Demencja – Patofizjologia i mechanizm

Demencja
Patofizjologia i mechanizm

Demencja to zespół objawów neurodegeneracyjnych, charakteryzujących się postępującym upośledzeniem funkcji poznawczych, w tym pamięci, myślenia i zachowania, z towarzyszącymi zaburzeniami emocjonalnymi i językowymi. Patofizjologia obejmuje agregację nieprawidłowo sfałdowanych białek (np. amyloid β i hiperfosforylowane tau w chorobie Alzheimera), chorobę naczyń mózgowych oraz dysfunkcję metabolizmu energetycznego neuronów, w szczególności niedobór NAD, który prowadzi do mitochondrialnej niewydolności i deficytu ATP. Mózg, stanowiący 2% masy ciała, zużywa do 20% tlenu i 25% glukozy (około 90 g dziennie), z czego 70% energii jest wykorzystywane na przekaźnictwo neuronalne. Czynniki ryzyka naczyniowego, takie jak nadciśnienie i cukrzyca, nasilają patogenezę demencji, wpływając zarówno na demencję naczyniową, jak i chorobę Alzheimera, poprzez uszkodzenie naczyń i zwiększenie odkładania neurotoksycznych białek. Nowe badania wskazują na mechanizmy molekularne, takie jak oddzielenie komórek mięśni gładkich od błony komórkowej naczyń mózgowych, co prowadzi do zaburzeń przepływu krwi i stanowi potencjalny cel terapeutyczny w demencji naczyniowej.

Demencja – podstawy patogenezy

Demencja (łac. Dementia) to zespół objawów wynikających z uszkodzenia mózgu spowodowanego urazem lub chorobą. Objawy te związane są z postępującym upośledzeniem pamięci, myślenia i zachowania, czemu zwykle towarzyszą problemy emocjonalne, trudności z językiem oraz zmniejszona motywacja. Choroba dotyka obecnie około 55 milionów ludzi na całym świecie i stanowi poważny problem zdrowia publicznego, szczególnie w starzejących się społeczeństwach Europy.¹²

Zrozumienie podstawowych mechanizmów neurodegeneracji w demencji jest kluczowym krokiem w kierunku znalezienia skutecznych opcji leczenia. Patofizjologia demencji charakteryzuje się szerokim spektrum zmian patologicznych, w tym agregacją nieprawidłowo sfałdowanych białek (takich jak płytki amyloidowe i splątki neurofibrylarne w chorobie Alzheimera) oraz chorobą naczyń mózgowych. U osób starszych z demencją często wykrywa się mieszane neuropatologie, co ma istotne implikacje kliniczne.³

Zaburzenia metabolizmu energetycznego

Jednym z głównych mechanizmów patogenetycznych w demencji jest związane z wiekiem upośledzenie metabolizmu energetycznego na poziomie komórkowym. Mózg ludzki jest organem o wysokim zapotrzebowaniu energetycznym, którego funkcjonowanie zależy przede wszystkim od stabilnego i wydajnego dopływu energii. W stanie czuwania mózg ludzki, stanowiący tylko 2% całkowitej masy ciała, zużywa w warunkach fizjologicznych do 20% tlenu i 25% krążącej glukozy. Dziennie mózg zużywa około 90 g glukozy, a główne zapotrzebowanie energetyczne związane jest z przekaźnictwem neuronalnym (około 70%).⁴⁵

Metabolizm energetyczny sieci neuronalnych opiera się wyłącznie na fosforylacji oksydacyjnej, przy czym tlen i glukoza są głównymi substratami tego procesu. Kinetyka oddychania neuronów jest ograniczona przez nieprzerwany cykl redukcji/utleniania dinukleotydu nikotynamido-adeninowego (NAD). NAD jest niezbędnym nukleotydem pirydynowym, który służy jako kofaktor i substrat dla krytycznych procesów komórkowych związanych z fosforylacją oksydacyjną i produkcją ATP, naprawą DNA, ekspresją genów modulowaną epigenetycznie, wewnątrzkomórkową sygnalizacją wapniową i funkcjami immunologicznymi.⁶⁷

Niedobór NAD, wynikający ze zwiększonego zapotrzebowania na enzymy zużywające NAD, co występuje w procesie starzenia się mózgu, powoduje, że mitochondria stają się mniej wydajne, a neurony nie mogą wytworzyć wystarczającej ilości energii, zwłaszcza ATP. Poziomy komórkowe NAD, a tym samym wydajność metabolizmu energetycznego, obniżają się w starzejących się neuronach. Poziomy NAD spadają na poziomie komórkowym, tkankowym/narządowym i organizmalnym podczas starzenia się. Związany z wiekiem spadek NAD prowadzi do dysfunkcji mitochondriów i nieprawidłowości metabolicznych.⁸⁹

Mechanizmy naczyniowe w demencji

Czynniki ryzyka naczyniowego, takie jak nadciśnienie i cukrzyca, wpływają na patogenezę demencji. Uszkodzenie naczyń mózgowych bezpośrednio wywołuje demencję naczyniową, a coraz bardziej oczywiste staje się, że czynniki ryzyka naczyniowego zwiększają również ryzyko neurodegeneracyjnej choroby Alzheimera, która wiąże się z gromadzeniem neurotoksycznych białek w mózgu.¹⁰

Nagromadzone dowody wskazują, że nadciśnienie w średnim wieku zwiększa ryzyko rozwoju choroby Alzheimera w późniejszym życiu. Zgłoszono, że te cechy neuropatologiczne (tj. płytki starcze i NFT) były zwiększone w pośmiertnych tkankach mózgowych pacjentów z nadciśnieniem, co sugeruje bezpośredni związek między nadciśnieniem a patogenezą choroby Alzheimera.¹¹

W demencji naczyniowej, jednym z mechanizmów jest choroba dużych naczyń (miażdżyca i inne arteriopatie), jednak udokumentowano również zaburzony przepływ mózgowy przy braku zawału jako konsekwencję zwężenia tętnic, choć jego konsekwencje kliniczne pozostają do pełnego zbadania. Ponadto, zmiany w małych naczyniach odgrywają rolę w powodowaniu uszkodzeń tkanki mózgowej i są potencjalnie odpowiedzialne za późniejszy rozwój zaburzeń poznawczych.¹²

Rola patologii białkowo-zależnych

Kluczowym mechanizmem w patogenezie demencji jest agregacja i akumulacja nieprawidłowo sfałdowanych białek (określanych jako proteinopatie) oraz zaburzenia związane z chorobą naczyń mózgowych. Najczęstszą przyczyną demencji o późnym początku jest choroba Alzheimera, a następnie demencja z ciałami Lewy’ego, demencja naczyniowa i otępienie czołowo-skroniowe.¹³

beta-amyloidu”>Patologia beta-amyloidu

Hipoteza kaskady amyloidowej pozostaje głównym modelem patologicznym w chorobie Alzheimera od dziesięcioleci, jednak istnieje coraz więcej dowodów potwierdzających wieloczynnikowość patofizjologii tej choroby. W mózgach pacjentów z chorobą Alzheimera obecne są duże złogi zagregowanego białka amyloidu β (Aβ), które powstaje jako produkt uboczny proteolitycznego przetwarzania białka prekursora amyloidu (APP).¹⁴¹⁵

Ostateczna reakcja rozszczepiania, która wytwarza Aβ z jego APP, jest mediowana przez γ-sekretazę. Główne wyniki badań wykazały, że γ-sekretaza znajduje się zarówno pre-synaptycznie, jak i post-synaptycznie, podczas gdy Aβ znajduje się tylko w pre-synapsie, potencjalnie w pęcherzykach synaptycznych.¹⁶

Aβ jest produkowany jako monomer i początkowo nie jest toksyczny. Gdy zaczyna polimeryzować, tworzy toksyczne oligomery. Łącząc techniki super-rozdzielczości z nowatorską techniką znakowania Aβ, możliwe jest śledzenie procesu polimeryzacji w żywych neuronach i dokładne określenie, gdzie on zachodzi.¹⁷

