K.; Peters, O.; Leroy, M.; Pasquier, F.; Laforce, M.; Gabelle, A.; Grasselli, C.; Leger, C.; Gillet, A.; Cadiet, C.; Boutoleau, C.; Guiguen, M.; Chaigneau, R.; Muraz, R.; Melcion, S.; Charriau, T.; Dinthilac, B.; Rieunier, B.; Vellas, B.; Coulange, C.; Pennetier, D.; Carrie, I.; Lapeyre, J. D.; Saint-Aubert, L.; Del Campo, N.; Batonneau, N.; Ousset, P. J.; Andrieu, S. S. A.; Mourgues, S.; Montoya, G.; Riverol, M.; Blasco, V.; Gerrish, A.; Majouni, E.; Sheppard, F.; Menzies, G.; Oldham, H.; Williams, J.; Sexton, K.; Sims, R.; Jones, S.; Head, S.; Bowen, T.; Cushion, T.; Scott-Price, V.; Chetelat, G.; Saver, A.; Albala, B.; Fry, D.; Potter, E.; Luthman, J.; Concepcion, J.; Bandara, L.; Kramer, L.; Rabe, M.; Valeri, M.; Sarwar, N.; Gordon, R.; Dispoto, S.; Kakad, S.; Dhadda, S.; Musku, S.; Braham, S.; Lyons, S.; Devenishmeares, S.; Wessels, A.; Smith, A. G.; Steckel-Hamann, B.; Spears, C.; Holding, D.; Siemers, E.; Bayard, F.; Zimmermann, H.; Embry, J.; Walgren, J. L.; Zimmer, J.; Hutton, M.; Irizarry, M. C.; Smart, T.; De Jong, A.; Van Duijn, C.; Bunnik, E.; Van Der Lei, J.; Tromp, K.; Hoezen, L.; Schermer, M.; Van Dijk, R.; Woerdeman, S.; Perpeet, F.; Wolff, H.; Zimmermann, M.; Hofmann-Apitius, M.; Sood, M.; Rechmann, T.; Pancho, A.; Cuevas, C.; Buendia, M.; Boada, M.; Garcia-Eizaga, A.; Tainta, M.; Martinez-Lage, P.; Saldias, J.; Canada, M.; Newton, B.; Foley, C.; Davies, A.; Mistry, H.; Leroi, I.; Rosenhead, R.; Dune, R.; Norton, R.; Langheinrich, T.; Tort, A.; Bosch, B.; Fernandez, G.; Balasa, M.; Fernandez, A.; Sanchez, J. P.; Lopez, S.; Ferrando, M.; Garcia, R.; Ghastin, A.; Arroyo, R.; Munoz, A.; Barro, A.; Fernandez, F. V.; Ashby, T.; Haber, T.; Ropacki, M.; Cincotti, A.; Gauthier, A.; Nier, A.; Dumonte, C.; Trecanne, F.; Carriere, I.; Geahel, I.; Ritchie, K.; Baquet, M.; Mortamais, M.; Boyer, V.; Satlin, A.; Macdonald, A.; Morton-Morys, A.; Danson, A.; Penny, A.; Cons, B.; Spence, B.; Cooke, B.; Brooker, C.; Vanbelle, C.; West, D.; Gilmour, E.; Parkinson, E.; Ramage, F.; Johnson, G.; Rattenbury, J.; Hall, J.; Chambers, J.; Tracey, J.; Milne, J.; Hughes, L.; Dvorak, M.; Nagle, R.; Beydoun, S.; Scott, S.; Kumar, S.; Haque, Z.; Redolfi, A.; Mega, A.; Altomare, D.; Rolandi, E.; Rampini, M.; Marizzoni, M.; Gipponi, S.; Nicolosi, V.; Saletti, V.; Galluzzi, S.; Wilson, C.; Hill, D.; Rees, E.; Welch, H.; Ababei, I.; Whitrow, J.; Munro, J.; Hall, J.; Woodside, J.; Barnes, K.; Mcleish, K.; Marai, L.; Meijer, M.; Austin, M.; Abaei, M.; Sousa, M.; Lax, M.; Radford, M.; Belov, O.; James, R.; Wolz, R.; Lowther, S.; Gower, A.; Smits, A.; Dierckx, A.; Vannieuwenhuyse, B.; Sage, C.; Cully, C.; Verbruggen, C.; Symnoski, D.; Ayaz, D.; Liu, E.; Crouthamel, E.; Romano, G.; Novak, G.; Sipma, H.; Greenberg, H.; Coste, I.; Schuermans, J.; Novak, J.; Kemp, J.; Beke, J.; Bachner, K.; Haeverans, K.; Wathen, K.; Carrera, L.; Steukers, L.; Cluckers, L.; Wouters, L.; Ford, L.; Truyen, L.; Yieh, L.; Van Dyck, M.; Samtani, M.; De