Demencja czołowo-skroniowa – Patofizjologia i mechanizm

Demencja czołowo-skroniowa
Patofizjologia i mechanizm

Demencja czołowo-skroniowa (FTD) to heterogeniczna grupa zaburzeń neurodegeneracyjnych charakteryzujących się postępującym zanikiem neuronów w płatach czołowych i skroniowych, prowadząca do zaburzeń funkcji wykonawczych, zachowania i języka. Patogeneza FTD obejmuje akumulację patologicznych białek: tau (około 40% przypadków), TDP-43 (około 50%) oraz FUS (5-10%), co skutkuje neurodegeneracją i zwyrodnieniem czołowo-skroniowym (FTLD). Genetycznie około 40% przypadków ma charakter rodzinny, z mutacjami w genach C9orf72 (25% rodzinnych przypadków), MAPT (11%) i GRN (10%), które wpływają na proteostazę, funkcję lizosomów i metabolizm komórkowy. Kluczowe mechanizmy patogenetyczne to zarówno zysk funkcji toksycznych białek, jak i ich utrata funkcji fizjologicznych, a także dysfunkcja lizosomów i zaburzenia metabolizmu glukozy, potwierdzone hipometabolizmem glukozy w badaniach FDG-PET, który poprzedza objawy kliniczne. Ponadto, istotną rolę odgrywa aktywacja układu odpornościowego mózgu, zwłaszcza mikrogleju, oraz zmiany w metabolizmie lipidów, takie jak obniżenie poziomów kardiolipiny i acylokarnityny, co wskazuje na dysfunkcję mitochondriów, stan zapalny i stres oksydacyjny.

Patogeneza demencji czołowo-skroniowej

Demencja czołowo-skroniowa (FTD) to heterogeniczna grupa zaburzeń neurodegeneracyjnych charakteryzujących się postępującym zanikiem neuronów w płatach czołowych i skroniowych mózgu. Choroba ta prowadzi do zaburzeń osobowości, zachowania, funkcji wykonawczych i języka. FTD jest jedną z głównych przyczyn otępienia u osób poniżej 65. roku życia, stanowiąc około 5-10% wszystkich przypadków otępienia.¹²³

Podstawowe mechanizmy patologiczne

Patogeneza FTD jest wieloczynnikowa i obejmuje zmiany degeneracyjne w obszarach czołowych i skroniowych mózgu. Główną cechą patologiczną choroby jest gromadzenie się nieprawidłowych złogów białkowych w neuronach i komórkach glejowych. Ta akumulacja patologicznych białek prowadzi do postępującej utraty neuronów, tworzenia mikrowakuoli i astrocytozy, co określa się mianem zwyrodnienia czołowo-skroniowego (FTLD).¹²

W przypadkach FTD obserwuje się utratę ponad 70% neuronów wrzecionowatych, podczas gdy inne typy neuronów pozostają względnie nienaruszone. Postępujący zanik neuronów dotyczy przede wszystkim obszarów czołowych i skroniowych mózgu, z początkowymi zmianami często występującymi w przedniej części zakrętu obręczy.¹²

Patologie białek w FTD

FTD charakteryzuje się obecnością nieprawidłowych złogów białkowych w neuronach i komórkach glejowych. Trzy główne białka związane z patogenezą FTD to:¹²³

Białko tau (FTLD-tau) – odpowiada za około 40% przypadków FTD. Charakteryzuje się obecnością cytoplazmatycznych, hiperfosforylowanych, nierozpuszczalnych włókien białka tau w neuronach i komórkach glejowych. Białko tau w warunkach prawidłowych bierze udział w stabilizacji mikrotubul, ale jego nieprawidłowa fosforylacja osłabia interakcję z mikrotubulami, prowadząc do dysocjacji i tworzenia nierozpuszczalnych agregatów.¹²
Białko TDP-43 (FTLD-TDP) – odpowiada za około 50% przypadków FTD. TDP-43 (TAR DNA-binding protein 43) występuje jako nieprawidłowo sfałdowane i ubikwitynowane agregaty w cytoplazmie i jądrach komórkowych neuronów.¹²
Białko FUS (FTLD-FUS) – odpowiada za około 5-10% przypadków FTD. Charakteryzuje się obecnością nieprawidłowych złogów białka FUS (Fused in Sarcoma) w neuronach.¹²

Te patologiczne białka są obecne w nieprawidłowych stężeniach lub formach w komórkach nerwowych, co prowadzi do ich śmierci i postępującego zaniku mózgu.¹²

Genetyczne podstawy FTD

Demencja czołowo-skroniowa ma znaczący komponent genetyczny. Około 40% przypadków FTD ma charakter rodzinny, a 10-30% wykazuje dziedziczenie autosomalnie dominujące. Zidentyfikowano mutacje w ponad 20 genach, które mogą przyczyniać się do rozwoju FTD.¹²³

Najważniejsze geny związane z FTD to:¹²³

C9orf72 – ekspansja powtórzeń heksanukleotydowych (GGGGCC) w pierwszym intronie genu C9orf72 jest najczęstszą przyczyną FTD o podłożu genetycznym na świecie. Stanowi ona około 25% przypadków rodzinnych FTD. Mutacja ta jest również związana z stwardnieniem zanikowym bocznym (ALS), co sugeruje wspólne mechanizmy patogenetyczne.¹²
MAPT (microtubule-associated protein tau) – mutacje w genie MAPT na chromosomie 17 odpowiadają za około 11% wszystkich przypadków FTD. Prowadzą one do niestabilności mikrotubul i zwiększonej skłonności białka tau do samoagregacji, co przyczynia się do neurodegeneracji.¹²
GRN (progranulin) – mutacje w genie progranulin na chromosomie 17 odpowiadają za około 10% wszystkich przypadków FTD i 22% przypadków rodzinnych. Progranulin bierze udział w modulacji zapalenia, wzroście aksonalnym i naprawie tkanek. Mutacje prowadzą do niedoboru progranulin, co skutkuje zaburzeniami w funkcjonowaniu lizosomów.¹²³

Mutacje te przyczyniają się do patologii tau lub TDP-43, co prowadzi do rozwoju FTD. Odkryto również, że uszkodzenia DNA i zaburzenia w ich naprawie są etiologicznie powiązane z FTD.¹²

Mechanizmy komórkowe w patogenezie FTD

Nieprawidłowy metabolizm białek

Kluczowym elementem patogenezy FTD jest nieprawidłowe fałdowanie i agregacja białek, co prowadzi do tworzenia toksycznych wewnątrz- lub zewnątrzkomórkowych inkluzji w neuronach i komórkach glejowych. Te procesy zaburzają proteostazę – równowagę w metabolizmie białek w komórce.¹²

W patogenezie FTD istotną rolę odgrywają dwa mechanizmy:¹

Mechanizm zysku funkcji (gain of function) – patologiczne białka nabywają nowe, toksyczne właściwości, które bezpośrednio szkodzą komórkom.
Mechanizm utraty funkcji (loss of function) – nieprawidłowe białka tracą swoje normalne funkcje fizjologiczne, co prowadzi do zaburzeń komórkowych.

Obecnie uważa się, że oba te mechanizmy odgrywają komplementarne role w patogenezie FTD, przyczyniając się do uszkodzenia neuronów i ekspresji klinicznej choroby.¹²

Dysfunkcja lizosomów i autofagia

Zaburzenia funkcji lizosomów i procesu autofagii są istotnym elementem patogenezy FTD. Lizosomy są odpowiedzialne za degradację i recykling składników komórkowych, w tym nieprawidłowo sfałdowanych białek. W FTD obserwuje się dysfunkcję lizosomów, co prowadzi do akumulacji toksycznych białek i śmierci komórek nerwowych.¹²

Szczególnie istotny jest związek między progranuliną a funkcją lizosomów. Progranulin reguluje funkcję lizosomów i jest niezbędna do prawidłowego usuwania toksycznych białek. Mutacje w genie GRN powodują niedobór progranulin, co prowadzi do dysfunkcji lizosomów i akumulacji patologicznych złogów białkowych.¹²

Badania wykazały, że progranulin w lizosomach pomaga utrzymać poziomy BMP (bis(monoacylglycero)phosphate) niezbędne do zapobiegania akumulacji gangliozydum w komórkach mózgowych – zjawiska, które może przyczyniać się do FTD. Niedobór progranulin prowadzi do zaburzeń w degradacji gangliozydum i ich akumulacji w neuronach.¹²

W modelu FTD związanym z mutacją C9ORF72 zaobserwowano również, że uszkodzenie prowadzi do zmniejszenia liczby lizosomów w komórkach nerwowych. Normalna ilość białka C9ORF72 jest wymagana do produkcji lizosomów, a jego niedobór powoduje akumulację toksycznych białek i śmierć komórek nerwowych.¹²

Zaburzenia metabolizmu glukozy

Zaburzenia metabolizmu glukozy są istotnym elementem patogenezy FTD. Badania z wykorzystaniem FDG-PET wykazały znaczący hipometabolizm glukozy u pacjentów z FTD, z charakterystycznymi wzorcami w różnych podtypach choroby.¹²

Badania podłużne wykazały, że hipometabolizm glukozy nasila się wraz z postępem choroby, a co ważniejsze, poprzedza on wystąpienie objawów klinicznych. U bezobjawowych nosicieli mutacji MAPT obserwowano hipometabolizm glukozy przy pośrednim poziomie atrofii mózgu w porównaniu do objawowych nosicieli.¹

Badania metabolomiczne wykazały również zaburzenia szlaków metabolizmu glukozy na bardziej globalną skalę. Hipometabolizm glukozy poprzedza wystąpienie objawów FTD, co sugeruje, że zaburzenia metabolizmu glukozy mogą odgrywać rolę w patofizjologii FTD.¹²

Badania mechanistyczne ujawniły, że białko TDP-43 odgrywa fundamentalną rolę w utrzymaniu metabolizmu glukozy i dostępności energii poprzez modulację ekspresji kluczowych składników tego szlaku. U pacjentów z FTD obserwuje się zmniejszenie glikolizy, zaburzenie sygnalizacji insulinowej i upośledzenie funkcji mitochondriów, co prowadzi do znaczącego deficytu energetycznego w neuronach.¹²