Patologia białka tau

Tau jest składnikiem wiążącym mikrotubule, który promuje polimeryzację i stabilność mikrotubul. Hiperfosforylowane tau jest wzbogacone w sparowanych helikalnych filamentach (PHFs) z mózgu pacjenta z chorobą Alzheimera lub modeli mysich AD. Hiperfosforylacja tau może być wczesnym zdarzeniem podczas patogenezy AD, ponieważ zwiększone poziomy fosforylowanego tau wykrywa się w płynie mózgowo-rdzeniowym od potencjalnych pacjentów z AD we wczesnych stadiach pojawienia się choroby i korelują z upośledzeniem poznawczym.¹⁸

Patologiczne tau może powodować utratę synaps i dysfunkcję. Dlatego patogenne tau i aktywacja mikrogleju mogą tworzyć cykliczne zdarzenia patogenne podczas rozwoju AD. Podsumowując, prawdopodobne jest, że patogeneza tau jest wyzwalana przez Aβ w AD, gdzie patogenne tau i Aβ synergistycznie przyczyniają się do gliozy i neurozapalenia.¹⁹

Mechanizmy neurozapalne

Neurozapalenie z aktywacją mikrogleju jest coraz częściej uznawane za odgrywające ważną rolę w patogenezie AD i jest zaangażowane w odkładanie się Aβ, uszkodzenie neuronów i śmierć komórek. Glejoza i mikroglejoza są wspólnymi cechami wielu chorób neurodegeneracyjnych o różnej etiologii. W OUN mikroglej służy jako rezydentne fagocyty, które dynamicznie monitorują środowisko, odgrywając kluczową rolę w utrzymaniu tkanki mózgowej, odpowiedzi na urazy i obronie przed patogenami.²⁰²¹

Mechanizmy zapalne i immunologiczne mogą odgrywać rolę w procesie degeneracyjnym w AD. Reaktywne komórki mikrogleju są wbudowane w płytki neurytyczne. Zwiększone poziomy cytokin obserwuje się w surowicy, płytkach korowych i neuronach pacjentów z AD w porównaniu z pacjentami dobranymi pod względem wieku.²²

Wieloczynnikowa patogeneza demencji

Demencja nie jest pojedynczą jednostką patogenetyczną, ale raczej wynikiem złożonych mechanizmów molekularnych i komórkowych, które prowadzą do upośledzenia poznawczego. Zrozumienie demencji podkreśla rolę mechanizmów patogennych poprzez ujawnienie nieprawidłowych zmian w mózgu. Mechanizmy te obejmują nadciśnienie, starzenie się, miażdżycę, nieprawidłowości białka tau i odkładanie amyloidu.²³

Zaburzenia funkcji synaptycznej

Kryzys energetyczny w starzejącym się mózgu i masowa śmierć nieprawidłowo funkcjonujących i niepotrzebnych neuronów utrudniają tworzenie nowych śladów pamięciowych. Najbardziej powszechną cechą demencji jest utrata zdolności do tworzenia nowych śladów pamięciowych. Sugeruje to, że starzenie się mózgu i wynikająca z tego postępująca degradacja korowych sieci funkcjonalnych kory mózgowej i hipokampa są pierwotnymi miejscami rozwoju demencji.²⁴²⁵

Procesy neurodegeneracyjne mogą następnie rozprzestrzeniać się na układ limbiczny, szczególnie ciało migdałowate, a także korę śródwęchową i obręczową. W chorobie Alzheimera mocno dotknięty jest układ adrenergiczny miejsca sinawego i neurony serotoninergiczne grzbietowego jądra szwu. Jądra szwu grzbietowego odgrywają ważną rolę w cyklu snu/czuwania, który jest zaburzony w procesie neurodegeneracji.²⁶

Rola dysfunkcji mitochondriów

Dysfunkcja mitochondriów została powiązana z patofizjologią starzenia się komórek i neurodegeneracji. Mitochondria sygnalizują stres poprzez zmiany w poziomach nukleotydów adeninowych, produkcję reaktywnych form tlenu (ROS), przepływy Ca2+, otwarcie pory przejściowej przepuszczalności i być może wydzielanie specyficznych białek/peptydów. Stres oksydacyjny zwiększa liczbę zniekształconych białek, które nie mogą zostać naprawione z powodu zmniejszonej syntezy enzymów zależnych od NAD.²⁷

Tempo obrotu w komórkowych szlakach metabolicznych jest regulowane na podstawie stechiometrii reakcji, szybkości wykorzystania metabolitów i tempa translokacji cząsteczek przez dwuwarstwy lipidowe. W konsekwencji niedoboru NAD w starzejących się neuronach, kumuluje się kryzys energetyczny i metaboliczny w komórkach. Gdy deficyt energetyczny przekracza poziom krytyczny, dotknięte neurony są kierowane na szlak apoptozy.²⁸

Rola zaburzeń naczyniowych

Cerebralny amyloid angiopatyczny (CAA) może być kluczowym graczem łączącym czynniki ryzyka naczyniowego, demencję naczyniową i chorobę Alzheimera. CAA powoduje degenerację ścian naczyń mózgowych, prowadząc do przerwania naczyń mózgowych, udaru krwotocznego lub niedokrwiennego, a ostatecznie do dysfunkcji poznawczej. Intensywne zarządzanie czynnikami ryzyka naczyniowego może być ważne u pacjenta z CAA w kontekście zapobiegania demencji.²⁹

Najnowsze badanie przeprowadzone przez Uniwersytet Vermont rzuca światło na mechanizm stojący za demencją naczyniową w modelu mysim. Jak donosi czasopismo PNAS, zmniejszony przepływ krwi do mózgu jest znanym kluczowym czynnikiem w procesie chorobowym demencji naczyniowej wywołanej nadciśnieniem, ale mechanizm stojący za tym był niejasny, co utrudniało opracowanie terapii poprawiających przepływ krwi.³⁰

Badania wykazały, że zmniejszony mózgowy przepływ krwi był spowodowany oddzieleniem się części komórek mięśni gładkich od błony komórkowej, co prowadzi do przerwania sygnalizacji komórkowej, która w normalnych okolicznościach prowadziłaby do rozluźnienia naczyń krwionośnych. Odkrywając, w jaki sposób wysokie ciśnienie krwi powoduje, że tętnice w mózgu pozostają zwężone, badania ujawniają nową drogę do odkrycia leków, które mogą pomóc w znalezieniu pierwszego leczenia demencji naczyniowej.³¹

Mechanizmy biologiczne w różnych typach demencji

Demencja z ciałami Lewy’ego

Demencja z ciałami Lewy’ego (DLB) jest jedną z najczęstszych przyczyn demencji po chorobie Alzheimera i demencji naczyniowej. DLB często stanowi wyzwanie diagnostyczne ze względu na swoją kliniczną heterogeniczność i nakładanie się z innymi chorobami neurodegeneracyjnymi.³²

Konstytutywne włókna ciała Lewy’ego zawierają wszystkie trzy podjednostki neurofilamentów w zmienionej formie. Nasze ostatnie badania hybrydyzacji in situ podjednostki neurofilamentu o niskiej masie cząsteczkowej sugerują, że zmieniona ekspresja neurofilamentu nie jest związana z tworzeniem się ciała Lewy’ego. Proponujemy spekulatywny model patogenezy ciała Lewy’ego, w którym neurofilamenty są normalnie montowane, a następnie przechodzą fosforylację, proteolizę i sieciowanie na etapie po-translacyjnym/po-montażowym.³³

Mutacje w białku trafiku pęcherzykowego RAB39B są związane z rzadką chorobą Parkinsona sprzężoną z chromosomem X. Wyniki badań potwierdzają udział RAB39B w patogenezie demencji z ciałami Lewy’ego. Dlatego RAB39B i związane z nim szlaki funkcjonalne mogą być uważane za potencjalne cele interwencji terapeutycznych w chorobach ciał Lewy’ego.³⁴

Demencja czołowo-skroniowa

Demencja czołowo-skroniowa (FTD) opisuje grupę chorób charakteryzujących się degeneracją komórek nerwowych – zwłaszcza w płatach czołowych i skroniowych mózgu. U około 50% osób z FTD w mózgu występuje nieprawidłowa forma białka tau, a około 50% osób z FTD ma akumulację białka TDP-43. Mały odsetek, około 5%, ma akumulację białka FUS. To zakłóca normalne aktywności komórkowe i może powodować śmierć komórek.³⁵