Vulder, M.; Jovanovic, M.; Ehinger, M.; Schmidt, M.; Warzeski, M.; Fogle, M.; Mangini, M.; Etropolski, M.; Manyakov, N.; Van Der Geyten, S.; Ness, S.; Lovestone, S.; Hendrik, S.; Katz, S.; Foy, S.; Martino, T.; Elliott, T.; Tracy, T.; Bosmans, V.; Dragalin, V.; Deneyer, W.; Godinov, Y.; Solomon, A.; Stromberg, A. -M.; Akter, A.; Kull, B.; Mangialasche, F.; Hagman, G.; Waldemar, G.; Johansson, G.; Soininen, H.; Kettley, I.; Risbecker, K.; Aspo, M.; Larksater, M.; Protsiv, M.; Bogdanovic, N.; Chareonto, P.; Sindi, S.; Hasselbalch, S.; Borg, S.; Akenine, U.; Jelic, V.; Kivipelto, M.; Rober, J.; Perneczky, R.; Gronning, B.; Baayen, C.; Moltzen, E. K.; Mengel, H. B.; Bolgan, H.; Thomsen, A. A. A.; Pedersen, J. L.; Windfeld, K.; Hellstrom, L.; Storck, M. S.; Rosted, M.; Hougaard, P.; Weidlich, T. D.; Djuika, C.; Frolich, L.; Trubacz, A.; Weber, C.; Randolph, C.; Hampel, H.; Ewers, M.; Harrison, J.; Donaldson, A.; Cairney, D.; Macfayden, S.; Baird, T.; Mander, A.; Wadeson, A.; Tom, B.; Di Fant, C.; Lingiah, G.; Howlett, J.; Merle, K.; Brown, L.; Davies, R.; Huang, R.; White, S.; Hill, S.; Chekani, F.; Swartz, J.; Reyniers, L.; Khandker, R.; Connelly, T.; Ryan, L.; Coulthard, E.; Selwood, J.; Rosewell, N.; Cousins, R.; Duggan, C.; Mcneill, C.; Brown, D.; Mckay, S.; Lawrie, A.; Darling, E.; Scott, J.; Mcclelland-Brooks, K.; Hudson, J.; Ferguson, K.; Connelly, P.; Ramkumar, P. G.; Stewart, T.; Graf, A.; Stolz, B.; Nussher, D.; Pigeolet, E.; Lestini, G.; Fillon, G.; Paule, I.; Maman, M.; Cheyun, S.; Korte, S.; Madawela, Y.; Kaye, J.; Akel, S.; Porte, B.; Dumurgier, J.; Indart, S.; Slama, Y.; Fayel, A.; Luscan, G.; Hurst, H.; Eshelby, J.; Gameiro, M.; Mirza, M.; Krylova, O.; Drap, O.; Marrone, P.; Schindler, R.; Brault, Y.; Iwaniuk, E.; Lapinska, M.; Maslowska, M.; Dobryniewski, J.; Gold, M.; Maciejowski, M. A. -L. -M.; Rabe, C.; Alibasic, E.; Krause, F.; Hanon, J.; Wright, J.; Srivastava, J.; Simon, M.; Batrla-Utermann, R.; Schmid, S. B.; Wahl, S.; Eichenlaub, U.; Neuhold, V.; Kilimann, I.; Teipel, S.; Peter, C.; Van Houdt, D. S.; Richard, E.; Birahy, J.; Smedinga, M.; Pascale, R.; Bemelmans, S.; Beukers, S.; Van Oijen Samodzielny Publiczny Szpital Kliniczny, W.; Lucka, K.; Rejdak, K.; Stjepanovic-Agovic, A.; Cohen, C.; Mockwitz, C.; Delalonde, F.; Clavier, I.; Dedieu, J. -F.; Mazuranok, L.; Hamdani, N.; Piton, N.; Rocolle, P.; Hahn, R.; Diaz, C.; Callado, E.; Coll, N.; Subirats, N.; Ramasastry, S.; Pla, S.; Fischer, A.; Schwarz, A.; Bowtell, A.; Chiucchiuini, A.; Andersson, H.; Naylor, M.; Khudyakov, P.; Perinpanayagam, R.; Zhong, W.; Feldman, H.; Tara, T.; Grimmer, T.; Brayne, C.; Ash, D.; Chan, D.; Barham, E.; Casy, G.; O'Brien, J.; Wilson, J.; Pilgrim, L.; York, M.; Smailagic, N.; Brenman, N.; Geach, P.; Farmer, P.; Schaeffer, R.; Milne, R.; Atkinson, S.; Findon, S.; Taylor, S.; Badger, S.; Black, S.; Edwards, T.; Clark, W.; Sahin, Z.; Boroojerdi, B.; Greve, B.; Derouane, D.; Marquet, D.; Streffer, J.; Angrosch, K.; Delval, M.; Verplancke, P.; Dresse, S.; Zanigni, S.; Mccabe, S.; Fox, N.; Markiewicz, P.; Kramer, J.; Erlhoff, S.; Schaffer, M.; Waldman, A.; Kennedy, A.; Kodiak, A.; Noble, A.; Anderson, A.; Borthwick, A.; Hall, A.; Bruce, B.; Mcteir, B.; Di