{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T07:55:42Z","timestamp":1772092542360,"version":"3.50.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Frontotemporal lobar degeneration (FTLD) encompasses heterogeneous clinical syndrome within the frontotemporal spectrum, where clinicopathological associations may be misleading. This case series illustrates clinicopathological variability and mismatches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A retrospective case series was conducted within the brain donation program at the Golgi Cenci Foundation. Cases presenting at onset with a frontotemporal-spectrum phenotype, longitudinal clinical data, and post-mortem neuropathological characterization were included.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Five cases (mean age at onset 65.4 years) were clinically diagnosed with major neurocognitive disorder due to frontotemporal dementia (FTD). Neuropathological examination revealed clinicopathological heterogeneity: two cases showed FTLD-TDP-A associated with GRN mutations, including a classic case and one with posterior (parieto-occipital) involvement; one non-fluent variant primary progressive aphasia (nfvPPA) case demonstrated FTLD-TDP-A with multiple co-pathologies; one semantic-variant-like case was driven by high Alzheimer\u2019s disease neuropathological changes; and one behavioral variant FTD-like case corresponded to frontal-variant Alzheimer\u2019s disease (fvAD) with extensive mixed pathology, including Lewy body disease, LATE-NC, and vascular pathology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Findings indicate that clinical phenotypes are more influenced by the anatomical distribution of pathology than by the specific molecular substrate. Frequent coexisting proteinopathies and asymmetric involvement contribute to phenotypic variability, reinforcing the role of neuropathological examination of both hemispheres for accurate clinicopathological correlations and definitive etiological diagnosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1774283","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:55:39Z","timestamp":1772088939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Frontotemporal lobar degeneration complexity: atypical presentations and heterogeneous proteinopathies in five cases"],"prefix":"10.3389","volume":"20","author":[{"given":"Giulia","family":"Negro","sequence":"first","affiliation":[{"name":"Ph.D. Program in Neuroscience, School of Medicine and Surgery, Universit\u00e0 degli Studi di Milano-Bicocca","place":["Milan, Italy"]},{"name":"Department of Neurology and Neuropathology, Fondazione Golgi Cenci","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla","family":"Poloni","sequence":"additional","affiliation":[{"name":"Department of Neurology, ASST Ovest Milano Legnano Hospital","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Medici","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Eastern Piedmont","place":["Novara, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Calatozzolo","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuropathology, Fondazione Golgi Cenci","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Canazza","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuropathology, Fondazione Golgi Cenci","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo Rocco","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology and Neurogenetics, Fondazione Golgi Cenci","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Cutaia","sequence":"additional","affiliation":[{"name":"Department of Dementia Care, ASP Golgi-Redaelli","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Davin","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology and Neurogenetics, Fondazione Golgi Cenci","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tino Emanuele","family":"Poloni","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neuropathology, Fondazione Golgi Cenci","place":["Milan, Italy"]},{"name":"Department of Rehabilitation, ASP Golgi-Redaelli","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"B1","volume-title":"Diagnostic and Statistical Manual of Mental Disorders","year":"2013"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.1016\/S0140-6736(15)00461-4","article-title":"Frontotemporal dementia.","volume":"386","author":"Bang","year":"2015","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1007\/s00401-009-0538-8","article-title":"Unified staging system for Lewy body disorders: Correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction.","volume":"117","author":"Beach","year":"2009","journal-title":"Acta Neuropathol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00401-008-0360-8","article-title":"Management of a twenty-first century brain bank: Experience in the BrainNet Europe consortium.","volume":"115","author":"Bell","year":"2008","journal-title":"Acta Neuropathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/ana.25333","article-title":"Prevalence of amyloid-\u03b2 pathology in distinct variants of primary progressive aphasia.","volume":"84","author":"Bergeron","year":"2018","journal-title":"Ann. Neurol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/S1474-4422(21)00341-0","article-title":"Advances and controversies in frontotemporal dementia: Diagnosis, biomarkers, and therapeutic considerations.","volume":"21","author":"Boeve","year":"2022","journal-title":"Lancet Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e209944","DOI":"10.1212\/WNL.0000000000209944","article-title":"Association of initial side of brain atrophy with clinical features and disease progression in patients with GRN frontotemporal dementia.","volume":"103","author":"Borrego-Ecija","year":"2024","journal-title":"Neurology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","article-title":"Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry.","volume":"112","author":"Braak","year":"2006","journal-title":"Acta Neuropathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1001\/jamaneurol.2014.3308","article-title":"Posterior cortical atrophy as an extreme phenotype of GRN mutations.","volume":"72","author":"Caroppo","year":"2015","journal-title":"JAMA Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3389\/fneur.2012.00073","article-title":"Behavioral and psychological symptoms of dementia.","volume":"3","author":"Cerejeira","year":"2012","journal-title":"Front. Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e70855","DOI":"10.1002\/hsr2.70855","article-title":"Advanced imaging techniques (PET, fMRI, DTI) in early detection of neurodegenerative diseases: A systematic review.","volume":"8","author":"Chandrasekar","year":"2025","journal-title":"Health Sci. Rep."},{"key":"B12","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1080\/13554790903193174","article-title":"Alzheimer\u2019s disease neuropathologic changes in semantic dementia.","volume":"16","author":"Chow","year":"2010","journal-title":"Neurocase"},{"key":"B13","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1016\/j.jalz.2017.01.014","article-title":"Consensus classification of posterior cortical atrophy.","volume":"13","author":"Crutch","year":"2017","journal-title":"Alzheimers Dement."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1093\/brain\/awh582","article-title":"The pathological basis of semantic dementia.","volume":"128","author":"Davies","year":"2005","journal-title":"Brain"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1212\/WNL.0b013e31824e8e7f","article-title":"Staging and natural history of cerebrovascular pathology in dementia.","volume":"78","author":"Deramecourt","year":"2012","journal-title":"Neurology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/s13195-021-00869-6","article-title":"White matter hyperintensities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer\u2019s disease.","volume":"13","author":"Desmarais","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1007\/s00415-012-6444-3","article-title":"Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: A peculiar phenotype?","volume":"259","author":"Floris","year":"2012","journal-title":"J. Neurol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1186\/1752-1947-7-223","article-title":"The CARE guidelines: Consensus-based clinical case reporting guideline development.","volume":"7","author":"Gagnier","year":"2013","journal-title":"J. Med. Case Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1093\/jnen\/nly018","article-title":"Combined pathologies in FTLD-TDP Types A and C.","volume":"77","author":"Gefen","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","article-title":"Classification of primary progressive aphasia and its variants.","volume":"76","author":"Gorno-Tempini","year":"2011","journal-title":"Neurology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/1471-2318-13-98","article-title":"Brain aging and dementia during the transition from late adulthood to old age: Design and methodology of the \u201cInvece.Ab\u201d population-based study.","volume":"13","author":"Guaita","year":"2013","journal-title":"BMC Geriatr."},{"key":"B22","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1177\/1533317513488920","article-title":"Frontal network syndrome testing: Clinical tests and positron emission tomography brain imaging help distinguish the 3 most common dementia subtypes.","volume":"28","author":"Hoffmann","year":"2013","journal-title":"Am. J. Alzheimers Dis. Other Demen."},{"key":"B23","doi-asserted-by":"publisher","first-page":"929","DOI":"10.3233\/JAD-160979","article-title":"The Mild Behavioral Impairment Checklist (MBI-C): A rating scale for neuropsychiatric symptoms in pre-dementia populations.","volume":"56","author":"Ismail","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"B24","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1001\/archneur.62.6.925","article-title":"Frontotemporal lobar degeneration: Demographic characteristics of 353 patients.","volume":"62","author":"Johnson","year":"2005","journal-title":"Arch. Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00401-013-1211-9","article-title":"Staging TDP-43 pathology in Alzheimer\u2019s disease.","volume":"127","author":"Josephs","year":"2014","journal-title":"Acta Neuropathol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1001\/jamaneurol.2020.1741","article-title":"Prevalence and clinical phenotype of quadruple misfolded proteins in older adults.","volume":"77","author":"Karanth","year":"2020","journal-title":"JAMA Neurol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1017\/s1355617700644041","article-title":"The frontal behavioral inventory in the differential diagnosis of frontotemporal dementia.","volume":"6","author":"Kertesz","year":"2000","journal-title":"J. Int. Neuropsychol. Soc."},{"key":"B28","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1007\/s00702-014-1353-5","article-title":"BrainNet Europe\u2019s code of conduct for brain banking.","volume":"122","author":"Klioueva","year":"2015","journal-title":"J. Neural. Transm."},{"key":"B29","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/s00401-011-0845-8","article-title":"A harmonized classification system for FTLD-TDP pathology.","volume":"122","author":"Mackenzie","year":"2011","journal-title":"Acta Neuropathol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.jalz.2007.04.374","article-title":"The Frontal Systems Behavior Scale discriminates frontotemporal dementia from Alzheimer\u2019s disease.","volume":"3","author":"Malloy","year":"2007","journal-title":"Alzheimers Dement."},{"key":"B31","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.bandl.2009.03.007","article-title":"The relation between content and structure in language production: An analysis of speech errors in semantic dementia.","volume":"110","author":"Meteyard","year":"2009","journal-title":"Brain Lang."},{"key":"B32","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s11910-013-0407-7","article-title":"Chronic traumatic encephalopathy: Where are we and where are we going?","volume":"13","author":"Mez","year":"2013","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1212\/wnl.