Przyczyna choroby Picka jest nieznana, ale występuje w niektórych rodzinach i dlatego prawdopodobnie jest przynajmniej częściowo spowodowana wadliwym genem lub genami. W niektórych przypadkach rodzinna FTD jest powiązana z mutacją w genie zwanym C9ORF72. Uważa się, że ta mutacja jest najczęstszą przyczyną rodzinnej FTD i rodzinnego ALS (stwardnienie zanikowe boczne lub choroba Lou Gheriga). To odkrycie zostało dokonane w 2011 roku, a badania szybko się rozwijają, aby lepiej zrozumieć mechanizm stojący za mutacją genetyczną, związek między chorobami i możliwe badania leczenia.³⁶

Naukowcy zidentyfikowali molekularny mechanizm, który prowadzi do śmierci neuronów w stwardnieniu zanikowym bocznym (znane również jako ALS lub choroba neuronu ruchowego) i powszechnej formie otępienia czołowo-skroniowego. W aktualnym badaniu naukowcy byli w stanie powiązać mutacje w genie, który koduje białko TIA1, z rozwojem zarówno ALS, jak i FTD. Zespół wykazał, że wadliwe białko zakłóca normalny demontaż ziarnistości stresowych – gęstych agregatów białek i RNA, które tworzą się w warunkach stresu – i promuje ich gromadzenie się w neuronach. To nagromadzenie prowadziło do śmierci neuronów w mózgu i rdzeniu kręgowym, które kontrolują mięśnie w ALS, oraz śmierci neuronów w mózgu w FTD.³⁷

Demencja zwązana z HIV

Po raz pierwszy naukowcy zidentyfikowali i zahamowali proces molekularny, który może prowadzić do neurodegeneracji u pacjentów z HIV, według badania Northwestern Medicine opublikowanego w Nature Communications. Nagromadzenie beta-amyloidu jest uważane za główny czynnik przyczyniający się do neurodegeneracji w różnych chorobach związanych z demencją, zwłaszcza chorobie Alzheimera, ale jak i dlaczego beta-amyloid jest produkowany u pacjentów zakażonych HIV i jego wkład w HAND (HIV-associated neurocognitive disorder) było tajemnicą.³⁸

Podczas infekcji komórki mikrogleju lub makrofaga, białko Gag HIV promuje przetwarzanie APP, zmniejszając odporność na przejęcie komórki, co ma również skutek uboczny w postaci produkcji toksycznych białek beta-amyloidowych. Wiążąc się z APP, w jakiś sposób Gag wciąga go do regionów błony komórkowej zwanych tratwami lipidowymi, gdzie są enzymy, które promują przetwarzanie APP w beta-amyloid. Aby zmniejszyć nagromadzenie beta-amyloidu, naukowcy skierowali się na enzym, który rozszczepia APP, zwany sekretazą gamma.³⁹

Nowe kierunki w leczeniu demencji

Dotychczas wszystkie próby leczenia demencji poprzez usuwanie ich objawów, a nie ich przyczyn, zakończyły się niepowodzeniem. Wiedza zgromadzona do tej pory pozwala nam stwierdzić, że podstawową przyczyną starzenia się mózgu jest utrata kontroli nad metabolizmem glukozy, co prowadzi do utraty równowagi energetycznej.⁴⁰

Podejście ukierunkowane na metabolizm energetyczny

Lekarz prowadzący zasugeruje leczenie, które spowolni rozwój demencji. Nie ma lekarstwa na chorobę Alzheimera, ale leczenie może zarządzać objawami, gdy się pojawią, i spowolnić postęp choroby. Istnieje wiele leków, które mogą zarządzać objawami choroby Alzheimera.⁴¹

Lekanemaab i donepezil to infuzje dożylne (IV). Są to dwa rodzaje przeciwciał monoklonalnych. Są to leki, które mogą pomóc układowi odpornościowemu organizmu w celowaniu i niszczeniu białek amyloidowych. Mogą one spowolnić postęp choroby Alzheimera, pozbywając się części amyloidu, zanim uszkodzi on mózg. Antagoniści NMDA blokują lub wypełniają receptory N-metylo-D-asparaginowe (NMDA), do których glutaminian wiąże się w mózgu. Może to spowolnić tempo postępu choroby Alzheimera.⁴²

Podejście cholinergiczne

System cholinergiczny jest zaangażowany w funkcje pamięciowe, a niedobór cholinergiczny został powiązany z poznawczym spadkiem i zmianami behawioralnymi w AD. Inhibitory cholinesterazy (AChE) są obecnie najczęściej przepisywanym leczeniem łagodnej do umiarkowanej AD. Podobnie, niedobory cholinergiczne istnieją u pacjentów z VaD; dlatego inhibitory AChE mogą również przynieść korzyści tym pacjentom.⁴³⁴⁴

Badanie Uniwersytetu Kraju Basków (UPV/EHU) udowadnia, że lek WIN55.212-2 chroni mózg i odwraca początkowe uszkodzenia poznawcze spowodowane demencją oraz wyjaśnia, jak działa. Badania pokazują, że lek aktywuje system neurotransmiteru kannabinoidowego (który chroni mózg), a to stymuluje system cholinergiczny (który kontroluje pamięć i uczenie się) poprzez zwiększenie syntezy acetylocholiny (neurotransmitera w mózgu, który kontroluje pamięć i uczenie się).⁴⁵

Po przetestowaniu efektu leku WIN55.212-2, który oddziałuje z receptorami kannabinoidowymi, na gryzoniach we wczesnych stadiach choroby, zespół odkrył, że „zachowywały się one w taki sam sposób jak te bez uszkodzenia mózgu: uczyły się i zapamiętywały orientację przestrzenną w taki sam sposób”. Można powiedzieć, że w pewien sposób lek odwrócił uszkodzenie lub chronił mózg.⁴⁶

Zapobieganie demencji

Badania sugerują, że styl życia może odgrywać rolę w zapobieganiu demencji. Na przykład, szczepienia przeciwko półpaścowi mogą bezpośrednio chronić przed demencją, jak sugerują sugestywne nowe dane. Szczepionka przeciwko półpaścowi może zapobiegać lub opóźniać demencję. Wyniki te potwierdzają „hipotezę wirusową” choroby Alzheimera, która zakłada, że infekcje wirusowe przyczyniają się do rozwoju tej choroby, która jest najczęstszą formą demencji.⁴⁷

Efekt ten nie był obserwowany w przypadku innych chorób przewlekłych, takich jak nadciśnienie, choroby serca lub cukrzyca, co sugeruje, że szczepionka przeciwko półpaścowi ma specyficzny efekt ochronny przeciwko demencji. Potrzebne są dalsze badania, aby zrozumieć mechanizm stojący za ochronnym działaniem szczepionki przeciwko demencji, ponieważ obecnie jest on niejasny. Jedna teoria sugeruje, że reaktywacja wirusa varicella-zoster może wywołać uszkodzenie mózgu poprzez szereg mechanizmów, w tym nagromadzenie nieprawidłowych białek i przewlekłe zapalenie. Zapobiegając reaktywacji, szczepionka przeciwko półpaścowi może teoretycznie zapobiec temu uszkodzeniu mózgu.⁴⁸

Interwencje aktywnego stylu życia i edukacji oferują istotny wkład w zdrowe starzenie się. Droga do demencji jest zróżnicowana i złożona, a my po prostu zrównaliśmy EOAD (early-onset Alzheimer’s disease) i LOAD (late-onset Alzheimer’s disease) na podstawie ich najbardziej uderzających zmian neuropatologicznych.⁴⁹

