Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report

Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report Gregory Mathoux, Cecilia Boccalini, Aurelien Lathuliere, Max Scheffler, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3902592/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Apr, 2024 Read the published version in EJNMMI Research → Version 1 posted 4 You are reading this latest preprint version Abstract Background: This case report presents a patient with progressive memory loss and choreiform movements. Case presentation: Neuropsychological tests indicated multi-domain amnestic mild cognitive impairment (aMCI), and neurological examination revealed asymmetrical involuntary hyperkinetic movements. Imaging studies showed severe left-sided atrophy and hypometabolism in the left frontal and temporoparietal cortex. [ 18 F]Flortaucipir PET exhibited moderately increased tracer uptake in hypometabolic areas. The diagnosis initially considered Alzheimer’s disease, frontotemporal degeneration (FTD), and corticobasal degeneration (CBD), cerebral hemiatrophy syndrome, but imaging and cerebrospinal fluid analysis excluded AD and suggested fused-in-sarcoma-associated FTLD-FUS, a subtype of bvFTD. Conclusions: Our case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case. PET neuroimaging FTLD-FUS pathology mild cognitive impairment chorea Figures Figure 1 Background Frontotemporal degeneration (FTD) is a heterogeneous group of pathologies. It is the second most frequent cause of dementia in the presenile age range (< 65 years), secondary only to AD, and accounts for 5–15% of all dementia. Progressive worsening in behavior, personality, and/or language, associated with a comparatively well-preserved memory, characterizes the clinical presentation. Chorea, that classically occurs in Huntington's disease, an inherited neurodegenerative disease characterized by striatal atrophy, is a rather uncommon sign of clinical presentation in neurodegenerative diseases, even though the striatum has been reported as severely affected in FTD [ 1 ]. Chorea has previously only rarely been described in cases with FTD, notably as a clinical feature of the basophilic inclusion body disease subtype (BIBD) of FTLD-FUS [ 1 ]. We report the case of a patient presenting with amnestic mild cognitive impairment, chorea and severe atrophy and reduced metabolism of the left hemisphere on imaging, combined with mild [ 18 F]flortaucipir uptake in the left caudate nucleus, leading to a diagnosis of probable FTLD-FUS pathology. Our case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case. Case presentation We report the case of a 75-year-old woman who was evaluated at the memory clinic of Geneva University Hospitals, with progressive memory loss for one year. Medical history included former thyroidectomy with subsequent hypothyroidism, adequately managed with substitution therapy. Apart from the uninvestigated late onset cognitive impairment of the patient’s mother, family history was unremarkable for neurodegenerative diseases. Neuropsychological exams showed multi-domain amnestic mild cognitive impairment (aMCI), mainly with episodic memory deficit, associated with minor deficiencies in executive functions and attention. The Mini-Mental State Examination (MMSE) was evaluated at 29/30, and the Montreal Cognitive Assessment (MOCA) at 23/30. The physical neurological exam revealed markedly asymmetric involuntary hyperkinetic movements affecting the distal right arm and the right leg, consistent with chorea. Occasional choreiform movements were observed in the left side and trunk. The patient herself did not complain about these involuntary movements. The rest of the exam was normal, with no evidence of parkinsonian features such as rigidity or bradykinesia, and no pyramidal or cerebellar signs were found. Language testing and behavioral assessment showed no significant abnormalities. Cerebrospinal fluid (CSF) analysis was then performed and revealed a mild elevation of total tau and phospho-tau, as well as a normal Ab42 level, with total tau 521 ng/l (normal value, < 400 ng/l), p-tau 69.4 ng/l (normal value, 725 ng/l), and Ab42/40 ratio 0.108 (normal value, > 0.069). In addition, the plasma concentration of progranulin was also tested, and it was within the normal range with a value of 109 ng/mL, (normal value > 85 ng/mL). Brain MRI demonstrated severe left-sided supra-tentorial atrophy, associated with Fazekas grade 1 leukoaraiosis, both stable since a previous MRI realized one year before. However, a head CT scan performed in 2005 for suspected rhinosinusitis showed less significantly less marked atrophy, as compared to both MRI studies, speaking in favor of a progressive neurodegenerative disease. The MRI exams showed the asymmetrical atrophy to be particularly severe in the region of the left caudate nucleus, and also evidenced important mineral deposits of the basal nuclei in the