Rola układu odpornościowego i neuronstanu zapalnego

Coraz więcej dowodów wskazuje na kluczową rolę układu odpornościowego mózgu w patogenezie FTD. Badania genetyczne wykazały nakładanie się genetyczne między FTD a dysfunkcją immunologiczną, szczególnie w regionie HLA na chromosomie 6, obszarze bogatym w geny ważne dla funkcjonowania mikrogleju – rezydentnych komórek odpornościowych mózgu.¹²

Badania na modelach mysich z mutacją w genie progranulin wykazały, że wraz z wiekiem dochodzi do stopniowego pogorszenia funkcjonowania systemów utylizacji odpadów komórkowych w komórkach mikrogleju, co prowadzi do nadmiernej aktywacji funkcji immunologicznych tych komórek, zwiększonej produkcji białek dopełniacza i nadmiernego przycinania synaps w wzgórzu – obszarze mózgu istotnym w FTD.¹

Progranulin działa jako hamulec zapobiegający nadmiernej aktywacji mikrogleju. Badania wykazały zwiększony poziom neuronapłniena w płatach czołowych i skroniowych mózgu u osób z FTD w porównaniu do zdrowych osób kontrolnych, co sugeruje możliwą rolę stanu zapalnego w patogenezie choroby.¹²

Badania modułów genowych związanych z FTD wykazały, że geny HLA-DRA i CTSC grupują się razem we wszystkich badanych regionach mózgu w obrębie zachowanych modułów wskazujących na procesy związane z odpornością i lizosomami w mikrogleju.¹

Zmiany w lipidach i ich rola w FTD

Badania lipidomiczne wykazały istotne zmiany w profilach lipidowych u pacjentów z FTD, co może pomóc wyjaśnić patofizjologię choroby. Analizy oparte na spektrometrii masowej wykazały, że kardiolipina, acylokarnityna, lizofosfatydylocholina, czynnik aktywujący płytki krwi, kwas o-acylo-β-hydroksy tłuszczowy i akroleina są specyficznie zmienione w FTD, z silną korelacją między lipidami.¹

Zmiany te wskazują na trzy kluczowe aspekty patofizjologii FTD:¹²³

Dysfunkcja mitochondriów – poziomy kardiolipiny (CL) i acylokarnityny (AC) były silnie skorelowane, mimo że te dwa lipidy są produkowane niezależnie. Poziomy ATP były znacząco zmniejszone u pacjentów z FTD w porównaniu do kontroli, co potwierdza dysfunkcję mitochondriów.
Stan zapalny – zwiększone poziomy lizofosfatydylocholiny (LPC) i czynnika aktywującego płytki krwi (PAF) wskazują na zwiększoną aktywność zapalną. Te wyniki są zgodne z wcześniejszymi badaniami pokazującymi, że poziomy prozapalnych cytokin są zwiększone w mózgu pacjentów z FTD.
Stres oksydacyjny – zmniejszone poziomy kwasu o-acylo-β-hydroksy tłuszczowego (OAHFA) sugerują zmniejszoną aktywność przeciwzapalną i zwiększony stres oksydacyjny.

Badania te wskazują na potencjalne wykorzystanie badań lipidów do wykrywania dysfunkcji mitochondriów, stanu zapalnego i stresu oksydacyjnego w FTD.¹

Mechanizmy neurodegeneracji w FTD

Przenoszenie patologii między neuronami

Najnowsze dowody wskazują na przenoszenie patologii między neuronami w FTD, podobnie jak w chorobie Alzheimera. Proces ten polega na transmisji nieprawidłowo sfałdowanych białek, takich jak tau czy TDP-43, z neuronu do neuronu w sposób przypominający choroby prionowe, jak choroba Creutzfeldta-Jakoba.¹

Badania wykazały, że patologiczne białka mogą rozprzestrzeniać się w specyficznych sieciach neuroanatomicznych, nadając unikalne cechy kliniczne obserwowane na każdym etapie choroby. Początkowo zmiany patologiczne pojawiają się w określonych, podatnych ośrodkach neuroanatomicznych, a następnie rozprzestrzeniają się na inne obszary mózgu.¹

Selektywna podatność regionów mózgu

W FTD obserwuje się wyraźną selektywną podatność określonych regionów mózgu na neurodegenerację. Badania pośmiertne wykazały atrofię w przedniej i tylnej części zakrętu obręczy w przypadkach FTD, ale tylko w tylnej części zakrętu obręczy w przypadkach choroby Alzheimera.¹

Co ważne, utrata neuronów w przedniej części zakrętu obręczy była obserwowana tylko w przypadkach z patologią tau. Bezpośrednie porównanie między grupami pacjentów wykazało znaczącą utratę neuronów w przedniej części zakrętu obręczy tylko w FTD i tylko w przypadkach z patologią choroby Picka.¹²

Badania te sugerują, że znacząca neurodegeneracja w przedniej części zakrętu obręczy może być użyteczna w różnicowaniu podtypów patologicznych in vivo. Szybka atrofia przedniej części zakrętu obręczy mogłaby być testowana jako wczesny biomarker dla FTLD-tau.¹

Rola elementów retroprzenosnych w FTD

Nowe badania sugerują rolę elementów retroprzenosnych (RE) w rozwoju FTD. Białka TDP-43, tau i FUS zaangażowane w patogenezę FTD posiadają właściwości przeciwwirusowe i wywierają hamujący wpływ na ludzkie elementy transpozycyjne.¹

Patologiczna aktywacja RE w FTD może być związana z indywidualnymi polimorfizmami w genach związanych z RE, ponieważ RE znajdują się głównie w obszarach międzygenowych, regulatorowych i intronowych ludzkiego genomu – obszarach, w których znajduje się większość polimorfizmów związanych z FTD.¹

Wpływ polimorfizmów jednონukleotydowych związanych z FTD zlokalizowanych w regionach RE można zilustrować na przykładzie produktu translacji ORF1p (open reading frame) LINE1, który tworzy agregaty cytoplazmatyczne i wykazuje podobieństwo do białek wiążących RNA zaangażowanych w neurodegenerację.¹

Głównymi czynnikami wyzwalającymi te patologiczne mechanizmy w FTD są starzenie się, które zwiększa aktywację RE, oraz infekcje wirusowe. Mechanizmy zaangażowania aktywowanych RE w patogenezie FTD opisane w literaturze pozwalają zaproponować nowe sposoby leczenia tej choroby ukierunkowane na tłumienie aktywności RE.¹

Związek z innymi chorobami neurodegeneracyjnymi

Związek między FTD i ALS

Badania patologiczne i biochemiczne TDP-43 i FUS pokazują, że pacjenci z FTD, a także osoby z FTD+ALS, jak również osoby z samym ALS, mogą mieć wspólną patogenetyczną podstawę choroby lub przynajmniej wiele wspólnych właściwości molekularnych.¹

Mutacja w genie C9ORF72 jest najczęstszą przyczyną rodzinnej FTD i rodzinnego ALS (stwardnienia zanikowego bocznego), co sugeruje ścisły związek między tymi chorobami.¹

Odkrycie to zostało dokonane w 2011 roku i badania szybko się rozwijają, aby lepiej zrozumieć mechanizm leżący u podstaw mutacji genetycznej, związek między chorobami oraz możliwe próby leczenia.¹

Związek między FTD i schizofrenią

Badania sugerują, że schizofrenia może być czynnikiem ryzyka dla otępienia wszystkich przyczyn, choroby Alzheimera i otępienia naczyniowego, ale nie dla FTD. Metaanaliza badań kohortowych wykazała, że pacjenci cierpiący na schizofrenię mają wyższe ryzyko rozwoju otępienia w porównaniu do osób bez schizofrenii.¹²

Badacze zaproponowali kilka hipotez wyjaśniających związek między schizofrenią a zwiększonym ryzykiem otępienia. Jedna z hipotez zakłada, że nieprawidłowości strukturalne mózgu i starzenie się u pacjentów ze schizofrenią mogą przyczyniać się do przedwczesnego wystąpienia otępienia. Badania wykazały podobne deficyty mikrostrukturalne w istocie białej u pacjentów ze schizofrenią i chorobą Alzheimera.¹²

Schizofrenia jest czasem uważana za chorobę przyspieszonego starzenia się, co może wyjaśniać wysoką częstość występowania otępienia u pacjentów ze schizofrenią. Duża metaanaliza z konsorcjum ENIGMA wykazała, że pacjenci ze schizofrenią mieli pomiary strukturalne mózgu równoważne osobom ponad trzy i pół roku starszym niż zdrowe osoby kontrolne.¹

Nowe kierunki w badaniach nad patogenezą FTD

Obiecujące strategie terapeutyczne

Badania nad patogenezą FTD prowadzą do opracowania nowych strategii terapeutycznych. Obecnie nie ma skutecznych metod leczenia modyfikującego przebieg choroby w FTD, ale trwają badania nad kilkoma obiecującymi podejściami:¹²

Blokowanie białka C1qa – badacze współpracują z firmą biotechnologiczną Annexon, aby przetestować terapie blokujące C1qa, białko dopełniacza związane z nadmiernym przycinaniem synaps w FTD.¹
Zwiększenie poziomu progranulin – AL001 to ludzkie przeciwciało monoklonalne zaprojektowane do modulacji progranulin poprzez hamowanie mechanizmu degradacji progranulin. Badania kliniczne na pacjentach z FTD z mutacją w genie progranulin oceniają bezpieczeństwo i farmakodynamikę tego podejścia.¹²
Zastąpienie BMP zamiast progranulin – badania sugerują, że możliwe jest opracowanie terapii skupiających się na zastępowaniu BMP zamiast progranulin, a tym samym celowanie w inną część mechanizmu.¹²
Przeciwciała protekcyjne – firma Alchemab zidentyfikowała przeciwciało u osób z mutacjami, które normalnie prowadzą do FTD, ale które pozostają zdrowe do późnej starości. Na podstawie sekwencji przeciwciała firma była w stanie zidentyfikować cel i wykazała jego znaczenie w neuroprotekcji w wielu chorobach neurodegeneracyjnych, w tym ALS i FTD.¹
Promowanie metabolizmu glukozy – badania wykazały, że promowanie metabolizmu glukozy w proteinopatiach FUS i TDP-43 łagodzi fenotypy chorobowe, co wskazuje, że metabolizm glukozy może być czynnikiem napędzającym patofizjologię FTD i dlatego może stać się obiecującym celem terapeutycznym.¹

Biomarkery w diagnostyce FTD

Badania nad patogenezą FTD prowadzą również do odkrycia potencjalnych biomarkerów, które mogłyby pomóc w diagnozie i monitorowaniu postępu choroby:¹