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Materiały źródłowe

#1 Pathogenesis of Dementia – PubMed
https://pubmed.ncbi.nlm.nih.gov/36613988/
According to Alzheimer’s Disease International, 55 million people worldwide are living with dementia. Dementia is a disorder that manifests as a set of related symptoms, which usually result from the brain being damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, usually accompanied by emotional problems, difficulties with language, and decreased motivation. The most common variant of dementia is Alzheimer’s disease with symptoms dominated by cognitive disorders, particularly memory loss, impaired personality, and judgmental disorders. […] So far, all attempts to treat dementias by removing their symptoms rather than their causes have failed. Therefore, in the presented narrative review, I will attempt to explain the etiology of dementia and Alzheimer’s disease from the perspective of energy and cognitive metabolism dysfunction in an aging brain. I hope that this perspective, though perhaps too simplified, will bring us closer to the essence of aging-related neurodegenerative disorders and will soon allow us to develop new preventive/therapeutic strategies in our struggle with dementia, Alzheimer’s disease, and Parkinson’s disease.
#2 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
Pathogenesis of Dementia […] According to Alzheimerâs Disease International, 55 million people worldwide are living with dementia. Dementia is a disorder that manifests as a set of related symptoms, which usually result from the brain being damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, usually accompanied by emotional problems, difficulties with language, and decreased motivation. The most common variant of dementia is Alzheimerâs disease with symptoms dominated by cognitive disorders, particularly memory loss, impaired personality, and judgmental disorders. So far, all attempts to treat dementias by removing their symptoms rather than their causes have failed. Therefore, in the presented narrative review, I will attempt to explain the etiology of dementia and Alzheimerâs disease from the perspective of energy and cognitive metabolism dysfunction in an aging brain. I hope that this perspective, though perhaps too simplified, will bring us closer to the essence of aging-related neurodegenerative disorders and will soon allow us to develop new preventive/therapeutic strategies in our struggle with dementia, Alzheimerâs disease, and Parkinsonâs disease. […]
#3 Pathophysiology of dementia
https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia
Dementia is a debilitating neurological condition that affects millions of patients and families worldwide and remains a significant public health concern. Understanding the underlying neurobiology and pathophysiology of dementia is an important step towards finding effective treatment options. […] The pathophysiology of dementia is broadly characterised by the aggregation of misfolded proteins (such as amyloid- plaques and neurofibrillary tangles in Alzheimers disease) and cerebrovascular disease. Mixed neuropathologies are frequently detected in the brains of older people with dementia and have important clinical implications. […] 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).
#4 Pathogenesis of Dementia
https://pmc.ncbi.nlm.nih.gov/articles/PMC9820433/
Dementia is a disorder that manifests as a set of related symptoms, which usually result from the brain being damaged by injury or disease. […] Therefore, in the presented narrative review, I will attempt to explain the etiology of dementia and Alzheimers disease from the perspective of energy and cognitive metabolism dysfunction in an aging brain. […] The main one is the age-related impairment of energy metabolism at the cellular level. It leads to gradually increasing metabolic disorders and disturbance of homeostasis, which is vital for brain activity. […] The human brain is a highly energy-demanding organ whose functioning depends firstly on a stable and efficient energy supply. […] The energy metabolism of neural networks relies exclusively on oxidative phosphorylation with oxygen and glucose being the main substrates for the process.
#5 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
Three of them seem to have a leading role in disturbances of consciousness. The main one is the age-related impairment of energy metabolism at the cellular level. It leads to gradually increasing metabolic disorders and disturbance of homeostasis, which is vital for brain activity. They result in several behavioral dysfunctions accompanying old age, such as limited physical and cognitive activity, and sleep disorders. These dysfunctions further exacerbate the pathophysiological changes in the brain, leading to the massive death of nerve cells. This rapidly growing process of self-destruction of the aging organism leads to dementia, i.e., inhibition of interaction with the environment, which is the meaning of life. […] […] The human brain has extraordinary cognitive abilities. This is due in particular to the enlarged neocortex and its unusual susceptibility to plastic changes. This allowed for the development of such human abilities as sentience, consciousness, perception, memory, speech, and abstract thinking. The brain is a highly energy-demanding organ whose functioning depends firstly on a stable and efficient energy supply. In the waking state, the human brain, constituting only 2% of the total body weight, consumes, under physiological conditions, up to 20% of oxygen and 25% circulating glucose. The human brain consumes about 90 g of glucose per day, and the major energy demands of the brain are associated with neuronal signaling and account for ~70%. […]
#6 Pathogenesis of Dementia
https://pmc.ncbi.nlm.nih.gov/articles/PMC9820433/
Dementia is a disorder that manifests as a set of related symptoms, which usually result from the brain being damaged by injury or disease. […] Therefore, in the presented narrative review, I will attempt to explain the etiology of dementia and Alzheimers disease from the perspective of energy and cognitive metabolism dysfunction in an aging brain. […] The main one is the age-related impairment of energy metabolism at the cellular level. It leads to gradually increasing metabolic disorders and disturbance of homeostasis, which is vital for brain activity. […] The human brain is a highly energy-demanding organ whose functioning depends firstly on a stable and efficient energy supply. […] The energy metabolism of neural networks relies exclusively on oxidative phosphorylation with oxygen and glucose being the main substrates for the process.
#7 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
Central nervous system (CNS) complications induced by toxic levels of glucose are multifactorial and are relatively little understood. It is now evident that malfunctioning of the bloodâbrain barrier may play a significant role in diabetes-dependent CNS disorders. Chronic exposure of cells and tissues to high glucose concentrations results in the non-enzymatic glycation of proteins that elevates the production of reactive oxygen species (ROS). A combination of hyperglycemia, protein glycation, and oxidative stress results in the massive synthesis of gluconic acid, a very toxic product of glucose oxidation. This organic compound is produced intensively in aging brain tissue. […] […] The energy metabolism of neural networks relies exclusively on oxidative phosphorylation with oxygen and glucose being the main substrates for the process. The kinetics of neuronal respiration is limited by an uninterrupted cycle of reduction/oxidation of nicotinamide adenine dinucleotide (NAD). NAD is an essential pyridine nucleotide that serves as a cofactor and substrate for critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. Consequently, NAD level is the rate-limiting factor in oxidative phosphorylation. The cellular NAD levels, and therefore the efficiency of energy metabolism, decline in senescence neurons. NAD levels decline at the cellular, tissue/organ, and organismal levels during aging. Age-related NAD decline leads to mitochondrial dysfunction and metabolic abnormalities. […]
#8 Pathogenesis of Dementia
https://pmc.ncbi.nlm.nih.gov/articles/PMC9820433/
The kinetics of neuronal respiration is limited by an uninterrupted cycle of reduction/oxidation of nicotinamide adenine dinucleotide (NAD). […] NAD deficiency, due to increasing demands for NAD-consuming enzymes as occurs in the aging process of the brain, causes the mitochondria to become less efficient and neurons cannot produce enough energy, especially ATP. […] The energy crisis in the aging brain and the mass death of malfunctioning and unnecessary neurons impede the formation of new memory traces. […] The most common feature of dementia is the loss of the ability to form new memory traces. This implies that brain aging and the resulting progressive degradation of cortical functional networks of the cerebral cortex and the hippocampus are the primary loci of dementia development.
#9 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
Central nervous system (CNS) complications induced by toxic levels of glucose are multifactorial and are relatively little understood. It is now evident that malfunctioning of the bloodâbrain barrier may play a significant role in diabetes-dependent CNS disorders. Chronic exposure of cells and tissues to high glucose concentrations results in the non-enzymatic glycation of proteins that elevates the production of reactive oxygen species (ROS). A combination of hyperglycemia, protein glycation, and oxidative stress results in the massive synthesis of gluconic acid, a very toxic product of glucose oxidation. This organic compound is produced intensively in aging brain tissue. […] […] The energy metabolism of neural networks relies exclusively on oxidative phosphorylation with oxygen and glucose being the main substrates for the process. The kinetics of neuronal respiration is limited by an uninterrupted cycle of reduction/oxidation of nicotinamide adenine dinucleotide (NAD). NAD is an essential pyridine nucleotide that serves as a cofactor and substrate for critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. Consequently, NAD level is the rate-limiting factor in oxidative phosphorylation. The cellular NAD levels, and therefore the efficiency of energy metabolism, decline in senescence neurons. NAD levels decline at the cellular, tissue/organ, and organismal levels during aging. Age-related NAD decline leads to mitochondrial dysfunction and metabolic abnormalities. […]