SWI sequence. [ 18 F]FDG PET of the brain showed severe asymmetric hypometabolism in the left frontal and temporoparietal cortex, the left caudate nucleus, and, to a lesser extent, in the left putamen (Fig. 1 A, B). The patient underwent [ 18 F]Flortaucipir tau PET study in the context of a research project of the memory clinic of Geneva University Hospitals. The visual assessment of the tau PET scan revealed an increased tracer uptake in areas characterized by hypometabolism as described before. Specifically, a weak neocortical uptake was found in the left frontal, parietal, temporal, and insular cortices, associated with a more intense uptake in the left caudate nucleus (Fig. 1 E, F). According to current U.S. Food and Drug Administration statement, the increased tracer uptake in those areas was considered nonsignificant for AD, since neocortical uptake in the left frontal, parietal, temporal, and insular cortices did not reach a signal of more than 65% above the cerebellar mean. In the context of diffuse off-target binding, we found an asymmetric and moderate uptake in the left caudate nucleus, exceeding 65% of the cerebellar mean. No abnormalities were observed in the right hemisphere (Fig. 1 E, F). At the beginning, the diagnosis was opened between Alzheimer’s disease (AD), frontotemporal degeneration (FTD), and corticobasal degeneration (CBD). Then, the imaging and CSF findings permitted to rule out an AD diagnosis and limited the differential diagnosis between CBD and a subtype of the FTD disease spectrum. CBD is a neurodegenerative tauopathy and one of the most common underlying pathologies of corticobasal syndrome (CBS), characterized by asymmetric rigidity, apraxia, dystonia, myoclonus, cortical sensory loss, and dystonia, as well as behavioral and cognitive impairments such as aphasia. FTD is a heterogeneous group of pathologies. It is the second most frequent cause of dementia in the presenile age range (< 65 years), secondary only to AD, and accounts for 5–15% of all dementia. Progressive worsening in behavior, personality, and/or language, associated with a comparatively well-preserved memory, characterizes the clinical presentation. FTD typically is divided into three clinical syndromes based on the predominant symptoms: the behavioral variant of FTD (bvFTD), and two types of primary progressive aphasia (PPA), namely a nonfluent variant (nfvPPA) or a semantic variant of PPA (svPPA). However, as the disease progresses, these phenotypes frequently converge [ 2 ]. MRI findings include in differential diagnosis also cerebral hemiatrophy syndrome, an uncommon disorder characterized in adults by unilateral brain volume loss, hemiparkinsonism, hemidystonia, hemiatrophy and, in exceptions, hemichorea [ 3 ]. These clinical features are not present in the presented case with the exception of chorea, asymmetrical but still bilateral. Taking together the clinical picture and imaging exams allowed the hypothetical diagnosis of a neurodegenerative condition, namely a subtype of the bvFTD, called the fused-in-sarcoma-associated FTLD (FTLD-FUS) with some features of CBS. On the one hand, the clinical evaluation revealed markedly asymmetric choreiform involuntary movements and, on the other hand, neuroimaging results showed the severe left hemisphere atrophy, the left frontotemporoparietal cortex and the left caudate nucleus hypometabolism on [ 18 F]FDG PET and the non-AD [ 18 F]Flortaucipir tau PET pattern with an asymmetric and moderate uptake in the left caudate nucleus. The presence of markedly asymmetric choreiform involuntary movements was an important feature in guiding the diagnosis. Chorea is usually characterized by excessive, spontaneous movements that are irregularly timed, nonrepetitive, randomly distributed, and abrupt. The classical form of chorea occurs in Huntington's disease, an inherited neurodegenerative disease characterized by striatal atrophy. Chorea is a rather uncommon sign of clinical presentation in neurodegenerative diseases, even though the striatum has been reported as severely affected in FTD [ 1 ]. Chorea has previously only rarely been described in cases with bvFTD, notably as a clinical feature of the basophilic inclusion body disease subtype (BIBD) of FTLD-FUS [ 1 ]. FUS is an RNA-binding protein with regulatory functions in the nucleus that accumulates pathologically in the cytoplasm in 5–10% of FTLD cases, whereas TDP-43 or tau-positive inclusions are associated with the majority of FTLD cases. Three rare forms of FTLD are considered to be subtypes of FTLD-FUS: atypical FTLD-U (aFTLD-U), BIBD, and neuronal intermediate filament inclusion disease (NIFID). Clinically, aFTLD-U is characterized by prominent obsessiveness, repetitive behaviors and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behavior (e.g., utilization behavior). NIFID and BIBD share several clinical features including dysarthria, motor neuron signs, parkinsonism, and memory