Obrazowanie FDG-PET – badania identyfikują znaczący hipometabolizm glukozy u pacjentów z FTD, z możliwymi do zidentyfikowania wzorcami w różnych podtypach, wskazując na potencjał skanów FDG-PET w diagnostyce FTD.¹
Obrazowanie strukturalne MRI – wyraźna asymetryczna atrofia płatów czołowych i/lub skroniowych jest cechą charakterystyczną FTD. W niektórych formach FTD atrofia może być uderzająco asymetryczna, np. w demencji semantycznej, podtypie choroby z postępującą afazją i zwyrodnieniem lewego płata skroniowego.¹
Biomarkery lipidowe – analiza lipidów w surowicy krwi może być użyteczna do wykrywania dysfunkcji mitochondriów, stanu zapalnego i stresu oksydacyjnego w FTD.¹²
Biomarkery immunologiczne – badania wskazują na potencjał metod obrazowania i leczenia dysfunkcji immunologicznej w mózgach pacjentów z FTD.¹

Podsumowanie patogenezy FTD

Patogeneza demencji czołowo-skroniowej jest złożona i wieloczynnikowa. Obejmuje nieprawidłowe gromadzenie się białek tau, TDP-43 i FUS, co prowadzi do neurodegeneracji w płatach czołowych i skroniowych mózgu. Procesy komórkowe zaangażowane w patogenezę FTD obejmują dysfunkcję lizosomów, zaburzenia metabolizmu glukozy, aktywację układu odpornościowego mózgu i zmiany w metabolizmie lipidów.¹²

Genetyczne formy FTD są związane głównie z mutacjami w genach C9orf72, MAPT i GRN, które prowadzą do zaburzeń w proteostazy, funkcji lizosomów i metabolizmu komórkowym. Patologia molekularna FTD obejmuje zarówno mechanizmy zysku funkcji, jak i utraty funkcji patologicznych białek.¹²³

Zrozumienie złożonych mechanizmów patogenetycznych FTD jest kluczowe dla opracowania skutecznych metod diagnostycznych i terapeutycznych. Obecne badania koncentrują się na identyfikacji biomarkerów, które mogłyby pomóc w diagnozie i monitorowaniu postępu choroby, oraz na opracowaniu terapii celowanych na konkretne mechanizmy molekularne zaangażowane w patogenezę FTD.¹²³