#10 Roles of vascular risk factors in the pathogenesis of dementia | Hypertension Research
https://www.nature.com/articles/s41440-019-0357-9
The results of recent clinical and basic studies have suggested that vascular risk factors, such as hypertension and diabetes mellitus, affect the pathogenesis of dementia. […] Cerebrovascular damage due to vascular risk factors directly triggers vascular dementia, and it is becoming more apparent that vascular risk factors also increase the risk of neurodegenerative Alzheimers disease, which is associated with the accumulation of neurotoxic proteins in the brain. […] Accumulating evidence indicates that hypertension during middle age increases the risk of developing Alzheimers disease in later life. […] It was reported that these neuropathological features (i.e., senile plaques and NFTs) were increased in the postmortem brain tissues of hypertensive patients, suggesting a direct association between hypertension and the pathogenesis of Alzheimers disease.
#11 Roles of vascular risk factors in the pathogenesis of dementia | Hypertension Research
https://www.nature.com/articles/s41440-019-0357-9
The results of recent clinical and basic studies have suggested that vascular risk factors, such as hypertension and diabetes mellitus, affect the pathogenesis of dementia. […] Cerebrovascular damage due to vascular risk factors directly triggers vascular dementia, and it is becoming more apparent that vascular risk factors also increase the risk of neurodegenerative Alzheimers disease, which is associated with the accumulation of neurotoxic proteins in the brain. […] Accumulating evidence indicates that hypertension during middle age increases the risk of developing Alzheimers disease in later life. […] It was reported that these neuropathological features (i.e., senile plaques and NFTs) were increased in the postmortem brain tissues of hypertensive patients, suggesting a direct association between hypertension and the pathogenesis of Alzheimers disease.
#12 Pathophysiology of vascular dementia | Immunity & Ageing | Full Text
https://immunityageing.biomedcentral.com/articles/10.1186/1742-4933-6-13
One of the mechanism involved in ischemic VaD is under the control of large vessels disease (atherosclerosis, and other arteriopathies), however, impaired cerebral flow in the absence of infarct as consequence of arterial stenosis has been documented, although its clinical consequences remain to be fully investigated. […] Moreover, the alterations of small vessels play a role in causing damage to the cerebral tissue and are potentially responsible for the subsequent development of cognitive alterations. […] The most common types of diseases affecting cerebral microvessels are: arteriosclerosis, lipohyalinosis, cerebral amyloid angiopathy, basal ganglia calcification, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy), other uncommon intracerebral vasculopathies.
#13 Pathophysiology of dementia
https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia
Dementia is a debilitating neurological condition that affects millions of patients and families worldwide and remains a significant public health concern. Understanding the underlying neurobiology and pathophysiology of dementia is an important step towards finding effective treatment options. […] The pathophysiology of dementia is broadly characterised by the aggregation of misfolded proteins (such as amyloid- plaques and neurofibrillary tangles in Alzheimers disease) and cerebrovascular disease. Mixed neuropathologies are frequently detected in the brains of older people with dementia and have important clinical implications. […] 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).
#14 Pathophysiology of dementia
https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia
The amyloid cascade hypothesis has remained the main pathological model in AD for decades; however, there is increasing evidence that supports multicausality of the pathophysiology of AD. […] Neuroinflammation with microglial activation has been increasingly recognised to play an important role in the pathogenesis of AD and is involved in A deposition, neuronal damage and cell death. […] Cerebral multimorbidity is increasingly recognised as having important pathological and clinical implications in older people with dementia.
#15 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
The most common feature of dementia is the loss of the ability to form new memory traces. This implies that brain aging and the resulting progressive degradation of cortical functional networks of the cerebral cortex and the hippocampus are the primary loci of dementia development. The neurodegenerative processes may be then spread to the limbic system, especially the amygdala as well as the entorhinal and cingulate cortex. […] […] In Alzheimerâs disease, the adrenergic system of the locus coeruleus and the serotonergic neurons of the dorsal raphe are heavily affected. The dorsal raphe nuclei play an important role in the sleep/wake cycle, which is disordered in the process of neurodegeneration. […] […] Misfolded proteins have been widely considered to be the triggering factors in Alzheimerâs disease. Indeed, the brains of patients contain large deposits of aggregated amyloid Î²-protein (AÎ²) which is generated as a byproduct of the proteolytic processing of the amyloid precursor protein (APP). […]
#16 Molecular Pathogenesis of Alzheimerâs Disease – touchNEUROLOGY
https://touchneurology.com/alzheimers-disease-dementia/journal-articles/molecular-pathogenesis-of-alzheimers-disease-an-expert-interview-with-lars-tjernberg-and-sophia-schedin-weiss-karolinska-institutet-stockholm-sweden/
Alzheimers disease was first described in 1906, and yet we have still not fully elucidated the pathogenesis of the condition. It is known that the disease is characterized by the polymerization of amyloid -peptide (A), leading to the formation of plaques. The cascade of events initiated by A polymerization eventually leads to progressive neurodegeneration and brain dysfunction. […] The most important factor in Alzheimers disease is a small piece of protein the A that comes in different lengths. One peptide with 42 amino acids has been found to be toxic in laboratory studies with cell lines and in animal studies. […] The final cleavage reaction that produces A from its APP is mediated by -secretase. […] The major findings were that -secretase is located both pre-synaptically and post-synaptically, whereas A is only located at the pre-synapse, potentially in synaptic vesicles.
#17 Molecular Pathogenesis of Alzheimerâs Disease – touchNEUROLOGY
https://touchneurology.com/alzheimers-disease-dementia/journal-articles/molecular-pathogenesis-of-alzheimers-disease-an-expert-interview-with-lars-tjernberg-and-sophia-schedin-weiss-karolinska-institutet-stockholm-sweden/
These results may be a starting point for thinking how to reach this particular pool of A at the pre-synapse and also that we should not reduce A production too much because it may have a physiological function. Our studies suggest that we can be more specific in our treatment approaches. […] We also have ways of looking at A when it polymerizes. A is produced as a monomer and initially it is not toxic. When it starts to polymerize, it forms toxic oligomers. Combining the super-resolution techniques that we use with a novel A labeling technique that we develop we will be able to follow the polymerization process in living neurons and elucidate exactly where it takes place.
#18 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimerâs disease | Molecular Neurodegeneration | Full Text
https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7
APP deficiency increases KCC2 degradation via tyrosine-phosphorylation and ubiquitination, therefore, leading to GABA reversal potential depolarization and impairment during GABAA receptor-mediated inhibition. […] The amyloidogenic pathway comprises sequential proteolytic cleavage of APP by -secretase and the -secretase complex. […] Therefore, A42 is thought to be a key player in initiating plaque formation and AD pathogenesis. […] Dysregulated APP processing may contribute to AD pathogenesis by elevating A production, and reducing the A40/42 ratio. […] Tau is a microtubule binding component that promotes the polymerization and stability of microtubules. […] Hyperphosphorylated tau is enriched in paired helical filaments (PHFs) from AD patient brain or AD mouse models. […] Tau hyperphosphorylation may be an early event during AD pathogenesis, since increased levels of phosphorylated tau are detected in the CSF from potential AD patients at early stages of disease onset, and correlate with cognitive impairment.
#19 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimerâs disease | Molecular Neurodegeneration | Full Text
https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7
Pathological tau can cause synaptic loss and dysfunction. […] Therefore, pathogenic tau and microglia activation may form cyclical pathogenic events during AD development. […] In conclusion, it is likely that tau pathogenesis is triggered by A in AD, where pathogenic tau and A synergistically contribute to gliosis and neuroinflammation.
#20 Pathophysiology of dementia
https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia
The amyloid cascade hypothesis has remained the main pathological model in AD for decades; however, there is increasing evidence that supports multicausality of the pathophysiology of AD. […] Neuroinflammation with microglial activation has been increasingly recognised to play an important role in the pathogenesis of AD and is involved in A deposition, neuronal damage and cell death. […] Cerebral multimorbidity is increasingly recognised as having important pathological and clinical implications in older people with dementia.
#21 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
The pathological changes may appear locally or cover larger cortical areas. Growing evidence suggests that neurodegenerative diseases are caused by cortical network dysfunction rather than the dysregulation of an isolated brain region. Local brain regions that are selectively damaged act as ânodesâ in functional networks, representing the basis of the network degradation hypothesis. […] […] Astrogliosis and microgliosis are common features of many neurodegenerative diseases with distinct etiologies. In the CNS, microglia serve as resident phagocytes that dynamically survey the environment, playing crucial roles in brain tissue maintenance, injury response, and pathogen defense. […] […] The increasing population of Europe coupled with the aging demographics in many European countries provides a clear indication that the overall number of people with dementia is likely to continue to increase significantly. Up to date all attempts to treat neurodegenerative diseases by removing their symptoms rather than their causes have failed. Therefore, in the presented narrative review, I attempt to explain the etiology of dementia and Alzheimerâs disease from the perspective of energy and cognitive metabolism dysfunction in an aging brain. […]
#22 Alzheimer Disease: Practice Essentials, Background, Anatomy
https://emedicine.medscape.com/article/2003174-overview
Although very popular, the amyloid hypothesis is not uniformly accepted. On post-mortem analysis, amyloid plaques may be undetectable in the brains of patients who had severe AD but may be present in the brains of elderly patients who did not have dementia. […] The tau protein stabilizes neuronal microtubules. Destabilization of the microtubular system is speculated to disrupt the Golgi apparatus, in turn inducing abnormal protein processing and increasing production of Ab. […] Inflammatory and immune mechanisms may play a role in the degenerative process in AD. Reactive microglia are embedded in neuritic plaques. Increased cytokine levels are seen in the serum, cortical plaques, and neurons of patients with AD, as compared with aged-matched control patients. […] The cholinergic system is involved in memory function, and cholinergic deficiency has been implicated in the cognitive decline and behavioral changes of AD.
#23 Pathogenesis of Dementia | SpringerLink
https://link.springer.com/chapter/10.1007/978-981-97-4117-5_1
Dementia is a pathological condition characterized by intricate molecular and cellular mechanisms that result in cognitive impairment. […] Understanding dementia highlights the role of pathogenic mechanisms by revealing aberrant alterations in the brain. These mechanisms include hypertension, ageing, atherosclerosis, tau protein abnormalities, and amyloid deposition. […] Converging pathogenic mechanisms, including Alzheimers disease, amyloid deposition, ageing, atherosclerosis, and hypertension, are responsible for vascular cognitive impairment, another factor contributing to dementia. These mechanisms worsen cognitive function by exacerbating cerebrovascular disease. […] There are still unanswered questions regarding the molecular and cellular pathogenesis of dementia.
#24 Pathogenesis of Dementia
https://pmc.ncbi.nlm.nih.gov/articles/PMC9820433/
The kinetics of neuronal respiration is limited by an uninterrupted cycle of reduction/oxidation of nicotinamide adenine dinucleotide (NAD). […] NAD deficiency, due to increasing demands for NAD-consuming enzymes as occurs in the aging process of the brain, causes the mitochondria to become less efficient and neurons cannot produce enough energy, especially ATP. […] The energy crisis in the aging brain and the mass death of malfunctioning and unnecessary neurons impede the formation of new memory traces. […] The most common feature of dementia is the loss of the ability to form new memory traces. This implies that brain aging and the resulting progressive degradation of cortical functional networks of the cerebral cortex and the hippocampus are the primary loci of dementia development.
#25 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
The most common feature of dementia is the loss of the ability to form new memory traces. This implies that brain aging and the resulting progressive degradation of cortical functional networks of the cerebral cortex and the hippocampus are the primary loci of dementia development. The neurodegenerative processes may be then spread to the limbic system, especially the amygdala as well as the entorhinal and cingulate cortex. […] […] In Alzheimerâs disease, the adrenergic system of the locus coeruleus and the serotonergic neurons of the dorsal raphe are heavily affected. The dorsal raphe nuclei play an important role in the sleep/wake cycle, which is disordered in the process of neurodegeneration. […] […] Misfolded proteins have been widely considered to be the triggering factors in Alzheimerâs disease. Indeed, the brains of patients contain large deposits of aggregated amyloid Î²-protein (AÎ²) which is generated as a byproduct of the proteolytic processing of the amyloid precursor protein (APP). […]
#26 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
The most common feature of dementia is the loss of the ability to form new memory traces. This implies that brain aging and the resulting progressive degradation of cortical functional networks of the cerebral cortex and the hippocampus are the primary loci of dementia development. The neurodegenerative processes may be then spread to the limbic system, especially the amygdala as well as the entorhinal and cingulate cortex. […] […] In Alzheimerâs disease, the adrenergic system of the locus coeruleus and the serotonergic neurons of the dorsal raphe are heavily affected. The dorsal raphe nuclei play an important role in the sleep/wake cycle, which is disordered in the process of neurodegeneration. […] […] Misfolded proteins have been widely considered to be the triggering factors in Alzheimerâs disease. Indeed, the brains of patients contain large deposits of aggregated amyloid Î²-protein (AÎ²) which is generated as a byproduct of the proteolytic processing of the amyloid precursor protein (APP). […]
#27 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
The energy crisis in the aging brain and the mass death of malfunctioning and unnecessary neurons impede the formation of new memory traces. The functional and trophic interaction inherent in the functioning of the brain has a particularly destructive effect on the functioning of the old and the formation of new functional networks in the elderly. This interaction ensures the correct energy supply and the necessary metabolites only of highly active neurons. It intensifies dysmetabolism, disturbs homeostasis, and accelerates the aging and death of nerve cells. The manifestation of these dysfunctions is late-onset neurodegenerative diseases. […] […] Mitochondrial dysfunction has been implicated in the pathophysiology of cellular aging and neurodegeneration. Mitochondria signal stress by alterations in adenine nucleotide levels, reactive oxygen species (ROS) production, Ca2+ fluxes, permeability transition pore opening, and perhaps secretion of specific proteins/peptides. Oxidative stress increases the number of malformed proteins that cannot be repaired due to a reduction in the synthesis of NAD-dependent enzymes. The rate of turnover in the cellular metabolic pathways is regulated based on reaction stoichiometry, the utilization rate of metabolites, and the translocation pace of molecules across the lipid bilayers. As a consequence of NAD deficiency in aging neurons, energy and metabolic crisis in the cells cumulate. When the energy deficit exceeds a critical level, the affected neurons are directed to the apoptotic pathway. […]
#28 Pathogenesis of Dementia
https://www.mdpi.com/1422-0067/24/1/543
The energy crisis in the aging brain and the mass death of malfunctioning and unnecessary neurons impede the formation of new memory traces. The functional and trophic interaction inherent in the functioning of the brain has a particularly destructive effect on the functioning of the old and the formation of new functional networks in the elderly. This interaction ensures the correct energy supply and the necessary metabolites only of highly active neurons. It intensifies dysmetabolism, disturbs homeostasis, and accelerates the aging and death of nerve cells. The manifestation of these dysfunctions is late-onset neurodegenerative diseases. […] […] Mitochondrial dysfunction has been implicated in the pathophysiology of cellular aging and neurodegeneration. Mitochondria signal stress by alterations in adenine nucleotide levels, reactive oxygen species (ROS) production, Ca2+ fluxes, permeability transition pore opening, and perhaps secretion of specific proteins/peptides. Oxidative stress increases the number of malformed proteins that cannot be repaired due to a reduction in the synthesis of NAD-dependent enzymes. The rate of turnover in the cellular metabolic pathways is regulated based on reaction stoichiometry, the utilization rate of metabolites, and the translocation pace of molecules across the lipid bilayers. As a consequence of NAD deficiency in aging neurons, energy and metabolic crisis in the cells cumulate. When the energy deficit exceeds a critical level, the affected neurons are directed to the apoptotic pathway. […]
#29 Roles of vascular risk factors in the pathogenesis of dementia | Hypertension Research
https://www.nature.com/articles/s41440-019-0357-9
CAA may be a key player linking vascular risk factors, vascular dementia, and Alzheimers disease. […] CAA induces the degeneration of the cerebrovascular walls, leading to cerebrovascular breakdown, hemorrhagic or ischemic stroke, and eventually cognitive dysfunction. […] The intensive management of vascular risk factors can be important in a patient with CAA in terms of dementia prevention.