impairment [ 1 ]. Few neuroimaging studies assessed the in vivo molecular pathology and neurodegeneration in these cases due to the rarity of the pathology-proven cases during lifetime. Soleimani-Meigooni and coworkers [ 4 ] previously described tau uptake assessed by PET in a patient with a pathological diagnosis of FTLD-FUS, revealing intense uptake in the left caudate. Our reported case resembles this aforementioned tracer uptake, and also minimal tracer retention corresponding to areas of significant atrophy (Fig. 1 E, F). The hypometabolism pattern described in our case adds molecular information to previous works about this rare entity. [ 18 F]Flortaucipir, formerly known as [ 18 F]-T807 and [ 18 F]-AV-1451, is one of the most widely used tau PET ligands. There is an excellent correlation between [ 18 F]Flortaucipir retention and the distribution of neurofibrillary tangles in AD, but there have been inconsistent reports on its utility for non-AD pathologies. In particular circumstances, the substrate of low-intensity tracer binding in these conditions is unknown. [ 18 F]Flortaucipir may bind to TDP-43 or FUS aggregates at low levels in vivo , however, this does not persist in vitro after tissue preparation for autoradiography. The tracer might also detect other local pathological alterations, such as monoamine oxidase B expressed in reactive astrocytes or iron (or related proteins) in degenerating axons [ 4 ], resembling our case cortical uptake. Augmented value can be conferred to our case through the integration of second-generation tau-PET tracers, which exhibit a superior off-target binding profile [ 5 ]. [ 18 F]FDG PET results in FTLD-FUS cases have not been systematically described, however, the few described patterns of hypometabolism appear to correspond to the FTLD spectrum [ 6 ]. Goodwill and coworkers described a case of FTLD-FUS with corticobasal clinical features showing normal symmetric cortical FDG uptake but a markedly decreased FDG uptake in the caudate nucleus bilaterally [ 7 ]. In our patient, severe hypometabolism was found in the left caudate nucleus, associated with a significant uptake reduction in the gray matter of the left hemisphere. In accordance with a study from Joseph et al [ 8 ], caudate atrophy on MRI appears to be significantly greater in FTLD-FUS compared with FTLD-TDP and FTLD-TAU, and the group suggests considering a diagnosis of FTLD-FUS in any patient presenting at a relatively young age, with behavioral variant frontotemporal dementia syndrome, negative family history, and severe caudate atrophy on head MRI, already in early stages of the disease course. Conclusion To conclude, the neuroimaging results and the presence of chorea lead to a diagnosis of probable FTLD-FUS in the here presented case. The absence of other typical clinical features of FTLD-FUS, at the moment of presentation, could be explained by the fact that the patient was still in a prodromic phase (aMCI), and specific behavioral changes might also have been missed during neuropsychological evaluation. The impossibility of achieving a complete match between phenotype and molecular pathology is not surprising given the well-known fact that the same neuropathology can cause multiple clinical phenotypes or, conversely, different neuropathologies can cause comparable phenotypes. Moreover, the individual phenotype is determined by the interaction of pathology with multiple genetic and acquired factors, making the picture even more complicated. Our case report highlights the importance of an integrated analysis of clinical features and neuroimaging results, including both the presence and topography of abnormalities, to reach a differential diagnosis also in the non-AD spectrum in the absence of specific molecular markers. Abbreviations aMCI: amnestic mild cognitive impairment FTD: frontotemporal degeneration CBD: corticobasal degeneration BIBD: basophilic inclusion body disease subtype MMSE: Mini‐Mental State Examination MOCA: Montreal Cognitive Assessment CSF: cerebrospinal fluid AD: Alzheimer’s disease bvFTD: behavioral variant of FTD PPA: primary progressive aphasia nfvPPA: nonfluent variant of PPA svPPA: a semantic variant of PPA FTLD-FUS: fused-in-sarcoma-associated FTLD Declarations Competing interests All authors disclose that they have no conflict of interest pertinent to this manuscript. Funding declaration Open access funding is provided by Université de Geneve. Ethics approval and consent to participate The local Ethics Committee (Commission cantonale d'éthique de la recherche, CCER) approved the imaging studies, which have been conducted under the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice. Each subject or their relatives provided voluntary written informed consent to participate in the studies or if participants are under 16, from a parent and/or legal guardian. Consent for publication All procedures were discussed with the patient and he has given his full consent in writing to the present publication and accompanying images. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study Author contributions G.M. performed imaging investigations, and drafted the manuscript. C.B. discussed clinical and imaging studies and contributed to the manuscript draft. M.S. contributed to per perform imaging investigations. A.L and G.B.F. performed clinical investigations. V.G. discussed clinical and imaging studies and supervised the manuscript. Acknowledgements Not applicable References Kawakami I, Kobayashi Z, Arai T, Yokota O, Nonaka T, Aoki N, et al. Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration. Acta Neuropathol Commun. 2016;4:36. Neumann M, Mackenzie IRA, Review. Neuropathology of non-tau frontotemporal lobar degeneration. Neuropathol Appl Neurobiol. 2019;45:19–40. Reiter E, Heim B, Scherfler C, Mueller C, Nocker M, Ndayisaba JP et al. Clinical Heterogeneity in Cerebral Hemiatrophy Syndromes. Mov Disord Clin Pract [Internet]. 2016 [cited 2023 Dec 15];3:382–8. Available from: https://onlinelibrary.wiley.com/doi/full/ 10.1002/mdc3.12301 . Soleimani-Meigooni DN, Iaccarino L, Joie R, La, Baker S, Bourakova V, Boxer AL, et al. 18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases. Brain. 2020;143:3477. Groot C, Villeneuve S, Smith R, Hansson O, Ossenkoppele R. Tau PET Imaging in Neurodegenerative Disorders. J Nucl Med. 2022;63:20S–6. Minoshima S, Cross D, Thientunyakit T, Foster NL, Drzezga A. 18F-FDG PET Imaging in Neurodegenerative Dementing Disorders: Insights into Subtype Classification, Emerging Disease Categories, and Mixed Dementia with Copathologies. J Nucl Med. 2022;63:2S–12S. Goodwill V, Coughlin D, Pizzo D, Galasko D, Hansen LA, Yuan SH, et al. A Case of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FET) With Corticobasal Features and Language Deficits. J Neuropathol Exp Neurol. 2021;80:890. Josephs KA, Whitwell JL, Parisi JE, Petersen RC, Boeve BF, Jack CR, et al. Caudate atrophy on MRI is a characteristic feature of FTLD-FUS. Eur J neurology: official J Eur Federation Neurol Soc. 2010;17:969. Cite Share Download PDF Status: Published Journal Publication published 04 Apr, 2024 Read the published version in EJNMMI Research → Version 1 posted Reviewers agreed at journal 26 Feb, 2024 Reviewers invited by journal 09 Feb, 2024 Editor assigned by journal 08 Feb, 2024 First submitted to journal 04 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3902592","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":272091292,"identity":"00541692-f29d-4cc0-acf1-2e1ad9a65756","order_by":0,"name":"Gregory Mathoux","email":"","orcid":"","institution":"Hopitaux Universitaires Geneve","correspondingAuthor":false,"prefix":"","firstName":"Gregory","middleName":"","lastName":"Mathoux","suffix":""},{"id":272091293,"identity":"a124a82f-5462-4db3-ae03-8f08b9132b59","order_by":1,"name":"Cecilia Boccalini","email":"","orcid":"","institution":"Universite de Geneve","correspondingAuthor":false,"prefix":"","firstName":"Cecilia","middleName":"","lastName":"Boccalini","suffix":""},{"id":272091294,"identity":"59d4afd4-916a-4135-a26c-f62064794111","order_by":2,"name":"Aurelien Lathuliere","email":"","orcid":"","institution":"Hopitaux Universitaires Geneve","correspondingAuthor":false,"prefix":"","firstName":"Aurelien","middleName":"","lastName":"Lathuliere","suffix":""},{"id":272091295,"identity":"c05a1fbd-75bd-46a8-92d7-6ed9a0017178","order_by":3,"name":"Max Scheffler","email":"","orcid":"","institution":"Hopitaux Universitaires Geneve","correspondingAuthor":false,"prefix":"","firstName":"Max","middleName":"","lastName":"Scheffler","suffix":""},{"id":272091296,"identity":"20b3f10a-53e5-43b2-83d4-6f6369292ece","order_by":4,"name":"Giovanni B. 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It is the second most frequent cause of dementia in the presenile age range (\u0026lt;\u0026thinsp;65 years), secondary only to AD, and accounts for 5\u0026ndash;15% of all dementia. Progressive worsening in behavior, personality, and/or language, associated with a comparatively well-preserved memory, characterizes the clinical presentation. Chorea, that classically occurs in Huntington's disease, an inherited neurodegenerative disease characterized by striatal atrophy, is a rather uncommon sign of clinical presentation in neurodegenerative diseases, even though the striatum has been reported as severely affected in FTD [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Chorea has previously only rarely been described in cases with FTD, notably as a clinical feature of the basophilic inclusion body disease subtype (BIBD) of FTLD-FUS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe report the case of a patient presenting with amnestic mild cognitive impairment, chorea and severe atrophy and reduced metabolism of the left hemisphere on imaging, combined with mild [\u003csup\u003e18\u003c/sup\u003eF]flortaucipir uptake in the left caudate nucleus, leading to a diagnosis of probable FTLD-FUS pathology. Our case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eWe report the case of a 75-year-old woman who was evaluated at the memory clinic of Geneva University Hospitals, with progressive memory loss for one year.