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Materiały źródłowe

#1 Frontotemporal dementia – Wikipedia
https://en.wikipedia.org/wiki/Frontotemporal_dementia
Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain’s frontal and temporal lobes. […] FTDs are mostly early onset syndromes linked to frontotemporal lobar degeneration (FTLD), which is characterized by progressive neuronal loss predominantly involving the frontal or temporal lobes, and a typical loss of more than 70% of spindle neurons, while other neuron types remain intact. […] With regard to the genetic defects that have been found, repeat expansion in the C9orf72 gene is considered a major contribution to FTLD, although defects in the GRN and MAPT genes are also associated with it. […] DNA damage and the defective repair of such damages have been etiologically linked to various neurodegenerative diseases including FTD.
#1 Frontotemporal Lobe Dementia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK559286/
Frontotemporal dementia (FTD) is a spectrum of clinical syndromes characterized by neuronal degeneration involving the frontal and anterior temporal lobes of the brain. […] FTD targets brain areas that are responsible for personality, behavior, language learning, motivation, abstract thinking, and executive function. […] Frontotemporal dementia is mainly a sporadic disease. Genetics also plays a key role where approximately 40% of cases are familial in origin. […] Mutations in over 20 genes have been identified in the possible development of FTD. […] Frontotemporal dementia has three distinct clinical syndromes based on the underlying pathologic mechanism characterized by intracellular deposition of abnormal proteins aggregates in the frontal and temporal lobes resulting in the degeneration of neurons, microvacuoles formation, and astrocytosis; hence the term frontotemporal lobar degeneration. […] The abnormal tau protein aggregates have been identified as the main culprit in patients with both sporadic and familial types of FTD except in the svPPA, in which TDP-43 aggregates predominate.
#1 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
Frontotemporal dementia (FTD), hallmarked by antero-temporal degeneration in the human brain, is the second most common early onset dementia. […] The exact pathophysiology of FTD remains to be elucidated. One common characteristic all forms of FTD share is the dysregulation of glucose metabolism in patientsâ brains. […] A better understanding of the link between FTD and glucose metabolism may yield further insight into FTD pathophysiology and aid the development of novel therapeutics. […] FTD is pathogenically diverse; different patients diagnosed with the same clinical form of FTD may present with distinct pathologies, characterized by the presence of misfolded protein aggregates (proteinopathies) in affected regions of the brain. […] To date, four major proteinopathies have been identified in FTD patients: Tau, TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), and ubiquitin positive inclusions.
#1 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
FTD-Tau accounts for 40% of all FTD cases and is characterized by the presence of cytosolic, hyperphosphorylated, insoluble filaments of the microtubule-associated protein Tau (MAPT) in neurons and glia. […] The brainâs glucose metabolism is coupled between neurons and glia via an astrocyte-neuron lactate shuttle (ANLS). […] Most cellular processes are directly linked to glucose metabolism. […] Hence it is unsurprising that many neurodegenerative diseases, including FTD, not only share the formation of protein aggregates, failed protein degradation and cell death, but also impaired glucose metabolism. […] Collectively, these studies identify significant glucose hypometabolism in FTD patients, with identifiable patterns across subtypes indicating the potential of FDG-PET scans in aiding FTD diagnostics.
#1 Role of Retroelements in Frontotemporal Dementia Development
https://www.imrpress.com/journal/FBS/17/1/10.31083/FBS25922/htm
Frontotemporal dementia (FTD) develops in proteinopathies involving TDP-43 (transactive response DNA-binding protein 43 kDa), tau, and FUS (fused in sarcoma) proteins, which possess antiviral properties and exert inhibitory effects on human transposable elements. […] The pathogenesis of FTD, in both familial and sporadic forms, involves the accumulation and misfolding of three primary proteins: TDP-43 (transactive response DNA binding Protein 43 kDa), FUS (fused in sarcoma protein) and microtubule-associated protein Tau, leading to the formation of pathological intracellular aggregates. […] Thus, FTD is one of the common neurodegenerative diseases associated with aging and in most cases is a multifactorial disease. […] The mechanisms of influence of retroelements on the development of FTD described in the article explain the mechanism of influence of disease-associated polymorphisms on the progressive accumulation of tau, TDP-43 and FUS proteins in the brain of patients.
#1 Frontotemporal dementia | Stanford Health Care
https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/dementia/types/frontotemporal-dementia.html
Frontotemporal dementia (FTD) describes a group of diseases characterized by degeneration of nerve cells – especially those in the frontal and temporal lobes of the brain. […] In approximately 50% of people with FTD, there is an abnormal form of tau protein in the brain and about 50% of people with FTD have TDP-43 protein accumulation. […] A small percentage, about 5%, have FUS protein accumulation. This disrupts normal cell activities and may cause the cells to die. […] The cause of Pick’s disease is unknown, but it runs in some families and thus it is probably due at least in part to a faulty gene or genes. […] In some cases, familial FTD is linked to a mutation in a gene called C9ORF72. This mutation is thought to be the most common cause of familial FTD and familial ALS (amyotrophic lateral sclerosis or Lou Gherig’s disease). […] This discovery was made in 2011 and research is rapidly expanding to better understand the mechanism behind the genetic mutation, the relationship between the diseases, and possible treatment trials. […] A mutation in the tau gene (MAPT) or progranulin gene can also cause familial FTD.
#1 What Is Frontotemporal Dementia?
https://www.alzheimers.gov/alzheimers-dementias/frontotemporal-dementia
Frontotemporal dementia is caused by a group of disorders that gradually damage the brains frontal and temporal lobes. […] The underlying causes of frontotemporal dementia are not yet fully understood. People with FTD have abnormal amounts or forms of proteins called tau and TDP-43 inside nerve cells, or neurons, in their brain. The neurons die because the buildup of these proteins causes damage. […] In some cases, changes or differences in genes can be identified as the cause of FTD. For example, about 10% to 30% of bvFTD cases can be attributed to genetic causes. People with a family history of FTD are more likely to have a genetic form of the disease.
#1 Genetics of Frontotemporal Dementia | American Journal of Neuroradiology
http://www.ajnr.org/content/38/1/10
Pathologically, FTD is associated with atrophy of the frontal and/or temporal lobes, gliosis, neuronal swelling, and eventual microvacuolation. […] Pick bodies are hyperphosphorylated tau accumulations in the neuronal cytoplasm, which may be found with silver staining but are not pathognomonic for the disease. […] TAR DNAbinding proteins are hyperphosphorylated, ubiquinated, cleaved proteins and are the most commonly found neuropathology in FTD. […] Approximately 20%40% of FTD cases have a family history of disease, and 10% of FTD cases are inherited in an autosomal dominant fashion. […] The most notable variants are found in MAPT (microtubule-associated protein tau), C9ORF72, and PGRN (progranulin). […] Mutations in the gene MAPT on chromosome 17 have been found to be associated with Pick bodies and FTD.
#1 Genetics of Frontotemporal Dementia | American Journal of Neuroradiology
http://www.ajnr.org/content/38/1/10
MAPT mutations have been shown to be responsible for 11% of overall FTD cases. […] C9ORF72 mutations result in hexanucleotide repeat expansions; however, the mechanism behind this expansion is unclear, and the length of repeats has not been shown to correlate with severity. […] C9ORF72 mutations have shown to result in 6% of overall FTD cases. […] PGRN gene mutations on chromosome 17 likely result in lysosomal impairment and cause ubiquitin-positive cytoplasmic and intranuclear inclusions. […] PGRN mutations have been found to result in 10% of total FTD cases and 22% of familial FTD cases. […] Genetic and idiopathic forms of FTD have similar imaging and genetic mutations, suggesting a common pathophysiology.
#1 Frontotemporal Dementia, Where Do We Stand? A Narrative Review
https://www.mdpi.com/1422-0067/24/14/11732
To date, autosomal dominant mutations in MAPT, GRN, and C9orf72 account for the majority of genetically determined FTD (about 30%), with large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9orf72 being the most common cause worldwide. […] The neuropathology underlying clinical FTD is also heterogeneous: TAR-DNA-binding protein-43 (TDP-43) proteinopathies, especially types A or B, are the commonest causes of genetic FTD, followed by tauopathies, fused-in-sarcoma (FUS) pathologies, and other rarer proteinopathies. […] As for other neurodegenerative diseases, FTD pathomechanism is hallmarked by protein misfolding leading to the formation of toxic extracellular or intracellular inclusions in neuronal and glial cells. […] Several genetic hits (loss of function and toxic gain of function) contribute to alter proteostasis, boosting or sustaining vicious cycles that ultimately dysregulate pivotal cellular components (lysosome, mitochondria, and endoplasmic reticulum) or processes (autophagolysosomal trafficking, RNA homeostasis, endoplasmic reticulum-mitochondrial signalling, and axonal transport) and cause protein accumulation, sensitising cells to insult and finally leading to cell death.
#1 Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects
https://pmc.ncbi.nlm.nih.gov/articles/PMC3445027/
This present paper attempts to critically examine the role of such proteins in relationship to whether they might evidence a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. […] The last decade has seen an extraordinary development in our understanding of FTLD. […] In short, we have provided evidence in this paper arguing as to whether the underlying pathogenetic mechanism(s) appertaining to the major pathological proteins of FTLD can be best represented by gain or loss of function effects. In reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.
#1 Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects
https://pmc.ncbi.nlm.nih.gov/articles/PMC3445027/
We conclude that although there is strong evidence for both gain and loss of function effects in respect of each of the proteins concerned, in reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease. […] Pathological and biochemical studies of TDP-43 and FUS show that patients with FTLD, and others with FTD+MND, as well as those with MND alone, may share a unifying pathogenetic basis for their disease, or at least have many molecular properties in common. However, it is still not clear whether the differing clinical, histological and genetic forms of FTLD represent variations on a common disease theme, or are, in fact, separate disorders in their own right, which coincidentally damage the same or overlapping key brain structures.
#1 Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis | Molecular Neurodegeneration | Full Text
https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-016-0085-4
Our data support the idea of a synergistic interplay between immune system and degradation processes relying on the activation of immune responses, phagocytosis and lysis in the lysosomes, particularly through: i) response to a stimulus (stress, chemical [interferon-gamma or cytokine] or biotic stimulus); ii) activation and aggregation of immune (microglial) cells; iii) signal transduction (mediated by interferon-gamma, cytokine and antigen receptor [MHC class II protein complexes] and transducer activities), and; iv) phagocytosis and lysosomal processing through endocytic vesicles, phagosomes, and endolysosomes. […] The second biological process was defined by HLA-DRA and CTSC that clustered together in all assessed brain regions within preserved modules indicating immune- and lysosomal-related processes in microglia.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/news/20221028/New-clues-into-a-serious-neurodegenerative-disease.aspx
In a study published Oct. 7 in Nature Communications, researchers discovered that a genetic form of frontotemporal dementia (FTD) is associated with accumulation of specific lipids in the brain – and this accumulation results from a protein deficiency that interferes with cell metabolism. […] Together, the findings suggest that progranulin in lysosomes helps maintain the BMP levels needed to prevent gangliosides from accumulating in brain cells – buildup that may contribute to FTD. […] „We’ve uncovered a role for progranulin in supporting proper degradation of gangliosides,” while also showing that it may be possible to correct the problem, Farese said. […] Moreover, it may be possible to develop therapies that focus on replacing BMP rather than progranulin, he said, and thus target a different part of the mechanism.
#1 Azthena logo with the word Azthena
https://www.news-medical.net/news/20180207/USC-scientists-uncover-cellular-mechanism-responsible-for-ALS-and-frontotemporal-dementia.aspx
