{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:59:28Z","timestamp":1776898768174,"version":"3.51.2"},"reference-count":92,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Memorabel ZonMW","award":["733050507"],"award-info":[{"award-number":["733050507"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,1,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD.<\/jats:p><jats:p>Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008\u20132017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-\u03b2, and \u03b1-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations.<\/jats:p><jats:p>In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-\u03b2 (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-\u03b2 burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of \u03b1-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative\/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007).<\/jats:p><jats:p>Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.<\/jats:p>","DOI":"10.1093\/brain\/awac043","type":"journal-article","created":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T20:08:43Z","timestamp":1644091723000},"page":"307-320","source":"Crossref","is-referenced-by-count":22,"title":["Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2420-6447","authenticated-orcid":false,"given":"Marta","family":"Scarioni","sequence":"first","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam University Medical Centers , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priya","family":"Gami-Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, Amsterdam Neuroscience , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carel F W","family":"Peeters","sequence":"additional","affiliation":[{"name":"Division of Mathematical and Statistical Methods\u2014Biometris, Wageningen University and Research , Wageningen , The Netherlands"},{"name":"Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, The Amsterdam Public Health Research Institute , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florianne","family":"de Koning","sequence":"additional","affiliation":[{"name":"Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam University Medical Centers , Amsterdam , The Netherlands"},{"name":"Department of Pathology, Amsterdam University Medical Centers, Amsterdam Neuroscience , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harro","family":"Seelaar","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus University Medical Center Rotterdam , Rotterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2533-2530","authenticated-orcid":false,"given":"Merel O","family":"Mol","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus University Medical Center Rotterdam , Rotterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C","family":"van Swieten","sequence":"additional","affiliation":[{"name":"Department of Neurology, Erasmus University Medical Center Rotterdam , Rotterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Netherlands Brain 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Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2160-587X","authenticated-orcid":false,"given":"Anke A","family":"Dijkstra","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam University Medical Centers, Amsterdam Neuroscience , Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"2023010803512625000_awac043-B1","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1212\/WNL.0000000000004614","article-title":"The social and economic burden of frontotemporal degeneration","volume":"89","author":"Galvin","year":"2017","journal-title":"Neurology"},{"key":"2023010803512625000_awac043-B2","doi-asserted-by":"crossref","first-page":"e190261","DOI":"10.1001\/jamanetworkopen.2019.0261","article-title":"Association of neuropathologically confirmed frontotemporal dementia and alzheimer 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