\u003c/p\u003e \u003cp\u003eMedical history included former thyroidectomy with subsequent hypothyroidism, adequately managed with substitution therapy. Apart from the uninvestigated late onset cognitive impairment of the patient\u0026rsquo;s mother, family history was unremarkable for neurodegenerative diseases.\u003c/p\u003e \u003cp\u003eNeuropsychological exams showed multi-domain amnestic mild cognitive impairment (aMCI), mainly with episodic memory deficit, associated with minor deficiencies in executive functions and attention. The Mini-Mental State Examination (MMSE) was evaluated at 29/30, and the Montreal Cognitive Assessment (MOCA) at 23/30. The physical neurological exam revealed markedly asymmetric involuntary hyperkinetic movements affecting the distal right arm and the right leg, consistent with chorea. Occasional choreiform movements were observed in the left side and trunk. The patient herself did not complain about these involuntary movements. The rest of the exam was normal, with no evidence of parkinsonian features such as rigidity or bradykinesia, and no pyramidal or cerebellar signs were found. Language testing and behavioral assessment showed no significant abnormalities.\u003c/p\u003e \u003cp\u003eCerebrospinal fluid (CSF) analysis was then performed and revealed a mild elevation of total tau and phospho-tau, as well as a normal Ab42 level, with total tau 521 ng/l (normal value, \u0026lt;\u0026thinsp;400 ng/l), p-tau 69.4 ng/l (normal value, \u0026lt;\u0026thinsp;56.5 ng/l), Ab42 2111 ng/l (normal value, \u0026gt;\u0026thinsp;725 ng/l), and Ab42/40 ratio 0.108 (normal value, \u0026gt;\u0026thinsp;0.069).\u003c/p\u003e \u003cp\u003eIn addition, the plasma concentration of progranulin was also tested, and it was within the normal range with a value of 109 ng/mL, (normal value\u0026thinsp;\u0026gt;\u0026thinsp;85 ng/mL).\u003c/p\u003e \u003cp\u003eBrain MRI demonstrated severe left-sided supra-tentorial atrophy, associated with Fazekas grade 1 leukoaraiosis, both stable since a previous MRI realized one year before. However, a head CT scan performed in 2005 for suspected rhinosinusitis showed less significantly less marked atrophy, as compared to both MRI studies, speaking in favor of a progressive neurodegenerative disease. The MRI exams showed the asymmetrical atrophy to be particularly severe in the region of the left caudate nucleus, and also evidenced important mineral deposits of the basal nuclei in the SWI sequence.\u003c/p\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG PET of the brain showed severe asymmetric hypometabolism in the left frontal and temporoparietal cortex, the left caudate nucleus, and, to a lesser extent, in the left putamen (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, B).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient underwent [\u003csup\u003e18\u003c/sup\u003eF]Flortaucipir tau PET study in the context of a research project of the memory clinic of Geneva University Hospitals. The visual assessment of the tau PET scan revealed an increased tracer uptake in areas characterized by hypometabolism as described before. Specifically, a weak neocortical uptake was found in the left frontal, parietal, temporal, and insular cortices, associated with a more intense uptake in the left caudate nucleus (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, F). According to current U.S. Food and Drug Administration statement, the increased tracer uptake in those areas was considered nonsignificant for AD, since neocortical uptake in the left frontal, parietal, temporal, and insular cortices did not reach a signal of more than 65% above the cerebellar mean. In the context of diffuse off-target binding, we found an asymmetric and moderate uptake in the left caudate nucleus, exceeding 65% of the cerebellar mean. No abnormalities were observed in the right hemisphere (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, F).