Background: The spectrum of fronto-temporal lobar degeneration (FTLD) encompasses several proteinopathies and clinico-pathological features ranging from “pure” typical variants (e.g. TDP-43 genetic forms) to atypical forms, such as behavioral Alzheimer’s disease (AD). Indeed, AD clinical manifestations may include early personality changes mimicking the clinical features of behavioral variant fronto-temporal dementia. In FTLD, behavioral and non-behavioral symptoms depend on the topography of the lesions, which determines alterations in language, executive/motor function and behavior, being psychotic and hyperactivity symptoms related to limbic lesions. FTLD pathology is complex and protein co-presence and interaction are poorly understood. Method: Three demented subjects belonging to the Abbiategrasso Brain Bank underwent serial neurological and neuropsychological evaluations until their death. According to the donation program, their brains were harvested and sections from both hemispheres were stained using hematoxylin-eosin, Nissl, Luxol fast blue, gallyas, and antibodies against β-amiloid (4G8), TAU (AT8), TDP-43, α-synuclein and GFAP to obtain a complete characterization of the vascular and degenerative lesions. Results: They all had a diagnosis of major-neurocognitive disorder (major-NCD) with an etiological definition through neuropathology. Case 1 (major frontotemporal NCD: nfPPA/CBS): progressive non-fluent aphasia (nfPPA), apraxia, severe right hemiparkinsonism, executive deficit, disinhibition, apathy and hyperorality; neuropathology: prevalent type A TDP-43 histopathology but with limbic co-localization of synuclein pathology. Case 2 (major frontotemporal NCD: bvFTD): progressive postural instability, bilateral parkinsonism, spatial disorientation with left visual perception deficit, wandering, disinhibition, delusions, apathy and hyperorality; neuropathology: pure type A TDP-43 histopathology. Case 3 (major-NCD due to AD: behavioral AD) progressive memory loss, logopenic language impairment, social withdrawal, apathy, aggressive behavior, wandering, sugar craving, sleep disturbances, delusions and hallucinations; neuropathology: in addition to the predominant AD pathology, pronounced limbic synuclein pathology and, to a lesser extent, TDP-43 pathology. Conclusion: The clinco-pathologic comparison of these cases demonstrates protein co-localization in FTLD confirming a possible pathological synergic role of TDP-43, synuclein and AD pathology, particularly in the limbic system. Indeed, cases with multiple limbic pathologies (1 & 3) show hippocampal sclerosis. TDP-43 cases (1 and 2) have prominent hemispheric asymmetry influencing the clinical phenotype, which depends on the topography of the lesions rather than on their molecular nature.
Studi neuropatologici di tre curiosi casi di degenerazione lobare frontotemporale dalla banca del cervello di Abbiategrasso Background: Lo spettro della degenerazione lobare frontotemporale (FTLD) comprende diverse proteinopatie e caratteristiche clinico-patologiche che variano dalle varianti tipiche "pure" (ad esempio forme genetiche TDP-43) a forme atipiche, come la variante comportamentale della malattia di Alzheimer (AD). In effetti, le manifestazioni cliniche dell’AD possono riguardare iniziali cambiamenti di personalità che imitano le caratteristiche cliniche della variante comportamentale della demenza frontotemporale. Nella FTLD, i sintomi comportamentali e non comportamentali dipendono dalla topografia delle lesioni, che determina alterazioni del linguaggio, della funzione esecutiva/motoria e del comportamento, essendo sintomi psicotici e di iperattività correlati alle lesioni limbiche. La patologia FTLD è complessa e la co-presenza e l'interazione tra le proteine è scarsamente compresa. Metodo: Tre soggetti dementi appartenenti alla banca del cervello di Abbiategrasso sono stati sottoposti a una serie di valutazioni neurologiche e neuropsicologiche fino alla morte. Secondo il programma di donazione, i loro cervelli sono stati raccolti e le sezioni di entrambi gli emisferi sono state colorate usando ematossilina-eosina, Nissl, Luxol fast blue, gallyas, e anticorpi contro β-amiloide (4G8), TAU (AT8), TDP-43, α -sinucleina e GFAP, per ottenere una completa caratterizzazione delle lesioni vascolari e degenerative. Risultati: Tutti i soggetti avevano una diagnosi di disturbo neurocognitivo (DNC) maggiore con una definizione eziologica attraverso la neuropatologia. Caso 1 (DNC frontotemporale