Perri, C.; Sudlow, C.; Kippen, C.; Dolan, C.; Ritchie, C.; Hill, D.; Matheson, D.; Young, D.; Souri, E.; Mcmaster, E.; Delpon, E.; Law, E.; Munro, E.; Campbell, F.; Edler, F.; Scott, F.; Terrera, G. M.; Jobse, H.; Milligan, H.; Topiwala, H.; Marriage, H.; Manson, J.; Middleton, J.; Swiderska, J.; Wardlaw, J.; Macconnell, J.; Syson, J.; Edwards, J.; Forsyth, K.; Carruthers, K.; Hervy, K.; Wells, K.; Draper, K.; Doull, L.; Petrie, L.; Niezynski, L.; Hampton, L.; Koutsoventi, L.; Stirland, L.; Bucukoglu, M.; Boughey, M.; Jenkins, N.; Duncan, N.; Fullerton, N.; Mitchell, N.; French, R.; Flory, R.; Buchan, R.; Al Shahi-Salman, R.; Danso, S.; Gregory, S.; Sparks, S.; Saunders, S.; Shepherd, S.; Watermeyer, T.; Macgillivray, T.; Russ, T.; Saunders, T.; Renton, V.; Leslie, V.; Dzerzga, A.; Doelle, B.; Gatzke, C.; Escher, C.; Schneider, D.; Sannemann, L.; Thelen, M.; Schreiner-Kaub, P.; Stockter, S.; Thielking, S.; Mueller, T.; Jessen, F.; Toja, A.; Chipi, E.; Farotti, L.; Parnetti, L.; Lancaster, O.; Brookes, A. J.; Berry, B.; Veal, C.; Thangavelu, D.; Sole, J.; Adams, M.; Maini, M.; Ketcher, N.; Ketcher, N. A.; Ladas, V.; Agogue, A.; Campillo, A.; Schmalz, A.; Auschra, B.; Pirotte, B.; Trombert, C.; Genaro, D.; Canzoneri, E.; Albanese, E.; Vilarino, E.; Frisoni, G. B.; Sturzmann, J.; Mauri, M.; Boccardi, M.; Boillat, M.; Parapini, M. M. P.; Almici, M.; Andryszak, P.; Haller, S.; Stevanovic, T.; Kipps, C.; Jackson, S.; Frick, C.; Zetterberg, H.; Blennow, K.; Petersson, L.; Berglund, M.; Kern, S.; Radford, A.; Venneri, A.; Sidebottom, J.; Easton, P.; Clegg, R.; Kullur, W.; Hartley, T.; Chinner, A.; Markova, A.; Sexton, A.; Jenkins, C.; Mackay, C.; Prescott, C.; Ruvolo, D.; Gheorghe, D.; Murphy, D.; Pope, G.; Cane, G.; Wells, G.; Koychev, I.; Blane, J.; Lawson, J.; Gallacher, J.; Ballaminut, J.; Lowen, J.; Westphal, K.; Shepherd, K.; Mcnamee, K.; Wolters, L.; Ben Yehuda, M.; Morgan, N.; Buckholtz, N.; Haque, N.; Burton, P.; Bauermeister, S.; Hoosdally, S.; Forster, S.; Osborne, T.; Raymont, V.; Van Den Eynde, A.; Engelborghs, S.; Vandenberghe, R.; Schildermans, C.; Wink, A. M.; Van Der Wal, A.; Hazelebach, A.; Leeuwis, A. E.; De Boer, C.; Heeman, F.; Barkhof, F.; Lopes-Alves, I.; Van Leur, J.; Ter Meulen, L.; Vermunt, L.; Lorenzini, L.; Collij, L. E.; Ten Kate, M.; Van Houten, M.; Stellingwerff, M.; Hermans, M.; Telkamp, M.; Prins, N.; Scheltens, P.; Visser, P. J.; Ingala, S.; Van Veen, W.; Mcdonald, M.; Taylor, C.; Morrison, G.; Golemme, M.; Malhotra, P.; Mahalingam, S.; Van Broechhoven, C.; Goeman, J.; Wittebolle, W.. - In: BRAIN COMMUNICATIONS. - ISSN 2632-1297. - 7:3(2025). [10.1093/braincomms/fcaf210]
Brain MRI signatures across sex and CSF Alzheimer's disease biomarkers
The relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegenerative effects is not fully understood. This study investigates neurodegeneration patterns across CSF Alzheimer's disease biomarker groups, the association of brain volumes with CSF amyloid and tau status and sex differences in these relationships in a clinical neurology sample. MRI and CSF Alzheimer's disease biomarkers data were analysed in 306 patients of the Mass General Brigham healthcare system aged 50+ (mean age = 68.4 ± 8.8 years; 43.1% female), who had lumbar punctures within 1 year of clinical MRI scans. We first analysed neurodegeneration patterns across four biomarker groups: 60 controls (A-T- amyloid negative, tau negative, cognitively unimpaired), 25 A+T- (amyloid positive, tau negative), 121 A+T+ (amyloid positive, tau positive) and 100 other dementia (A-T- amyloid negative, tau negative, cognitively impaired). Second, we examined volumetric associations with amyloid (amyloid positive, tau negative versus control) and tau in the presence of amyloid (amyloid positive, tau positive versus amyloid positive, tau negative) across 52 brain areas. Third, we examined sex differences in these relationships. Finally, we validated core analyses across three independent datasets - NACC (National Alzheimer's Coordinating Center), ADNI (Alzheimer's Disease Neuroimaging Initiative) and EPAD (European Prevention of Alzheimer's Dementia) - totalling 3137 participants, and performed meta-analyses to obtain more robust estimates. We observed distinct neurodegeneration patterns across biomarker groups, with disrupted connectivity (brain volume covariance networks) in amyloid positive and other dementia groups, while amyloid and tau negative, cognitively unimpaired controls exhibited the most connected network. Amyloid was associated with subcortical, cerebellar and brainstem atrophy, with consistent association observations in the thalamus and amygdala across all four datasets. Tau in the presence of amyloid demonstrated general brain shrinkage through enlargement of extracerebral CSF, alongside unexpected ventricle shrinkages. Sex-based analyses revealed that A+T+ (amyloid positive, tau positive) had lower sex differences in connectivity patterns compared with other groups. Sex differences were also noted in amyloid-related ventricular volume changes. This study reveals how amyloid and tau affect brain connectivity and volume across sex and CSF biomarker groups, emphasizing global brain changes and sex differences. By leveraging automated pipelines and advanced MRI and biomarker analyses, we extracted meaningful and replicable findings from heterogeneous clinical samples from real-world data. The meta-analyses across four datasets enhance the generalizability of our results.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/3030271
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Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
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