#30 Discovery of Mechanism behind Vascular Dementia Could Help Develop Treatments | Inside Precision Medicine
https://www.insideprecisionmedicine.com/news-and-features/discovery-of-mechanism-behind-vascular-dementia-could-help-develop-treatments/
Research led by the University of Vermont shines a light on the mechanism behind vascular dementia in a mouse model, which the investigators hope will lead to better treatments being developed for the neurodegenerative condition. […] As reported in the journal PNAS, reduced blood flow to the brain is known to be a key factor in the hypertension-induced vascular dementia disease process, but the mechanism behind this was unclear, making it difficult to design therapies to improve blood flow. […] The current study investigated this mechanism in model mice and found the reduced cerebral blood flow was caused by a part of the smooth muscle cells becoming separated from the plasma membrane leading to a breakdown in cell signaling that would lead to the blood vessels relaxing under normal circumstances.
#31 Discovery of Mechanism behind Vascular Dementia Could Help Develop Treatments | Inside Precision Medicine
https://www.insideprecisionmedicine.com/news-and-features/discovery-of-mechanism-behind-vascular-dementia-could-help-develop-treatments/
To try and understand the mechanism behind hypertension-triggered vascular dementia better, Mark Nelson, a professor at the University of Vermont, and colleagues at the University of Manchester in the U.K. used a mouse model (BPH/2) of hypertension and vascular dementia to study the physiological mechanism behind the condition. […] Using a combination of techniques, the team found that the arteries in the brains of the mice were constricted, because a part of the smooth muscle cell known as the sarcoplasmic reticulum had separated from the plasma membrane. This separation stopped calcium signals that would normally trigger relaxation of the blood vessels from reaching their potassium channel targets. […] By uncovering how high blood pressure causes arteries in the brain to remain constricted, our research reveals a new avenue for drug discovery that may help to find the first treatment for vascular dementia. Allowing blood to return as normal to damaged areas of the brain will be crucial to stopping this devastating condition in its tracks.
#32 Epidemiology, pathology, and pathogenesis of dementia with Lewy bodies – UpToDate
https://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-dementia-with-lewy-bodies
Dementia with Lewy bodies (DLB) is one of the most common causes of dementia after Alzheimer disease (AD) and vascular dementia. DLB often presents a diagnostic challenge given its clinical heterogeneity and overlap with other neurodegenerative diseases. […] This topic will describe the epidemiology, neuropathologic findings, and potential pathogenic mechanisms of DLB. […] DLB, although once considered rare, is recognized as a common cause of neurodegenerative dementia, affecting up to 5 percent of the general population and accounting for as much as 30 percent of all dementia cases. […] Such prevalence estimates place DLB as one of the most common causes of dementia, superseded only by Alzheimer disease (AD) and vascular dementia.
#33 Pathogenesis of the Lewy body (Chapter 24) – Dementia with Lewy Bodies
https://www.cambridge.org/core/books/dementia-with-lewy-bodies/pathogenesis-of-the-lewy-body/09B6D4B4276AEF92E6D8AE8882835DC9
The constitutive fibrils of the Lewy body contain all three neurofilament subunits in an altered form. Our recent in situ hybridization studies of the low molecular weight subunit of the neurofilament suggest that altered neurofilament expression is not implicated in the formation of the Lewy body. […] We propose a speculative model of Lewy body pathogenesis in which neurofilaments are assembled normally and subsequently undergo phosphorylation, proteolysis and crosslinking at a post-translational/post-assembly stage. […] The presence of ubiquitin, ubiquitin-C-terminal hydrolase and ingestin (multicatalytic proteinase or proteasome) in the LB also suggests that proteolysis is implicated in its pathogenesis. Finally, the detergent-insolubility of these fibrils indicates that the NF proteins which form the LB are further altered and probably crosslinked. Taken together, these studies suggest that altered phosphorylation/dephosphorylation and proteolysis of NF are key post-translational events in LB pathogenesis.
#34 RAB39B involved in the pathogenesis of dementia with Lewy bodies – VJNeurology
https://www.vjneurology.com/video/95x-0hqkjne-rab39b-involved-in-the-pathogenesis-of-dementia-with-lewy-bodies/
Mutations within the vesicular trafficking protein RAB39B are associated with rare X-linked Parkinsons disease. […] Results support the involvement of RAB39B in the pathogenesis of dementia with Lewy bodies. […] Therefore, RAB39B and its associated functional pathways may be considered potential targets for therapeutic interventions in Lewy body diseases.
#35 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.
#36 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.
#37 Scientists Discover Novel Mechanism Underlying ALS and Related Dementia – News Center
https://news.feinberg.northwestern.edu/2017/09/18/scientists-discover-novel-mechanism-underlying-als-and-related-dementia/
A multi-organization team of scientists has discovered a novel mechanism for how a gene mutation leads to the death of neurons in amyotrophic lateral sclerosis (ALS) and the related disease frontotemporal dementia (FTD, findings which could inform the development of new treatments. […] In the current study, the scientists were able to link mutations in the gene that encodes the protein TIA1 to the development of both ALS and FTD. […] The team demonstrated that the faulty protein disrupted the normal disassembly of stress granules dense aggregations of proteins and RNA that form under stress conditions and promoted their accumulation in neurons. […] This accumulation led to the death of neurons in the brain and spinal cord that control muscles in ALS, and the death of neurons in the brain in FTD. […] The research, by identifying a novel cellular malfunction driving ALS and FTD, may offer scientists a new pathway towards the development of treatment for both disorders.
#38 Molecular Mechanism Behind HIV-Associated Dementia Revealed – News Center
https://news.feinberg.northwestern.edu/2018/01/03/molecular-mechanism-behind-hiv-associated-dementia-revealed/
For the first time, scientists have identified and inhibited a molecular process that can lead to neurodegeneration in patients with HIV, according to a Northwestern Medicine study published in Nature Communications. […] Buildup of beta-amyloid is thought to be a major contributor to neurodegeneration in a variety of dementia-associated diseases, especially Alzheimers, but how and why beta-amyloid is produced in HIV-infected patients and its contribution to HAND was a mystery, Naghavi said. […] The first clue came when Naghavi and her colleagues performed a large-scale assay looking for unusual interactions between cellular proteins and Gag, an important HIV protein. […] We put two and two together: We knew APP is a precursor to beta-amyloid, so we looked for APP and found increased processing of this protein into beta-amyloid in infected macrophages and microglia, Naghavi said.
#39 Molecular Mechanism Behind HIV-Associated Dementia Revealed – News Center
https://news.feinberg.northwestern.edu/2018/01/03/molecular-mechanism-behind-hiv-associated-dementia-revealed/
During infection of a microglia or macrophage cell, HIVs Gag protein promotes processing of APP, reducing resistance to cell takeover, which also has the side-effect of producing toxic beta-amyloid proteins, Naghavi said. […] By binding to APP, somehow Gag drags it into cell membrane regions called lipid rafts, where there are enzymes that promote processing of APP into beta-amyloid, she said. […] To reduce buildup of beta-amyloid, the scientists targeted the enzyme that cleaves APP, called gamma secretase. […] When the drug blocks APP processing, it reduces beta amyloid and increases APP compared to non-drugged models. This results in the combined benefits of reduced neurodegeneration and sustaining APPs original function of blocking infection. […] Weve opened the door for how these drugs might be used to block both HIV replication and treat HIV-associated dementia, Naghavi said.
#40 Pathogenesis of Dementia
https://pmc.ncbi.nlm.nih.gov/articles/PMC9820433/
Mitochondrial dysfunction has been implicated in the pathophysiology of cellular aging and neurodegeneration. […] The correlation of pathological changes in the brain with accompanying symptoms allows for a better understanding of the pathophysiology of dementia. […] The aging-related collapse of osteoblast-controlled calcium/phosphate homeostasis may act like the mythological Atropos cutting the thread of human life. […] The glucose/energy crisis also impacts emotional control. […] The increasing population of Europe coupled with the aging demographics in many European countries provides a clear indication that the overall number of people with dementia is likely to continue to increase significantly. […] The knowledge gathered so far allows us to posit that the basic cause of brain aging is the loss of control over glucose metabolism, resulting in the loss of energy balance.
#41 Alzheimerâs Disease: Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease
Your provider will suggest treatments to slow down how fast you develop dementia. Theres no cure for Alzheimers, but treatments may manage symptoms as they happen and slow down the conditions progression. […] There are many medications that can manage Alzheimers symptoms. […] Lecanemab and donanemab are intravenous (IV) infusions. Theyre two types of monoclonal antibodies. These are medications that can help your bodys immune system target and destroy amyloid proteins. They can slow down Alzheimers progression by getting rid of some of the amyloid before it damages your brain. […] NMDA antagonists block or fill up the N-methyl-D-aspartate (NMDA) receptors glutamate binds to in your brain. This can slow down how fast Alzheimers progresses.