Scientists have for the first time discovered a mechanism that limits the number of „cellular janitors” in the nervous system, leading to increased risk for two neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, according to a Keck School of Medicine of USC study published today in Nature Medicine. […] In the study, Yingxiao „TK” Shi and Shaoyu Sebastian Lin in the Justin Ichida Laboratory at USC Stem Cell describe how a mutation in a gene called C9ORF72 leads to toxicity in nerve cells. It causes 10 percent of all cases of ALS and an additional 10 percent of frontotemporal dementia. […] Damage begins as a cellular chain reaction. Normally, the C9ORF72 gene, or C9, produces a protein that is required to make lysosomes, which act as cellular janitors to capture and remove toxic proteins and garbage. Without a normal amount of lysosomes, motor nerve cells accumulate toxic garbage and die.
#1 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
These findings also indicate that glucose hypometabolism may have a role in FTD pathogenesis. […] Longitudinal studies concluded there is a continual spread of glucose hypometabolism over time and disease progression. […] These findings indicate that glucose hypometabolism has a role in FTD pathogenesis, not only accompanying but also predating phenotypic disease onset and progression. […] This is supported by the finding that pre-symptomatic FTD causing mutant MAPT carriers had intermediate levels of brain atrophy compared to symptomatic carriers but comparable glucose hypometabolism. […] Considering the close coupling of glucose uptake and cerebral blood flow it is unsurprising that in FTD patients, hypoperfusion and glucose hypometabolism co-localize. […] However, the opposite was observed in FTD patients, with glucose hypometabolism extending beyond the borders of hypoperfusion.
#1 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
Studies looking at the metabolic profile of FTD patients revealed dysregulation of glucose metabolism pathways on a more global scale. […] Collectively both imaging studies and metabolic studies indicate widespread impairment of glucose metabolism across FTD patients, with the brain in particular presenting with glucose hypometabolism. […] These studies indicated that glucose hypometabolism precedes FTD disease onset, suggesting that glucose metabolism dysregulation may play a role in FTD pathophysiology. […] Therefore, understanding the mechanism of impaired glucose metabolism could help clarify FTD pathogenesis and aid the search for novel therapeutics. […] Research has begun to focus on identifying mechanistic links between glucose metabolism and FTD pathophysiology. […] These studies, therefore, suggest that TDP-43 plays a fundamental role in sustaining glucose metabolism, and therefore energy availability, by modulating the expression of key components of the pathway.
#1 Establishing a Link Between Frontotemporal Dementia (FTD) and Immune Dysfunction | UCSF Radiology
https://radiology.ucsf.edu/blog/establishing-link-between-frontotemporal-dementia-ftd-and-immune-dysfunction
Researchers from UC San Francisco have discovered a new link between frontotemporal dementia (FTD) and immune dysfunction. […] This genetic overlap is concentrated within the HLA region on Chromosome 6, an area rich in genes important for the function of microglia the brains resident immune cells. The results suggest that for a subset of FTD patients immune dysfunction may contribute to disease risk and holds promise for future clinical trials targeting immune dysfunction in patients with FTD. […] These SNPs implicate a novel set of genes in the pathogenesis of FTD; genes that the researchers show are overexpressed in the brains of patients with FTD compared to controls, and in microglia compared to other cell types within the brain. […] This study suggests that one important direction for this future work will be the development of methods for imaging and treating immune dysfunction in the brains of patients with FTD.
#1 Brainâs Immune System May Trigger Frontotemporal Dementia | UC San Francisco
https://www.ucsf.edu/news/2016/04/402451/brains-immune-system-may-trigger-frontotemporal-dementia
The researchers found that as the mice aged, the mutation caused a gradual breakdown of microglial cells waste disposal systems, which led to excessive activation of these cells aggressive immune functions, heightened production of complement proteins, and excessive synaptic pruning in the thalamus, a part of the brain that is highly relevant to human FTD. […] Additional experiments on isolated microglia made it clear to the researchers that progranulin normally acts as a brake to prevent excessive microglia activation. […] Huang and his team are now collaborating with a biotech company called Annexon to test therapies that block C1qa. […] Huang says he hopes future research will allow physicians to use this signal to enable earlier diagnosis and to test the effectiveness of potential treatments.
#1 Uncovering pathophysiological changes in frontotemporal dementia using serum lipids | Scientific Reports
https://www.nature.com/articles/s41598-020-60457-w
Blood serum is enriched in lipids and has provided a platform to understand the pathogenesis of a number of human diseases with improved diagnosis and development of biomarkers. […] Frontotemporal dementia (FTD) is a common cause of early onset dementia, characterized by brain atrophy in the frontal and temporal regions, concomitant loss of lipids and dyslipidemia. However, little is known about the link between dyslipidemia and FTD pathophysiology. […] Here, we utilized an innovative approach lipidomics based on mass spectrometry to investigate three key aspects of FTD pathophysiology mitochondrial dysfunction, inflammation, and oxidative stress. […] We found that cardiolipin, acylcarnitine, lysophosphatidylcholine, platelet-activating factor, o-acyl–hydroxy fatty acid and acrolein were specifically altered in FTD with strong correlation between the lipids, signifying pathophysiological changes in FTD.
#1 Uncovering pathophysiological changes in frontotemporal dementia using serum lipids | Scientific Reports
https://www.nature.com/articles/s41598-020-60457-w
These findings are consistent with earlier studies that showed pro-inflammatory cytokine levels are increased in FTD brain. […] We found that the OAHFA levels were significantly decreased in FTD compared to controls (Fig. 3K), suggesting decreased anti-inflammatory activity. […] These results support the use of lipid assays to detect oxidative stress in FTD.
#1 Frontotemporal Dementia and Frontotemporal Lobar Degeneration: Overview, Etiology, Genetic Distribution and Variation
https://emedicine.medscape.com/article/1135164-overview
Tau and progranulin mutations appear to account for the most cases of FTD, and at least in familial cases, true examples of dementia lacking distinctive histologic features have become much less common. […] The most important differential diagnoses for FTD involve focal pathologies such as brain tumors, abscesses, and strokes, as well as Alzheimer disease, which is a more common dementing illness than FTD. […] The findings in electroencephalography (EEG) are commonly abnormal in FTD, often showing focal slowing of electrical activity over 1 or both frontal or temporal lobes. […] Recent evidence supports neuron-to-neuron transmission of pathology in both Alzheimer disease and FTD, involving transmission of the abnormal misfolded proteins of tau or beta-amyloid from neuron to neuron in a way reminiscent of the prion diseases like Creutzfeldt-Jakob disease.
#1 Frontotemporal dementia | MedLink Neurology
https://www.medlink.com/articles/frontotemporal-dementia
Frontotemporal dementia is thought to be caused by the abnormal aggregation of proteins in the brain, which begin in selective, vulnerable neuroanatomical hubs. As the disease progresses, the proteins disseminate through specific neuroanatomical networks, conferring the unique clinical characteristics seen at each stage of the disease. The pathology is heterogeneous, though three major proteins have now been shown to cause the majority of cases of frontotemporal dementia. A large proportion of cases are genetic and caused by mutations in the tau and progranulin genes on chromosome 17 and the C9ORF72 gene on chromosome 9. […] The first protein to be identified in the pathogenesis of frontotemporal dementia was tau (FTLD-tau). Normal tau proteins contribute to axonal transport by binding to microtubular proteins. However, abnormally phosphorylated and aggregated tau proteins are biochemical markers of various forms of degenerative dementia, collectively referred to as tauopathies, and include Alzheimer disease, Pick disease, corticobasal degeneration, progressive supranuclear palsy, and chronic traumatic encephalopathy (amongst others).
#1 The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimerâs disease | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-30
Early atrophy of the cingulate cortex is a feature of both behavioral variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD), with degeneration of the anterior cingulate region increasingly recognized as a strong predictor of bvFTD. […] The present study assesses total neuronal number, as well as characteristic pathologies, in the anterior and posterior cingulate cortices of pathologically confirmed bvFTD (N=11) and AD (N=9) patients compared with age-matched controls (N=14). […] At postmortem, atrophy was detected in the anterior and posterior cingulate cortices of bvFTD cases, but only in the posterior cingulate cortex of AD cases. […] Importantly, neuronal loss in the anterior cingulate cortex was only observed in cases with tau pathology. […] This study confirms significant neuronal loss in the posterior but not anterior cingulate cortex in AD, and demonstrates that significant neuron loss in bvFTD occurs only in the anterior cingulate cortex but only in cases with tau pathology compared with cases with TDP pathology.
#1 The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimerâs disease | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-30
We propose that significant neurodegeneration in the anterior cingulate cortex may be useful in differentiating the pathological subtypes in vivo. […] The degree of cingulate atrophy demonstrated in structural imaging suggests considerable degeneration of neurons in both dementia groups, which our data supports. […] However, direct comparison between patient groups showed significant AC neuronal loss only in bvFTD and only in cases with Pick disease pathology, while we can confirm significant PC neuronal loss occurs in AD. […] In bvFTD, neuronal loss in AC was observed only in cases with FTLD-tau (Pick bodies) compared to those with FTLD-TDP. […] This suggests that rapid AC atrophy could be tested as an early biomarker for FTLD-tau, although this finding would need to be confirmed in other tauopathies as only Pick disease was included in the present study. […] The present findings suggest that greater atrophy of AC may predict FTLD-tau, a finding worthy of further clinicopathological validation.
#1 Role of Retroelements in Frontotemporal Dementia Development
https://www.imrpress.com/journal/FBS/17/1/10.31083/FBS25922/htm
Pathological activation of REs in FTD could be linked to individual polymorphisms within RE-associated genes, as REs are primarily located in intergenic, regulatory, and intronic regions of the human genome – regions where most FTD-associated polymorphisms are found. […] The influence of FTD-associated SNPs localized in REs regions can be illustrated by the ORF1p (open reading frame) translation product of LINE1, which forms cytoplasmic aggregates and shares similarity with RNA-binding proteins implicated in neurodegeneration. […] The primary triggers of these pathological mechanisms in FTD are aging, which enhances the activation of REs, and viral infections. […] The mechanisms of involvement of activated REs in the pathogenesis of FTD described in the article allow us to propose new ways of treating this disease aimed at suppressing the activity of REs.
#1 Causal relationship between schizophrenia and five types of dementia: A bidirectional two-sample Mendelian randomization study | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322752
Although observational research indicates an association between schizophrenia and dementia, it is unclear whether the two are causally related. […] In order to examine the causal relationship between schizophrenia and five types of dementia (all-cause dementia, Alzheimers disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies), we performed a bidirectional two-sample Mendelian randomization analysis. […] Our findings suggest that schizophrenia may be a risk factor for all-cause dementia, Alzheimers disease, and vascular dementia, but no dementia of any kind was found to be a risk factor for schizophrenia. […] However, the pathogenesis of dementia is complex, and no curative treatments are currently available. […] Emerging evidence suggests that dementia and schizophrenia may share a common genetic basis.
#1 Causal relationship between schizophrenia and five types of dementia: A bidirectional two-sample Mendelian randomization study | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322752
A meta-analysis of cohort studies indicated that patients living with schizophrenia have a higher risk of developing dementia compared to those without schizophrenia. […] A cohort study in Danish, based on 2.8 million people, conducted follow-up for 18 years and found that the risk of all-cause dementia (ACD) in patients living with schizophrenia is more than twice that of the general population. […] Our findings suggest that schizophrenia may be a risk factor for ACD, AD, and VaD, aligning with previous observational studies. […] So far, the exact mechanism by which schizophrenia affects dementia remains unclear. […] Scholars have proposed several hypotheses to explain the association between schizophrenia and increased dementia risk. […] One hypothesis is that structural brain abnormalities and aging in patients living with schizophrenia may contribute to premature onset of dementia.
#1 Causal relationship between schizophrenia and five types of dementia: A bidirectional two-sample Mendelian randomization study | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322752