\u003c/p\u003e \u003cp\u003eAt the beginning, the diagnosis was opened between Alzheimer\u0026rsquo;s disease (AD), frontotemporal degeneration (FTD), and corticobasal degeneration (CBD). Then, the imaging and CSF findings permitted to rule out an AD diagnosis and limited the differential diagnosis between CBD and a subtype of the FTD disease spectrum. CBD is a neurodegenerative tauopathy and one of the most common underlying pathologies of corticobasal syndrome (CBS), characterized by asymmetric rigidity, apraxia, dystonia, myoclonus, cortical sensory loss, and dystonia, as well as behavioral and cognitive impairments such as aphasia. FTD is a heterogeneous group of pathologies. It is the second most frequent cause of dementia in the presenile age range (\u0026lt;\u0026thinsp;65 years), secondary only to AD, and accounts for 5\u0026ndash;15% of all dementia. Progressive worsening in behavior, personality, and/or language, associated with a comparatively well-preserved memory, characterizes the clinical presentation. FTD typically is divided into three clinical syndromes based on the predominant symptoms: the behavioral variant of FTD (bvFTD), and two types of primary progressive aphasia (PPA), namely a nonfluent variant (nfvPPA) or a semantic variant of PPA (svPPA). However, as the disease progresses, these phenotypes frequently converge [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMRI findings include in differential diagnosis also cerebral hemiatrophy syndrome, an uncommon disorder characterized in adults by unilateral brain volume loss, hemiparkinsonism, hemidystonia, hemiatrophy and, in exceptions, hemichorea [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These clinical features are not present in the presented case with the exception of chorea, asymmetrical but still bilateral.\u003c/p\u003e \u003cp\u003eTaking together the clinical picture and imaging exams allowed the hypothetical diagnosis of a neurodegenerative condition, namely a subtype of the bvFTD, called the fused-in-sarcoma-associated FTLD (FTLD-FUS) with some features of CBS. On the one hand, the clinical evaluation revealed markedly asymmetric choreiform involuntary movements and, on the other hand, neuroimaging results showed the severe left hemisphere atrophy, the left frontotemporoparietal cortex and the left caudate nucleus hypometabolism on [\u003csup\u003e18\u003c/sup\u003eF]FDG PET and the non-AD [\u003csup\u003e18\u003c/sup\u003eF]Flortaucipir tau PET pattern with an asymmetric and moderate uptake in the left caudate nucleus.\u003c/p\u003e \u003cp\u003eThe presence of markedly asymmetric choreiform involuntary movements was an important feature in guiding the diagnosis. Chorea is usually characterized by excessive, spontaneous movements that are irregularly timed, nonrepetitive, randomly distributed, and abrupt. The classical form of chorea occurs in Huntington's disease, an inherited neurodegenerative disease characterized by striatal atrophy. Chorea is a rather uncommon sign of clinical presentation in neurodegenerative diseases, even though the striatum has been reported as severely affected in FTD [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eChorea has previously only rarely been described in cases with bvFTD, notably as a clinical feature of the basophilic inclusion body disease subtype (BIBD) of FTLD-FUS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFUS is an RNA-binding protein with regulatory functions in the nucleus that accumulates pathologically in the cytoplasm in 5\u0026ndash;10% of FTLD cases, whereas TDP-43 or tau-positive inclusions are associated with the majority of FTLD cases. Three rare forms of FTLD are considered to be subtypes of FTLD-FUS: atypical FTLD-U (aFTLD-U), BIBD, and neuronal intermediate filament inclusion disease (NIFID). Clinically, aFTLD-U is characterized by prominent obsessiveness, repetitive behaviors and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behavior (e.g., utilization behavior). NIFID and BIBD share several clinical features including dysarthria, motor neuron signs, parkinsonism, and memory impairment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFew neuroimaging studies assessed the \u003cem\u003ein vivo\u003c/em\u003e molecular pathology and neurodegeneration in these cases due to the rarity of the pathology-proven cases during lifetime. Soleimani-Meigooni and coworkers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] previously described tau uptake assessed by PET in a patient with a pathological diagnosis of FTLD-FUS, revealing intense uptake in the left caudate. Our reported case resembles this aforementioned tracer uptake, and also minimal tracer retention corresponding to areas of significant atrophy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE, F). The hypometabolism pattern described in our case adds molecular information to previous works about this rare entity.\u003c/p\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]Flortaucipir, formerly known as [\u003csup\u003e18\u003c/sup\u003eF]-T807 and [\u003csup\u003e18\u003c/sup\u003eF]-AV-1451, is one of the most widely used tau PET ligands. There is an excellent correlation between [\u003csup\u003e18\u003c/sup\u003eF]Flortaucipir retention and the distribution of neurofibrillary tangles in AD, but there have been inconsistent reports on its utility for non-AD pathologies.