maggiore: nfPPA / CBS): afasia non fluente progressiva (nfPPA), aprassia, grave emiparkinsonismo destro, deficit esecutivo, disinibizione, apatia e iperoralità; neuropatologia: prevalentemente istopatologia TDP-43 di tipo A ma con co-localizzazione limbica della patologia delle sinucleine. Caso 2 (DNC frontotemporale maggiore: bvFTD): progressiva instabilità posturale, parkinsonismo bilaterale, disorientamento spaziale con deficit della percezione visiva a sinistra, vagabondaggio, disinibizione, deliri, apatia e iperoralità; neuropatologia: istopatologia TDP-43 di tipo A. Caso 3 (DNC maggiore dovuto all'AD: variante comportamentale dell’AD): perdita progressiva di memoria, compromissione del linguaggio logopenico, isolamento sociale, apatia, comportamento aggressivo, vagabondaggio, predilezione per il sapore dolce, disturbi del sonno, deliri e allucinazioni; neuropatologia: oltre alla patologia dovuta all’AD, pronunciata patologia della sinucleina limbica e, in misura minore, patologia TDP-43. Conclusione: Il confronto clinico-patologico tra questi casi dimostra che nell’FTLD vi è una co-localizzazione delle proteine, confermando un possibile ruolo patologico sinergico di TDP-43, sinucleina e patologia dell'AD, in particolare nel sistema limbico. In effetti, i casi con patologie limbiche multiple (1 e 3) mostrano sclerosi ippocampale. I casi TDP-43 (1 e 2) presentano un'asimmetria emisferica prominente che ne influenza il fenotipo clinico, che dipende dalla topografia delle lesioni piuttosto che dalla loro natura molecolare.
Neuropathological studies from 3 peculiar FTLD cases from the Abbiategrasso brainbank
BOZZO, MARCO
2019/2020
Abstract
Background: The spectrum of fronto-temporal lobar degeneration (FTLD) encompasses several proteinopathies and clinico-pathological features ranging from “pure” typical variants (e.g. TDP-43 genetic forms) to atypical forms, such as behavioral Alzheimer’s disease (AD). Indeed, AD clinical manifestations may include early personality changes mimicking the clinical features of behavioral variant fronto-temporal dementia. In FTLD, behavioral and non-behavioral symptoms depend on the topography of the lesions, which determines alterations in language, executive/motor function and behavior, being psychotic and hyperactivity symptoms related to limbic lesions. FTLD pathology is complex and protein co-presence and interaction are poorly understood. Method: Three demented subjects belonging to the Abbiategrasso Brain Bank underwent serial neurological and neuropsychological evaluations until their death. According to the donation program, their brains were harvested and sections from both hemispheres were stained using hematoxylin-eosin, Nissl, Luxol fast blue, gallyas, and antibodies against β-amiloid (4G8), TAU (AT8), TDP-43, α-synuclein and GFAP to obtain a complete characterization of the vascular and degenerative lesions. Results: They all had a diagnosis of major-neurocognitive disorder (major-NCD) with an etiological definition through neuropathology. Case 1 (major frontotemporal NCD: nfPPA/CBS): progressive non-fluent aphasia (nfPPA), apraxia, severe right hemiparkinsonism, executive deficit, disinhibition, apathy and hyperorality; neuropathology: prevalent type A TDP-43 histopathology but with limbic co-localization of synuclein pathology. Case 2 (major frontotemporal NCD: bvFTD): progressive postural instability, bilateral parkinsonism, spatial disorientation with left visual perception deficit, wandering, disinhibition, delusions, apathy and hyperorality; neuropathology: pure type A TDP-43 histopathology. Case 3 (major-NCD due to AD: behavioral AD) progressive memory loss, logopenic language impairment, social withdrawal, apathy, aggressive behavior, wandering, sugar craving, sleep disturbances, delusions and hallucinations; neuropathology: in addition to the predominant AD pathology, pronounced limbic synuclein pathology and, to a lesser extent, TDP-43 pathology. Conclusion: The clinco-pathologic comparison of these cases demonstrates protein co-localization in FTLD confirming a possible pathological synergic role of TDP-43, synuclein and AD pathology, particularly in the limbic system. Indeed, cases with multiple limbic pathologies (1 & 3) show hippocampal sclerosis. TDP-43 cases (1 and 2) have prominent hemispheric asymmetry influencing the clinical phenotype, which depends on the topography of the lesions rather than on their molecular nature.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/11725