#42 Alzheimerâs Disease: Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease
Your provider will suggest treatments to slow down how fast you develop dementia. Theres no cure for Alzheimers, but treatments may manage symptoms as they happen and slow down the conditions progression. […] There are many medications that can manage Alzheimers symptoms. […] Lecanemab and donanemab are intravenous (IV) infusions. Theyre two types of monoclonal antibodies. These are medications that can help your bodys immune system target and destroy amyloid proteins. They can slow down Alzheimers progression by getting rid of some of the amyloid before it damages your brain. […] NMDA antagonists block or fill up the N-methyl-D-aspartate (NMDA) receptors glutamate binds to in your brain. This can slow down how fast Alzheimers progresses.
#43 Alzheimer Disease: Practice Essentials, Background, Anatomy
https://emedicine.medscape.com/article/2003174-overview
Although very popular, the amyloid hypothesis is not uniformly accepted. On post-mortem analysis, amyloid plaques may be undetectable in the brains of patients who had severe AD but may be present in the brains of elderly patients who did not have dementia. […] The tau protein stabilizes neuronal microtubules. Destabilization of the microtubular system is speculated to disrupt the Golgi apparatus, in turn inducing abnormal protein processing and increasing production of Ab. […] Inflammatory and immune mechanisms may play a role in the degenerative process in AD. Reactive microglia are embedded in neuritic plaques. Increased cytokine levels are seen in the serum, cortical plaques, and neurons of patients with AD, as compared with aged-matched control patients. […] The cholinergic system is involved in memory function, and cholinergic deficiency has been implicated in the cognitive decline and behavioral changes of AD.
#44 Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment | Acta Pharmacologica Sinica
https://www.nature.com/articles/aps200982
Cholinergic deficits have been found in AD patients, and AChE inhibitors are currently the most commonly prescribed treatment for mild to moderate AD. […] Similarly, cholinergic deficits exist in VaD patients as well; therefore, AChE inhibitors may also provide benefit for these patients. […] The beneficial effects and mechanisms involved in the protection by donepezil were further studied in animal models of VaD. […] The above-mentioned findings indicate that rivastigmine may influence central nervous system inflammation by up-regulating cholinergic function, which may contribute to its protective effects in VaD patients and animal models. […] Although the precise mechanisms by which huperzine A produced the above-mentioned preclinical and clinical effects remain unclear, our previous study indicated that the benefits of huperzine A may depend at least partly on the anti-inflammatory property. […] These findings provide new insight into the pharmacological application of cholinergic functional enhancement accompanied by the adoption of the cholinergic anti-inflammation pathway.
#45 Azthena logo with the word Azthena
https://www.news-medical.net/news/20250115/Study-uncovers-mechanism-for-cognitive-improvement-in-dementia.aspx
A University of the Basque Country (UPV/EHU) study proves that the WIN55.212-2 drug protects the brain and reverses the initial cognitive damage caused by dementia, and explains how it works. […] Research shows that the drug activates the cannabinoid neurotransmitter system (which protects the brain), and this stimulates the cholinergic system (which controls memory and learning) by increasing the synthesis of acetylcholine (a neurotransmitter in the brain that controls memory and learning). […] The researcher Rodrguez-Puertas explained that „analyses carried out over the years on a very large sample of brain tissue from autopsies of patients who were at different stages of development of the disease enabled us, intriguingly, to see that when the first clinical symptoms of Alzheimer’s emerge, damage is found in the area that is initially affected in patients and is caused by one of the interneuronal transmission systems, the cholinergic system (which controls memory and learning and uses acetylcholine as a neurotransmitter); by contrast, we saw that another neurotransmission system, the cannabinoid system, increases”.
#46 Azthena logo with the word Azthena
https://www.news-medical.net/news/20250115/Study-uncovers-mechanism-for-cognitive-improvement-in-dementia.aspx
„It’s as if this cannabinoid system has an initial protective response to the damage of the cholinergic system and tries to protect the brain,” he said. „It is therefore a therapeutic target on which to act.” […] After testing the effect of the drug WIN55.212-2, which interacts with cannabinoid receptors, on rodents in the early stages of the disease, the team found „that they behaved in the same way as those without brain damage: they learned and remembered spatial orientation in the same way”, explained Marta Moreno. „You could say that in some way the drug reversed the damage or protected the brain.” […] The research group was able to understand the mechanism of this cognitive improvement „by using a novel technique developed and fine-tuned by the research group at the UPV/EHU and which enables the lipids in the brain to be identified and anatomically located.
#47 Shingles vaccine may directly guard against dementia, study hints | Live Science
https://www.livescience.com/health/alzheimers-dementia/shingles-vaccine-may-directly-guard-against-dementia-study-hints
The lower incidence of dementia seen in adults who received the shingles vaccine is likely not just a correlation, scientists say, based on new results of an observational study. […] The shingles vaccine may prevent or delay dementia, compelling new data suggest. […] These findings support the „viral hypothesis” of Alzheimer’s disease, which posits that viral infections contribute to the development of the condition, which is the most common form of dementia. […] This effect was not observed for other chronic conditions, such as high blood pressure, heart disease or diabetes, suggesting that the shingles vaccine had a specific protective effect against dementia. […] More studies are needed to understand the mechanism behind the vaccine’s protective effect against dementia, as that’s currently unclear. One theory suggests that reactivation of the varicella-zoster virus may trigger brain damage through a range of mechanisms, including the buildup of abnormal proteins and chronic inflammation. By preventing reactivation, the shingles vaccine may theoretically prevent this brain damage. […] Another hypothesis is that the vaccine provides protection not by targeting viruses directly but by tuning the immune system in a way that slows or alters the course of dementia.
#48 Shingles vaccine may directly guard against dementia, study hints | Live Science
https://www.livescience.com/health/alzheimers-dementia/shingles-vaccine-may-directly-guard-against-dementia-study-hints
The lower incidence of dementia seen in adults who received the shingles vaccine is likely not just a correlation, scientists say, based on new results of an observational study. […] The shingles vaccine may prevent or delay dementia, compelling new data suggest. […] These findings support the „viral hypothesis” of Alzheimer’s disease, which posits that viral infections contribute to the development of the condition, which is the most common form of dementia. […] This effect was not observed for other chronic conditions, such as high blood pressure, heart disease or diabetes, suggesting that the shingles vaccine had a specific protective effect against dementia. […] More studies are needed to understand the mechanism behind the vaccine’s protective effect against dementia, as that’s currently unclear. One theory suggests that reactivation of the varicella-zoster virus may trigger brain damage through a range of mechanisms, including the buildup of abnormal proteins and chronic inflammation. By preventing reactivation, the shingles vaccine may theoretically prevent this brain damage. […] Another hypothesis is that the vaccine provides protection not by targeting viruses directly but by tuning the immune system in a way that slows or alters the course of dementia.
#49 Alzheimerâs disease syndrome â Recognizing the complexity of dementia
https://www.oatext.com/alzheimers-disease-syndrome-recognizing-the-complexity-of-dementia.php
The pathogenesis and pathophysiology of LOAD may be complicated by systemic diseases and environmental factors such as cardiovascular dysregulation. […] The intricate interrelationship between dementia and diabetes suggests that successful long term mitigation will also necessitate careful management of insulin and glucose levels. […] It is clear that amyloid plays a pivotal role in the pathogenesis and pathophysiology of AD. […] Although there seem to be several pathways to dementia, it is important to recognize the contributions to healthy aging that active lifestyle interventions and education offer. […] The route to dementia is varied and complex and we have simply equated EOAD and LOAD on the bases of their most striking neuropathological lesions. […] New technologies embracing the use of human pluripotent stem cells and 3-dimensional human cell culture systems, which mimic the biochemistry and physiology of the human brain, may offer suitable models to better understand the dynamics of dementia than phylogenetically distant animal paradigms. […] The availability of biopsied brain tissue will also enable the discovery of uniquely time-dependent epigenetic changes and disturbed metabolic pathways involved in the pathogenesis and evolution of the different types of dementia.