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease.","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National institute on Aging-Alzheimer\u2019s association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: A practical approach.","volume":"123","author":"Montine","year":"2013","journal-title":"Acta Neuropathol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1513644","DOI":"10.3389\/frdem.2025.1513644","article-title":"Investigating neuropathological correlates of hyperactive and psychotic symptoms in dementia: A systematic review.","volume":"4","author":"Negro","year":"2025","journal-title":"Front. Dement."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1093\/brain\/awz099","article-title":"Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report.","volume":"142","author":"Nelson","year":"2019","journal-title":"Brain"},{"key":"B37","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/s40478-023-01576-z","article-title":"Neurodegenerative pathologies associated with behavioral and psychological symptoms of dementia in a community-based autopsy cohort.","volume":"11","author":"Nelson","year":"2023","journal-title":"Acta Neuropathol. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1111\/neup.12427","article-title":"Molecular mechanisms of the co-deposition of multiple pathological proteins in neurodegenerative diseases.","volume":"38","author":"Nonaka","year":"2018","journal-title":"Neuropathology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s11910-016-0707-9","article-title":"Genetics of frontotemporal dementia.","volume":"16","author":"Olszewska","year":"2016","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2732","DOI":"10.1093\/brain\/awv191","article-title":"The behavioural\/dysexecutive variant of Alzheimer\u2019s disease: Clinical, neuroimaging and pathological features.","volume":"138","author":"Ossenkoppele","year":"2015","journal-title":"Brain"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3791\/60296","article-title":"Abbiategrasso brain bank protocol for collecting, processing and characterizing aging brains.","author":"Poloni","year":"2020","journal-title":"J. Vis. Exp."},{"key":"B42","doi-asserted-by":"publisher","first-page":"375","DOI":"10.2165\/11533100-000000000-00000","article-title":"Frontotemporal lobar degeneration: Epidemiology, pathophysiology, diagnosis and management.","volume":"24","author":"Rabinovici","year":"2010","journal-title":"CNS Drugs"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.1093\/brain\/awr179","article-title":"Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.","volume":"134","author":"Rascovsky","year":"2011","journal-title":"Brain"},{"key":"B44","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1097\/NEN.0b013e318292492a","article-title":"Consensus recommendations on pathologic changes in the hippocampus: A postmortem multicenter inter-rater study.","volume":"72","author":"Rauramaa","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.bbadis.2011.07.014","article-title":"Structural brain imaging in frontotemporal dementia.","volume":"1822","author":"Rohrer","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e66932","DOI":"10.1371\/journal.pone.0066932","article-title":"Diffusion tensor tractography versus volumetric imaging in the diagnosis of behavioral variant frontotemporal dementia.","volume":"8","author":"Santillo","year":"2013","journal-title":"PLoS One"},{"key":"B47","doi-asserted-by":"publisher","first-page":"e1047","DOI":"10.1212\/WNL.0000000000005163","article-title":"Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration.","volume":"90","author":"Seo","year":"2018","journal-title":"Neurology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1093\/brain\/aww214","article-title":"Vascular Cognitive Impairment Neuropathology Guidelines (VCING): The contribution of cerebrovascular pathology to cognitive impairment.","volume":"139","author":"Skrobot","year":"2016","journal-title":"Brain"},{"key":"B49","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1002\/ana.24885","article-title":"Typical and atypical pathology in primary progressive aphasia variants.","volume":"81","author":"Spinelli","year":"2017","journal-title":"Ann. Neurol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1159\/000521968","article-title":"Frontotemporal brain sagging syndrome as a treatable cause mimicking frontotemporal dementia: A case report.","volume":"14","author":"Sugiyama","year":"2022","journal-title":"Case Rep. Neurol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1212\/wnl.58.12.1791","article-title":"Phases of A beta-deposition in the human brain and its relevance for the development of AD.","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1080\/02687038.2014.912744","article-title":"Grammatical Impairments in PPA.","volume":"28","author":"Thompson","year":"2014","journal-title":"Aphasiology"},{"key":"B53","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1007\/s00401-007-0311-9","article-title":"Twenty-first century brain banking. Processing brains for research: The Columbia University methods.","volume":"115","author":"Vonsattel","year":"2008","journal-title":"Acta Neuropathol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"E710","DOI":"10.1212\/WNL.0000000000006913","article-title":"The influence of \u03b2-amyloid on [18F]AV-1451 in semantic variant of primary progressive aphasia.","volume":"92","author":"Whitwell","year":"2019","journal-title":"Neurology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"729381","DOI":"10.3389\/fneur.2021.729381","article-title":"The psychiatric misdiagnosis of behavioral variant frontotemporal dementia in a colombian sample.","volume":"12","author":"Zapata-Restrepo","year":"2021","journal-title":"Front. Neurol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1774283\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:55:43Z","timestamp":1772088943000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1774283\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":55,"alternative-id":["10.3389\/fnins.2026.1774283"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2026.1774283","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]},"article-number":"1774283"}}