\u003c/p\u003e \u003cp\u003eIn particular circumstances, the substrate of low-intensity tracer binding in these conditions is unknown. [\u003csup\u003e18\u003c/sup\u003eF]Flortaucipir may bind to TDP-43 or FUS aggregates at low levels \u003cem\u003ein vivo\u003c/em\u003e, however, this does not persist \u003cem\u003ein vitro\u003c/em\u003e after tissue preparation for autoradiography. The tracer might also detect other local pathological alterations, such as monoamine oxidase B expressed in reactive astrocytes or iron (or related proteins) in degenerating axons [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], resembling our case cortical uptake.\u003c/p\u003e \u003cp\u003eAugmented value can be conferred to our case through the integration of second-generation tau-PET tracers, which exhibit a superior off-target binding profile [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG PET results in FTLD-FUS cases have not been systematically described, however, the few described patterns of hypometabolism appear to correspond to the FTLD spectrum [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Goodwill and coworkers described a case of FTLD-FUS with corticobasal clinical features showing normal symmetric cortical FDG uptake but a markedly decreased FDG uptake in the caudate nucleus bilaterally [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our patient, severe hypometabolism was found in the left caudate nucleus, associated with a significant uptake reduction in the gray matter of the left hemisphere. In accordance with a study from Joseph et al [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], caudate atrophy on MRI appears to be significantly greater in FTLD-FUS compared with FTLD-TDP and FTLD-TAU, and the group suggests considering a diagnosis of FTLD-FUS in any patient presenting at a relatively young age, with behavioral variant frontotemporal dementia syndrome, negative family history, and severe caudate atrophy on head MRI, already in early stages of the disease course.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo conclude, the neuroimaging results and the presence of chorea lead to a diagnosis of probable FTLD-FUS in the here presented case. The absence of other typical clinical features of FTLD-FUS, at the moment of presentation, could be explained by the fact that the patient was still in a prodromic phase (aMCI), and specific behavioral changes might also have been missed during neuropsychological evaluation. The impossibility of achieving a complete match between phenotype and molecular pathology is not surprising given the well-known fact that the same neuropathology can cause multiple clinical phenotypes or, conversely, different neuropathologies can cause comparable phenotypes. Moreover, the individual phenotype is determined by the interaction of pathology with multiple genetic and acquired factors, making the picture even more complicated.\u003c/p\u003e \u003cp\u003eOur case report highlights the importance of an integrated analysis of clinical features and neuroimaging results, including both the presence and topography of abnormalities, to reach a differential diagnosis also in the non-AD spectrum in the absence of specific molecular markers.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eaMCI: amnestic mild cognitive impairment\u003c/p\u003e\n\u003cp\u003eFTD: frontotemporal degeneration\u003c/p\u003e\n\u003cp\u003eCBD: corticobasal degeneration\u003c/p\u003e\n\u003cp\u003eBIBD: basophilic inclusion body disease subtype\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMMSE: Mini‐Mental State Examination\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMOCA: Montreal Cognitive Assessment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCSF: cerebrospinal fluid\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAD: Alzheimer\u0026rsquo;s disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ebvFTD: behavioral variant of FTD\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePPA: \u0026nbsp;primary progressive aphasia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003enfvPPA: nonfluent variant of PPA\u0026nbsp;\u003c/p\u003e\n\u003cp\u003esvPPA: a semantic variant of PPA\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFTLD-FUS: fused-in-sarcoma-associated FTLD\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors disclose that they have no conflict of interest pertinent to this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOpen access funding is provided by Universit\u0026eacute; de Geneve.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe local Ethics Committee (Commission cantonale d\u0026apos;\u0026eacute;thique de la recherche, CCER) approved the imaging studies, which have been conducted under the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice. Each subject or their relatives provided voluntary written informed consent to participate in the studies\u0026nbsp;or if participants are under 16, from a parent and/or legal guardian.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures were discussed with the patient and he has given his full consent in writing to the present publication and accompanying images.