A study found that strikingly similar microstructural deficits in the white matter of patients living with schizophrenia and AD. […] Additionally, schizophrenia is sometimes hypothesized to be a disease of accelerated aging, which may explain the high incidence of dementia in patients living with schizophrenia. […] A large meta-analysis from the ENIGMA consortium found that patients living with schizophrenia had structural brain measurements equivalent to those of individuals more than three and a half years older than healthy controls. […] Second, metabolic dysfunction might contribute to premature dementia in patients living with schizophrenia. […] Third, psychotropic medications may exacerbate cognitive impairment in patients living with schizophrenia. […] No causal association was found between schizophrenia and FTD or DLB, according to this MR study.
#1 Frontotemporal dementia (FTD) â what is it and how close is a cure? – Alzheimer’s Research UK
https://www.alzheimersresearchuk.org/news/frontotemporal-dementia-ftd-what-is-it-and-how-close-is-a-cure/
A lot of research currently focusses on how these tau tangles start to form, and then spread throughout the frontal and temporal lobes to cause FTD. […] The mechanisms behind this are complex and not yet fully understood, but research is helping to identify why this happens. […] Sadly, there are currently no approved treatments available that can slow, stop or cure the diseases that cause FTD. […] Thatâs why we urgently need more research into FTD, so that we can understand the complexities of this heart-breaking condition and use this information to identify how we can treat it. […] While investigating this process in fruit flies, we found a way to help flies with the C9orf72 mutation live for longer. […] If this also works in humans, it could be the basis of searching for new FTD treatments.
#1 Alector Announces First Frontotemporal Dementia Patient Dosed in Phase 1b Study of AL001 | Alector
https://investors.alector.com/news-releases/news-release-details/alector-announces-first-frontotemporal-dementia-patient-dosed
Phase 1b study of AL001 enrolling frontotemporal dementia (FTD) patients with a mutation in the progranulin gene will assess safety and pharmacodynamics, and will monitor target specific biomarkers […] In a subset of FTD patients, mutations in a single copy of the progranulin gene lead to a 50% or greater decrease in the level of progranulin, which in turn leads to development of FTD with greater than 90% penetrance. This subset of patients is known as FTD-GRN. Alector aims to deploy AL001 to increase the level of progranulin in FTD-GRN patients, by inhibiting a progranulin degradation mechanism. […] AL001âs therapeutic approach is conceptually similar to enzyme replacement therapy and as such AL001 is designed to increase the level of progranulin in these FTD-GRN patients. […] Mutations in a single copy of progranulin lead to a 50% or greater decrease in the level of progranulin and lead to development of FTD with greater than 90% penetrance. To date researchers have identified over 70 inherited loss of function mutations in progranulin that lead to FTD.
#1 Alchemab Therapeutics signs landmark $415m licensing agreement for ATLX-1282 with Eli Lilly and Company
https://www.prnewswire.co.uk/news-releases/alchemab-therapeutics-signs-landmark-415m-licensing-agreement-for-atlx-1282-with-eli-lilly-and-company-302446217.html
Through its research, Alchemab has identified an antibody in people with mutations that normally lead to frontotemporal dementia (FTD), but who remain well into old age. […] Starting from the antibody sequence, Alchemab was able to identify the target and has subsequently demonstrated its importance in neuroprotection, and across multiple neurodegenerative conditions including ALS and FTD.
#1 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
In summary, impaired glucose metabolism is extensively observed in FTD patients, and modeling of the underlying proteinopathies suggests direct modulation of glucose metabolism. […] Common themes appear to emerge, most proteinopathies lead to reduced glycolysis, defective insulin signaling and impaired mitochondrial function. […] The concomitant impairment of glycolysis and mitochondrial activity could lead to a substantial energetic deficit in neurons in FTD. […] However, glucose metabolism dysregulation can also act upstream of the proteinopathies: genetic risk factors (such as C9) can modulate glucose metabolism in the absence of downstream proteinopathy, and a reduction of insulin signaling can exacerbate Tauopathies, suggesting glucose metabolism dysregulation may act to exacerbate proteinopathy as well as downstream toxicity. […] The finding that promoting glucose metabolism in FUS and TDP-43 proteinopathies ameliorates disease phenotypes indicates that glucose metabolism could be a driver of FTD pathophysiology and therefore could become a promising therapeutic target.
#1 Frontotemporal dementia: Epidemiology, pathology, and pathogenesis – UpToDate
https://www.uptodate.com/contents/frontotemporal-dementia-epidemiology-pathology-and-pathogenesis/print
Frontotemporal dementia (FTD) is a clinically and neuropathologically heterogeneous disorder characterized by disturbances in behavior, personality, and language accompanied by focal neurodegeneration of the frontal and/or temporal lobes. […] Each clinical FTD syndrome may be associated with different neuropathologies, which poses a significant challenge to the development and testing of therapies designed to target specific protein dysfunction in neurodegeneration. […] This topic will review the epidemiology, pathogenesis, and pathology of FTD.
#1 The Radiology Assistant : Dementia – Role of MRI
https://radiologyassistant.nl/neuroradiology/dementia/role-of-mri
Frontotemporal Lobar Degeneration (FTLD): (asymmetric) frontal lobe atrophy and atrophy of the temporal pole. […] FTLD, formerly called Pick’s disease, is a progressive dementia, that accounts for 5-10% of cases of dementia., and occurs relatively more frequently in presenile subjects FTLD is clinically characterized by behavioral and language disturbances that may precede or overshadow memory deficits. […] Imaging plays an important role in the diagnosis as the findings are easy to recognize. Radiological findings are pronounced atrophy of frontal and / or temporal lobes. […] In some forms of FTLD the atrophy might be strikingly asymmetric, e.g. in Semantic Dementia, a disease subtype with progressive aphasia and left-sided temporal lobe degeneration. […] The most prominent finding is the striking asymmetric atrophy of the temporal lobe on the left side with not only atrophy of the hippocampus, but also the temporal poles. The atrophy has resulted in gyri that appear as sharp as knives (’knife blade atrophy’). […] These findings are pathognomonic for the diagnosis of FTLD.
#2 Frontotemporal Lobe Dementia – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK559286/
Frontotemporal dementia (FTD) is a spectrum of clinical syndromes characterized by neuronal degeneration involving the frontal and anterior temporal lobes of the brain. […] FTD targets brain areas that are responsible for personality, behavior, language learning, motivation, abstract thinking, and executive function. […] Frontotemporal dementia is mainly a sporadic disease. Genetics also plays a key role where approximately 40% of cases are familial in origin. […] Mutations in over 20 genes have been identified in the possible development of FTD. […] Frontotemporal dementia has three distinct clinical syndromes based on the underlying pathologic mechanism characterized by intracellular deposition of abnormal proteins aggregates in the frontal and temporal lobes resulting in the degeneration of neurons, microvacuoles formation, and astrocytosis; hence the term frontotemporal lobar degeneration. […] The abnormal tau protein aggregates have been identified as the main culprit in patients with both sporadic and familial types of FTD except in the svPPA, in which TDP-43 aggregates predominate.
#2
https://journals.lww.com/neur/fulltext/2021/69050/frontotemporal_dementia___current_concepts.3.aspx
Frontotemporal dementia (FTD) is an entity that includes a group of neurodegenerative disease with symptoms predominantly pertaining to deficits in behavior, executive function (or) language. […] Frontotemporal dementia (FTD) has an insidious onset and slowly progressive course, which is characterized by progressive impairment in behavior, language, and functions associated with execution. It is considered as the third most common cause of dementia and one of the most common cause of early onset dementia. […] FTD is characterized predominantly by gliosis, neuronal loss, and microvacuolar changes, which were predominantly seen in anterior temporal lobe, frontal lobe, insular cortex, and anterior cingulate cortex with initial changes occurring in anterior cingulate cortex in most of the cases.
#2 The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimerâs disease | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-30
Early atrophy of the cingulate cortex is a feature of both behavioral variant frontotemporal dementia (bvFTD) and Alzheimers disease (AD), with degeneration of the anterior cingulate region increasingly recognized as a strong predictor of bvFTD. […] The present study assesses total neuronal number, as well as characteristic pathologies, in the anterior and posterior cingulate cortices of pathologically confirmed bvFTD (N=11) and AD (N=9) patients compared with age-matched controls (N=14). […] At postmortem, atrophy was detected in the anterior and posterior cingulate cortices of bvFTD cases, but only in the posterior cingulate cortex of AD cases. […] Importantly, neuronal loss in the anterior cingulate cortex was only observed in cases with tau pathology. […] This study confirms significant neuronal loss in the posterior but not anterior cingulate cortex in AD, and demonstrates that significant neuron loss in bvFTD occurs only in the anterior cingulate cortex but only in cases with tau pathology compared with cases with TDP pathology.
#2 Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects
https://pmc.ncbi.nlm.nih.gov/articles/PMC3445027/
Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Three major proteins are implicated in its pathogenesis. About half of cases are characterized by depositions of the microtubule associated protein, tau (FTLD-tau). In most of the remaining cases, deposits of the transactive response (TAR) DNA-binding protein with Mw of 43 kDa, known as TDP-43 (FTLD-TDP), are seen. Lastly, about 510 % of cases are characterized by abnormal accumulations of a third protein, fused in sarcoma (FTLD-FUS). […] This present paper attempts to critically examine the role of such proteins in the pathogenesis of FTLD and MND as to whether they might exert a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect.
#2 Frontotemporal dementia | MedLink Neurology
https://www.medlink.com/articles/frontotemporal-dementia
Frontotemporal dementia is thought to be caused by the abnormal aggregation of proteins in the brain, which begin in selective, vulnerable neuroanatomical hubs. As the disease progresses, the proteins disseminate through specific neuroanatomical networks, conferring the unique clinical characteristics seen at each stage of the disease. The pathology is heterogeneous, though three major proteins have now been shown to cause the majority of cases of frontotemporal dementia. A large proportion of cases are genetic and caused by mutations in the tau and progranulin genes on chromosome 17 and the C9ORF72 gene on chromosome 9. […] The first protein to be identified in the pathogenesis of frontotemporal dementia was tau (FTLD-tau). Normal tau proteins contribute to axonal transport by binding to microtubular proteins. However, abnormally phosphorylated and aggregated tau proteins are biochemical markers of various forms of degenerative dementia, collectively referred to as tauopathies, and include Alzheimer disease, Pick disease, corticobasal degeneration, progressive supranuclear palsy, and chronic traumatic encephalopathy (amongst others).
#2 Frontotemporal dementia | MedLink Neurology
https://www.medlink.com/articles/frontotemporal-dementia
The majority of cases of frontotemporal dementia, however, are not tau-reactive. Rather, they display ubiquitin-immunopositive histology. These cases were termed dementia lacking distinctive histology for many years. It was eventually found that these cases displayed ubiquitinated protein inclusions (FTLD-U); however, the exact protein was unknown. This changed in 2006, when it was determined that transactive response DNA-binding protein 43kDa (TDP-43) was the protein responsible for most ubiquitin-positive cases of frontotemporal dementia. It has now been shown that approximately 50% of all cases of frontotemporal dementia have TDP-43 pathology, as well as the vast majority of cases with amyotrophic lateral sclerosis. […] In 2009, ubiquitinated FUS protein inclusions were found to be responsible for the majority of the remaining tau/TDP-43 negative frontotemporal dementia cases, constituting the third major pathological subtype of frontotemporal dementia.
#2 Frontotemporal Dementia (FTD) | Symptoms & Treatments | alz.org
https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/frontotemporal-dementia
Frontotemporal dementia (FTD) or frontotemporal degeneration refers to a group of disorders caused by progressive nerve cell loss in the brain’s frontal lobes (the areas behind your forehead) or its temporal lobes (the regions behind your ears). […] The nerve cell damage caused by frontotemporal dementia leads to loss of function in these brain regions, which variably cause deterioration in behavior, personality and/or difficulty with producing or comprehending language. […] There are a number of different diseases that cause frontotemporal degeneration. The two most prominent are 1) a group of brain disorders involving the protein tau and 2) a group of brain disorders involving the protein called TDP43. For reasons that are not yet known, these two groups have a preference for the frontal and temporal lobes that cause dementia.
#2 Frontotemporal Dementia, Where Do We Stand? A Narrative Review