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analysed during the current study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eG.M. performed imaging investigations, and drafted the manuscript. C.B. discussed clinical and imaging studies and contributed to the manuscript draft. M.S. contributed to per perform imaging investigations. A.L and G.B.F. performed clinical investigations. V.G. discussed clinical and imaging studies and supervised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKawakami I, Kobayashi Z, Arai T, Yokota O, Nonaka T, Aoki N, et al. Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration. Acta Neuropathol Commun. 2016;4:36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeumann M, Mackenzie IRA, Review. Neuropathology of non-tau frontotemporal lobar degeneration. Neuropathol Appl Neurobiol. 2019;45:19\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReiter E, Heim B, Scherfler C, Mueller C, Nocker M, Ndayisaba JP et al. Clinical Heterogeneity in Cerebral Hemiatrophy Syndromes. Mov Disord Clin Pract [Internet]. 2016 [cited 2023 Dec 15];3:382\u0026ndash;8. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/full/\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/full/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/mdc3.12301\u003c/span\u003e\u003cspan address=\"10.1002/mdc3.12301\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoleimani-Meigooni DN, Iaccarino L, Joie R, La, Baker S, Bourakova V, Boxer AL, et al. 18F-flortaucipir PET to autopsy comparisons in Alzheimer\u0026rsquo;s disease and other neurodegenerative diseases. Brain. 2020;143:3477.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGroot C, Villeneuve S, Smith R, Hansson O, Ossenkoppele R. Tau PET Imaging in Neurodegenerative Disorders. J Nucl Med. 2022;63:20S\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMinoshima S, Cross D, Thientunyakit T, Foster NL, Drzezga A. 18F-FDG PET Imaging in Neurodegenerative Dementing Disorders: Insights into Subtype Classification, Emerging Disease Categories, and Mixed Dementia with Copathologies. J Nucl Med. 2022;63:2S\u0026ndash;12S.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoodwill V, Coughlin D, Pizzo D, Galasko D, Hansen LA, Yuan SH, et al. A Case of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FET) With Corticobasal Features and Language Deficits. J Neuropathol Exp Neurol. 2021;80:890.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJosephs KA, Whitwell JL, Parisi JE, Petersen RC, Boeve BF, Jack CR, et al. Caudate atrophy on MRI is a characteristic feature of FTLD-FUS. Eur J neurology: official J Eur Federation Neurol Soc. 2010;17:969.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"PET, neuroimaging, FTLD-FUS pathology, mild cognitive impairment, chorea","lastPublishedDoi":"10.21203/rs.3.rs-3902592/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3902592/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e This case report presents a patient with progressive memory loss and choreiform movements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e Neuropsychological tests indicated multi-domain amnestic mild cognitive impairment (aMCI), and neurological examination revealed asymmetrical involuntary hyperkinetic movements. Imaging studies showed severe left-sided atrophy and hypometabolism in the left frontal and temporoparietal cortex. [\u003csup\u003e18\u003c/sup\u003eF]Flortaucipir PET exhibited moderately increased tracer uptake in hypometabolic areas. The diagnosis initially considered Alzheimer’s disease, frontotemporal degeneration (FTD), and corticobasal degeneration (CBD), cerebral hemiatrophy syndrome, but imaging and cerebrospinal fluid analysis excluded AD and suggested fused-in-sarcoma-associated FTLD-FUS, a subtype of bvFTD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-13 19:13:08","doi":"10.21203/rs.3.rs-3902592/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-02-26T14:45:55+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-09T13:18:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-09T00:38:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Research","date":"2024-02-05T04:02:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"856ee864-2c02-48be-919a-5d11263c4819","owner":[],"postedDate":"February 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-08T15:12:28+00:00","versionOfRecord":{"articleIdentity":"rs-3902592","link":"https://doi.org/10.1186/s13550-024-01102-9","journal":{"identity":"ejnmmi-research","isVorOnly":false,"title":"EJNMMI Research"},"publishedOn":"2024-04-04 15:01:26","publishedOnDateReadable":"April 4th, 2024"},"versionCreatedAt":"2024-02-13 19:13:08","video":"","vorDoi":"10.1186/s13550-024-01102-9","vorDoiUrl":"https://doi.org/10.1186/s13550-024-01102-9","workflowStages":[]},"version":"v1","identity":"rs-3902592","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3902592","identity":"rs-3902592","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}