https://www.mdpi.com/1422-0067/24/14/11732
Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. […] Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. […] Advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). […] FTD is a highly heritable group of neurodegenerative disorders with a vast genetical heterogeneity. Overall, about 40% of FTD patients have a positive family history of dementia, psychiatric diseases, or motor symptoms with 10% of them showing an autosomal dominant inheritance pattern.
#2 Frontotemporal Dementia, Where Do We Stand? A Narrative Review
https://www.mdpi.com/1422-0067/24/14/11732
To date, autosomal dominant mutations in MAPT, GRN, and C9orf72 account for the majority of genetically determined FTD (about 30%), with large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9orf72 being the most common cause worldwide. […] The neuropathology underlying clinical FTD is also heterogeneous: TAR-DNA-binding protein-43 (TDP-43) proteinopathies, especially types A or B, are the commonest causes of genetic FTD, followed by tauopathies, fused-in-sarcoma (FUS) pathologies, and other rarer proteinopathies. […] As for other neurodegenerative diseases, FTD pathomechanism is hallmarked by protein misfolding leading to the formation of toxic extracellular or intracellular inclusions in neuronal and glial cells. […] Several genetic hits (loss of function and toxic gain of function) contribute to alter proteostasis, boosting or sustaining vicious cycles that ultimately dysregulate pivotal cellular components (lysosome, mitochondria, and endoplasmic reticulum) or processes (autophagolysosomal trafficking, RNA homeostasis, endoplasmic reticulum-mitochondrial signalling, and axonal transport) and cause protein accumulation, sensitising cells to insult and finally leading to cell death.
#2 Frontotemporal dementia | Stanford Health Care
https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/dementia/types/frontotemporal-dementia.html
Frontotemporal dementia (FTD) describes a group of diseases characterized by degeneration of nerve cells – especially those in the frontal and temporal lobes of the brain. […] In approximately 50% of people with FTD, there is an abnormal form of tau protein in the brain and about 50% of people with FTD have TDP-43 protein accumulation. […] A small percentage, about 5%, have FUS protein accumulation. This disrupts normal cell activities and may cause the cells to die. […] The cause of Pick’s disease is unknown, but it runs in some families and thus it is probably due at least in part to a faulty gene or genes. […] In some cases, familial FTD is linked to a mutation in a gene called C9ORF72. This mutation is thought to be the most common cause of familial FTD and familial ALS (amyotrophic lateral sclerosis or Lou Gherig’s disease). […] This discovery was made in 2011 and research is rapidly expanding to better understand the mechanism behind the genetic mutation, the relationship between the diseases, and possible treatment trials. […] A mutation in the tau gene (MAPT) or progranulin gene can also cause familial FTD.
#2 Pathophysiology of dementia
https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia
The pathophysiology of dementia is broadly thought to be related to the aggregation and accumulation of misfolded proteins (termed proteinopathies) and/or associated with cerebrovascular disease (CVD). The most common cause of late-onset dementia is AD, followed by dementia with Lewy bodies (DLB), vascular dementia and frontotemporal dementia (FTD). […] As suggested by the name, the common neuropathological feature of FTD is the relatively selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration) associated with characteristic protein inclusions, such as microtubule-associated protein tau (MAPT) and TDP-43. […] Genetic factors play an important role in the pathogenesis of FTD. A family history of dementia has been implicated in up to 40% of cases of FTD and approximately 20% of cases of FTD are attributed to a genetic mutation, with the most common mutations being associated with the MAPT, progranulin and chromosome 9 open reading frame 72 (C9orf72) genes.
#2
https://journals.lww.com/neur/fulltext/2021/69050/frontotemporal_dementia___current_concepts.3.aspx
Either TAR DNA-binding protein 43 (TDP-43) (or) microtubule-associated protein Tau (MAPT) (or) Fused in sarcoma (FUS) protein account for almost all cases of FTLD. Based on this, the FTD was sub categorized into FTLD-TDP, FTLD-Tau, FTLD-FUS. […] Around 40% of patients with FTLD have family history, of which mutations involving GRN, MAPT, and C9orf72 (chromosome 9 open reading frame 72) accounts for 60% of all inherited FTLD. […] MAPT mutations were the first to be identified as the cause of inherited FTD. These mutations lead to microtubule instability with increased propensity of Tau self-aggregation which may lead to neurodegeneration. […] Progranulin (GRN) is involved in modulation of inflammation, axonal growth, and wound repair. […] C9orf72 gene mutation is the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) spectrum, and it constitutes for about 25% of familial cases of FTLD due to expansion of noncoding GGGGCC hexanucleotide repeat. […] There are no specific treatment options available for FTD; most often the treatment is aimed at educating the patient caregivers about the disease condition and symptomatic pharmacotherapy.
#2 Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects
https://pmc.ncbi.nlm.nih.gov/articles/PMC3445027/
This present paper attempts to critically examine the role of such proteins in relationship to whether they might evidence a direct pathogenetic effect (gain of function), or simply act as relatively innocent witnesses to a more fundamental loss of function effect. […] The last decade has seen an extraordinary development in our understanding of FTLD. […] In short, we have provided evidence in this paper arguing as to whether the underlying pathogenetic mechanism(s) appertaining to the major pathological proteins of FTLD can be best represented by gain or loss of function effects. In reality, it is likely that each is a single face of either side of the coin, and that both will play separate, though complementary, roles in driving the damage which ultimately leads to the downfall of neurons and clinical expression of disease.
#2 Azthena logo with the word Azthena
https://www.news-medical.net/news/20180207/USC-scientists-uncover-cellular-mechanism-responsible-for-ALS-and-frontotemporal-dementia.aspx
Scientists have for the first time discovered a mechanism that limits the number of „cellular janitors” in the nervous system, leading to increased risk for two neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, according to a Keck School of Medicine of USC study published today in Nature Medicine. […] In the study, Yingxiao „TK” Shi and Shaoyu Sebastian Lin in the Justin Ichida Laboratory at USC Stem Cell describe how a mutation in a gene called C9ORF72 leads to toxicity in nerve cells. It causes 10 percent of all cases of ALS and an additional 10 percent of frontotemporal dementia. […] Damage begins as a cellular chain reaction. Normally, the C9ORF72 gene, or C9, produces a protein that is required to make lysosomes, which act as cellular janitors to capture and remove toxic proteins and garbage. Without a normal amount of lysosomes, motor nerve cells accumulate toxic garbage and die.
#2 Brainâs Immune System May Trigger Frontotemporal Dementia | UC San Francisco
https://www.ucsf.edu/news/2016/04/402451/brains-immune-system-may-trigger-frontotemporal-dementia
The researchers found that as the mice aged, the mutation caused a gradual breakdown of microglial cells waste disposal systems, which led to excessive activation of these cells aggressive immune functions, heightened production of complement proteins, and excessive synaptic pruning in the thalamus, a part of the brain that is highly relevant to human FTD. […] Additional experiments on isolated microglia made it clear to the researchers that progranulin normally acts as a brake to prevent excessive microglia activation. […] Huang and his team are now collaborating with a biotech company called Annexon to test therapies that block C1qa. […] Huang says he hopes future research will allow physicians to use this signal to enable earlier diagnosis and to test the effectiveness of potential treatments.
#2 Azthena logo with the word Azthena
https://www.news-medical.net/news/20221028/New-clues-into-a-serious-neurodegenerative-disease.aspx
The researchers also think that a similar lysosome-based mechanism could be relevant for neurodegenerative diseases beyond FTD – an idea that they note is rapidly gaining ground in the field. […] More research is needed, Farese added, to understand precisely how various lipids and proteins interact with lysosomes within the context of different neurodegenerative diseases. […] A central remaining question is how progranulin elevates BMP levels in the brain. Additional studies are needed to further elucidate the steps of the mechanism the team uncovered and to explain how lipid accumulation translates into cognitive decline.
#2 Azthena logo with the word Azthena
https://www.news-medical.net/news/20180207/USC-scientists-uncover-cellular-mechanism-responsible-for-ALS-and-frontotemporal-dementia.aspx
Specifically, insufficient lysosomes cause cells to accumulate two key types of garbage: a big, toxic protein produced by the mutated C9 gene and molecules that receive signals from a neurotransmitter known as glutamate. Too much glutamate hyperstimulates motor nerve cells to death, a phenomenon known as „excitotoxicity.” […] Guided by these discoveries, the Ichida Lab is now using the patient-derived motor nerve cells to test thousands of potential drugs, with focus on those that affect lysosomes. The goal is to find potential drugs that slow or stop degeneration of these motor nerve cells in petri dishes – and eventually in patients.
#2 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
These findings also indicate that glucose hypometabolism may have a role in FTD pathogenesis. […] Longitudinal studies concluded there is a continual spread of glucose hypometabolism over time and disease progression. […] These findings indicate that glucose hypometabolism has a role in FTD pathogenesis, not only accompanying but also predating phenotypic disease onset and progression. […] This is supported by the finding that pre-symptomatic FTD causing mutant MAPT carriers had intermediate levels of brain atrophy compared to symptomatic carriers but comparable glucose hypometabolism. […] Considering the close coupling of glucose uptake and cerebral blood flow it is unsurprising that in FTD patients, hypoperfusion and glucose hypometabolism co-localize. […] However, the opposite was observed in FTD patients, with glucose hypometabolism extending beyond the borders of hypoperfusion.
#2 Metabolic dysregulation in Frontotemporal Dementia – Rhode Island IDeA Network of Biomedical Research Excellence
https://web.uri.edu/riinbre/32882-2/
Metabolic processes are dysregulated in FTD and contribute to disease pathogenesis. […] This project aims to identify the metabolic pathways that are altered in FTD and determine the cause of this dysregulation with the goal of providing targets for potential treatment options.
#2 Frontiers | Frontotemporal Dementia and Glucose Metabolism
https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.812222/full
In summary, impaired glucose metabolism is extensively observed in FTD patients, and modeling of the underlying proteinopathies suggests direct modulation of glucose metabolism. […] Common themes appear to emerge, most proteinopathies lead to reduced glycolysis, defective insulin signaling and impaired mitochondrial function. […] The concomitant impairment of glycolysis and mitochondrial activity could lead to a substantial energetic deficit in neurons in FTD. […] However, glucose metabolism dysregulation can also act upstream of the proteinopathies: genetic risk factors (such as C9) can modulate glucose metabolism in the absence of downstream proteinopathy, and a reduction of insulin signaling can exacerbate Tauopathies, suggesting glucose metabolism dysregulation may act to exacerbate proteinopathy as well as downstream toxicity. […] The finding that promoting glucose metabolism in FUS and TDP-43 proteinopathies ameliorates disease phenotypes indicates that glucose metabolism could be a driver of FTD pathophysiology and therefore could become a promising therapeutic target.
#2 Brainâs Immune System May Trigger Frontotemporal Dementia | UC San Francisco
https://www.ucsf.edu/news/2016/04/402451/brains-immune-system-may-trigger-frontotemporal-dementia
Frontotemporal dementia (FTD), the second most common cause of dementia in people under 65, may be triggered by a defect in immune cells called microglia that causes them to consume the brains synaptic connections, according to new research led by UCSF scientists. […] The new study published April 21, 2016 in the journal Cell adds to growing evidence that the brains immune system is a driving force behind many neurodegenerative diseases, and suggests new approaches to diagnosing and treating patients with FTD, which currently affects as many as 22 out of 100,000 adults, with typical onset between the ages of 45 and 65. […] The brains innate immune system is emerging as a common pathway behind many neurodegenerative disorders, said senior author Eric Huang, MD, PhD, a professor of pathology at UCSF and pathologist at the UCSF-affiliated San Francisco VA Medical Center.
#2 Frontotemporal Dementia (FTD) & Brain Research – Precisionary
https://precisionary.com/frontotemporal-dementia-ftd-brain-research/?srsltid=AfmBOorjq12mjwOU3vnbhZsBmc5-_rWpCMB7zGjh73MhsdmBLqUv6mW4
One study published in the Journal of Neuropathology and Experimental Neurology in 2021 used the Compresstome to prepare brain tissue sections for analysis of neuroinflammation in FTD. The researchers found evidence of increased neuroinflammation in the frontal and temporal lobes of the brain in people with FTD compared to healthy controls, suggesting a possible role for inflammation in the pathogenesis of the disease. […] Another study published in Acta Neuropathologica Communications in 2019 used the Compresstome to prepare brain tissue sections for analysis of tau protein aggregation in FTD. The researchers found evidence of widespread tau pathology in the brains of people with FTD, which is a hallmark feature of the disease.
#2 Uncovering pathophysiological changes in frontotemporal dementia using serum lipids | Scientific Reports
https://www.nature.com/articles/s41598-020-60457-w
The second aim was to uncover lipid species and lipid synthesis pathways that could be exploited to develop biomarkers for FTD. […] We compared the levels of CL and AC in FTD and control sera. […] Importantly, CL levels were strongly correlated to AC levels (Pearsons correlation = 0.910; P=1.11024) despite the fact that the two lipids are produced independently. These results strongly suggest mitochondrial dysfunction in FTD. […] We found that the ATP levels were significantly decreased in FTD compared to controls (Fig. 2H), supporting our lipid data. […] We were interested in whether inflammation in FTD could be detected by analysis of serum lipids. […] Increases in LPC and PAF levels would indicate increased inflammatory activity. […] Our data is consistent with earlier findings that both ATP level and ATP synthase expression/activity are decreased in FTD brain and FTD mouse models.
#2 The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimerâs disease | Acta Neuropathologica Communications | Full Text
https://actaneurocomms.biomedcentral.com/articles/10.1186/2051-5960-1-30
We propose that significant neurodegeneration in the anterior cingulate cortex may be useful in differentiating the pathological subtypes in vivo. […] The degree of cingulate atrophy demonstrated in structural imaging suggests considerable degeneration of neurons in both dementia groups, which our data supports. […] However, direct comparison between patient groups showed significant AC neuronal loss only in bvFTD and only in cases with Pick disease pathology, while we can confirm significant PC neuronal loss occurs in AD. […] In bvFTD, neuronal loss in AC was observed only in cases with FTLD-tau (Pick bodies) compared to those with FTLD-TDP. […] This suggests that rapid AC atrophy could be tested as an early biomarker for FTLD-tau, although this finding would need to be confirmed in other tauopathies as only Pick disease was included in the present study. […] The present findings suggest that greater atrophy of AC may predict FTLD-tau, a finding worthy of further clinicopathological validation.
#2 Causal relationship between schizophrenia and five types of dementia: A bidirectional two-sample Mendelian randomization study | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322752
A meta-analysis of cohort studies indicated that patients living with schizophrenia have a higher risk of developing dementia compared to those without schizophrenia. […] A cohort study in Danish, based on 2.8 million people, conducted follow-up for 18 years and found that the risk of all-cause dementia (ACD) in patients living with schizophrenia is more than twice that of the general population. […] Our findings suggest that schizophrenia may be a risk factor for ACD, AD, and VaD, aligning with previous observational studies. […] So far, the exact mechanism by which schizophrenia affects dementia remains unclear. […] Scholars have proposed several hypotheses to explain the association between schizophrenia and increased dementia risk. […] One hypothesis is that structural brain abnormalities and aging in patients living with schizophrenia may contribute to premature onset of dementia.
#2 Causal relationship between schizophrenia and five types of dementia: A bidirectional two-sample Mendelian randomization study | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322752
A study found that strikingly similar microstructural deficits in the white matter of patients living with schizophrenia and AD. […] Additionally, schizophrenia is sometimes hypothesized to be a disease of accelerated aging, which may explain the high incidence of dementia in patients living with schizophrenia. […] A large meta-analysis from the ENIGMA consortium found that patients living with schizophrenia had structural brain measurements equivalent to those of individuals more than three and a half years older than healthy controls. […] Second, metabolic dysfunction might contribute to premature dementia in patients living with schizophrenia. […] Third, psychotropic medications may exacerbate cognitive impairment in patients living with schizophrenia. […] No causal association was found between schizophrenia and FTD or DLB, according to this MR study.
#2 Frontotemporal Dementia (FTD) | Symptoms & Treatments | alz.org
https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/frontotemporal-dementia
Frontotemporal degeneration is inherited in about a third of all cases. Genetic counseling and testing are available now for individuals with family histories of frontotemporal degeneration. There are no known risk factors for any frontotemporal degeneration except for a family history or a similar disorder. […] There are no specific treatments for any of the frontotemporal subtypes. There are medications that can reduce agitation, irritability and/or depression. These treatments should be used to help improve quality of life. […] Frontotemporal dementia inevitably gets worse over time and the speed of decline differs from person to person. For many years, individuals with frontotemporal dementia show muscle weakness and coordination problems, leaving them needing a wheelchair or unable to leave the bed. These muscle issues can cause problems swallowing, chewing, moving and controlling bladder and/or bowels. Eventually, people with frontotemporal degeneration die because of the physical changes that can cause skin, urinary tract and/or lung infections.
#2 Alector Announces First Frontotemporal Dementia Patient Dosed in Phase 1b Study of AL001 | Alector
https://investors.alector.com/news-releases/news-release-details/alector-announces-first-frontotemporal-dementia-patient-dosed
AL001 is Alectorâs wholly-owned human monoclonal antibody designed to modulate progranulin, a regulator of immune activity in the brain with genetic links to multiple neurodegenerative disorders, including FTD, Alzheimerâs disease, and Parkinsonâs disease. It aims to increase the level of progranulin in humans by inhibiting a progranulin degradation mechanism.
#2 Uncovering pathophysiological changes in frontotemporal dementia using serum lipids | Scientific Reports
https://www.nature.com/articles/s41598-020-60457-w
These findings are consistent with earlier studies that showed pro-inflammatory cytokine levels are increased in FTD brain. […] We found that the OAHFA levels were significantly decreased in FTD compared to controls (Fig. 3K), suggesting decreased anti-inflammatory activity. […] These results support the use of lipid assays to detect oxidative stress in FTD.
#2 Frontotemporal Dementias: Emerging Milestones of the 21st Century | SpringerLink
https://link.springer.com/book/10.1007/978-3-030-51140-1
Ilustrates contemporary advances in our understanding of the causes and pathogenesis of frontotemporal dementias […] It captures the current central elements that are relevant to an up-to-date understanding of causes and pathogenesis of multiple forms of FTD. […] Thus, the book represents a moment of reflection on the present state of our knowledge of FTD and a collective vision toward scientific progress.
#3
https://www.grc.org/frontotemporal-dementia-and-related-rare-dementias-conference/2026/
FTD is the most common pre-senile dementia under the age of 60. Highly distinctive from Alzheimers Disease (AD) and Parkinsons Disease (PD), FTD manifests as personality changes, impaired language production and other executive function abnormalities due to progressive focal degeneration of the frontal and temporal lobes. […] FTD and other rare dementias are much less well understood at the mechanistic level than AD and PD. […] The inaugural Gordon Conference on Frontotemporal Dementia (FTD) and Related Rare Dementias: Pathology, Molecular Pathogenesis and Therapeutic Landscape will highlight exciting recent discoveries across the spheres of basic, translational and clinical investigation. The meeting will highlight the evolving nosology of these disorders, biomarker development and the mechanistic basis for genetic and sporadic forms of disease.
#3
https://journals.lww.com/neur/fulltext/2021/69050/frontotemporal_dementia___current_concepts.3.aspx
Either TAR DNA-binding protein 43 (TDP-43) (or) microtubule-associated protein Tau (MAPT) (or) Fused in sarcoma (FUS) protein account for almost all cases of FTLD. Based on this, the FTD was sub categorized into FTLD-TDP, FTLD-Tau, FTLD-FUS. […] Around 40% of patients with FTLD have family history, of which mutations involving GRN, MAPT, and C9orf72 (chromosome 9 open reading frame 72) accounts for 60% of all inherited FTLD. […] MAPT mutations were the first to be identified as the cause of inherited FTD. These mutations lead to microtubule instability with increased propensity of Tau self-aggregation which may lead to neurodegeneration. […] Progranulin (GRN) is involved in modulation of inflammation, axonal growth, and wound repair. […] C9orf72 gene mutation is the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) spectrum, and it constitutes for about 25% of familial cases of FTLD due to expansion of noncoding GGGGCC hexanucleotide repeat. […] There are no specific treatment options available for FTD; most often the treatment is aimed at educating the patient caregivers about the disease condition and symptomatic pharmacotherapy.
#3 Frontotemporal Dementia (FTD) | Symptoms & Treatments | alz.org
https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/frontotemporal-dementia
Frontotemporal degeneration is inherited in about a third of all cases. Genetic counseling and testing are available now for individuals with family histories of frontotemporal degeneration. There are no known risk factors for any frontotemporal degeneration except for a family history or a similar disorder. […] There are no specific treatments for any of the frontotemporal subtypes. There are medications that can reduce agitation, irritability and/or depression. These treatments should be used to help improve quality of life. […] Frontotemporal dementia inevitably gets worse over time and the speed of decline differs from person to person. For many years, individuals with frontotemporal dementia show muscle weakness and coordination problems, leaving them needing a wheelchair or unable to leave the bed. These muscle issues can cause problems swallowing, chewing, moving and controlling bladder and/or bowels. Eventually, people with frontotemporal degeneration die because of the physical changes that can cause skin, urinary tract and/or lung infections.
#3 Alector Announces First Frontotemporal Dementia Patient Dosed in Phase 1b Study of AL001 | Alector
https://investors.alector.com/news-releases/news-release-details/alector-announces-first-frontotemporal-dementia-patient-dosed
Phase 1b study of AL001 enrolling frontotemporal dementia (FTD) patients with a mutation in the progranulin gene will assess safety and pharmacodynamics, and will monitor target specific biomarkers […] In a subset of FTD patients, mutations in a single copy of the progranulin gene lead to a 50% or greater decrease in the level of progranulin, which in turn leads to development of FTD with greater than 90% penetrance. This subset of patients is known as FTD-GRN. Alector aims to deploy AL001 to increase the level of progranulin in FTD-GRN patients, by inhibiting a progranulin degradation mechanism. […] AL001âs therapeutic approach is conceptually similar to enzyme replacement therapy and as such AL001 is designed to increase the level of progranulin in these FTD-GRN patients. […] Mutations in a single copy of progranulin lead to a 50% or greater decrease in the level of progranulin and lead to development of FTD with greater than 90% penetrance. To date researchers have identified over 70 inherited loss of function mutations in progranulin that lead to FTD.
#3 Uncovering pathophysiological changes in frontotemporal dementia using serum lipids | Scientific Reports
https://www.nature.com/articles/s41598-020-60457-w
These findings are consistent with earlier studies that showed pro-inflammatory cytokine levels are increased in FTD brain. […] We found that the OAHFA levels were significantly decreased in FTD compared to controls (Fig. 3K), suggesting decreased anti-inflammatory activity. […] These results support the use of lipid assays to detect oxidative stress in FTD.
#3 Frontotemporal Dementia, Where Do We Stand? A Narrative Review
https://www.mdpi.com/1422-0067/24/14/11732
To date, autosomal dominant mutations in MAPT, GRN, and C9orf72 account for the majority of genetically determined FTD (about 30%), with large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9orf72 being the most common cause worldwide. […] The neuropathology underlying clinical FTD is also heterogeneous: TAR-DNA-binding protein-43 (TDP-43) proteinopathies, especially types A or B, are the commonest causes of genetic FTD, followed by tauopathies, fused-in-sarcoma (FUS) pathologies, and other rarer proteinopathies. […] As for other neurodegenerative diseases, FTD pathomechanism is hallmarked by protein misfolding leading to the formation of toxic extracellular or intracellular inclusions in neuronal and glial cells. […] Several genetic hits (loss of function and toxic gain of function) contribute to alter proteostasis, boosting or sustaining vicious cycles that ultimately dysregulate pivotal cellular components (lysosome, mitochondria, and endoplasmic reticulum) or processes (autophagolysosomal trafficking, RNA homeostasis, endoplasmic reticulum-mitochondrial signalling, and axonal transport) and cause protein accumulation, sensitising cells to insult and finally leading to cell death.