The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.
- MeSH
- Alzheimerova nemoc * metabolismus patologie etiologie MeSH
- amyloidní beta-protein * metabolismus MeSH
- buněčná membrána metabolismus MeSH
- fosforylace MeSH
- lidé MeSH
- peptidové fragmenty metabolismus MeSH
- protein 1 související s LDL-receptory * metabolismus MeSH
- proteiny tau * metabolismus MeSH
- tauopatie * metabolismus patologie etiologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Creutzfeldtova‐Jakobova choroba (CJD) je nezvratně smrtící onemocnění zapříčiněné patologicky konformovaným prionovým proteinem. Ač se může vyskytovat i v mladším věku, v překvapivě vysokém procentu ji u všech věkových kategorií nacházíme v komorbiditě s dalšími neuropatologickými jednotkami. To může v řadě případů měnit typické klinické obtíže pacientů, a tím výrazně znesnadňovat klinickou diagnostiku. Předkládáme kazuistiku 75leté pacientky, u níž byla definitivním neuropatologickým vyšetřením odhalena kombinace sporadické CreutzfeldtovyJakobovy choroby, plně vyvinuté demence s Lewyho tělísky, plně vyvinuté pozdní formy Alzheimerovy choroby, frontotemporální lobární degenerace s převahou rysů věkově vázané astrogliální tauopatie a relativně pokročilého vaskulárního postižení. Přestože jsou komorbidity jiných neurodegenerativních onemocnění u CJD časté, v tomto případě se jednalo o velmi neobvyklou kombinaci vícera vyvinutých entit.
Creutzfeldt-Jakob disease (CJD) is an irreversibly fatal disease caused by a pathologically conformed prion protein. Although it can also occur at a younger age, it is found in a surprisingly high percentage in all age groups in comorbidity with other neuropathological entities. In many cases, the comorbidities can change the typical clinical symptomatology of patients and thus significantly complicate clinical diagnosis. We present the case report of a 75-year-old female patient, in whom definitive neuropathological examination revealed a combination of sporadic Creutzfeldt-Jakob disease, fully developed dementia with Lewy bodies, fully developed Alzheimer's disease, frontotemporal lobar degeneration with predominance of features of age-related astrogliopathy, and relatively advanced vascular dementia. Although comorbidities of other neurodegenerative diseases are common in CJD, in this case it was a very unusual combination of multiple developed neurodegenerations.
Lidská prionová onemocnění (TSE) jsou skupinou progresivních fatálních neurodegenerativních onemocnění způsobených agregací patologicky konformovaného prionového proteinu v nervové tkáni. Vzhledem k riziku přenosu podléhají aktivní surveillance – v České republice jsou data centralizována v Národní referenční laboratoři pro diagnostiku prionových chorob (NRL) při Ústavu patologie a molekulární medicíny 3. LF UK a FTN. Veškeré případy klinicky možné či pravděpodobné TSE jsou podrobeny povinné pitvě na pracovišti NRL dle standardizovaného protokolu. Od začátku existence NRL v roce 2001 do roku 2022 bylo v ČR potvrzeno 361 případů sporadických či genetických TSE, včetně 10 vzácných případů Gerstmannova‐Sträusslerova‐Scheinkerova syndromu (GSS). Od ledna 2007 v rámci NRL navíc běží celosvětově unikátní projekt testování mozkové tkáně všech dárců rohovky pro zvýšení bezpečnosti korneálních transplantací. Všech 7 950 doposud vyšetřených vzorků mozkové tkáně dárců rohovky bylo negativních na přítomnost depozit patologicky konformovaného prionového proteinu.
Human prion diseases (TSEs) are a group of progressive fatal neurodegenerative diseases caused by aggregation of pathologically conformed prion protein in nervous tissue. Due to the risk of transmission, they are subject to active surveillance - in the Czech Republic, the data are centralized in the National Reference Laboratory for the Diagnosis of Prion Diseases (NRL) at the Institute of Pathology and Molecular Medicine of the Third Faculty of Medicine of Charles University and FTN. All cases of clinically possible or probable TSEs are subjected to a mandatory autopsy at the NRL according to a standardized protocol. Since the beginning of the NRL in 2001 to 2022, 361 cases of sporadic or genetic TSEs were confirmed in the Czech Republic, including 10 rare cases of Gerstmann-Sträussler-Scheinker syndrome (GSS). Since January 2007, the NRL has been running a globally unique project to test the brain tissue of all corneal donors to increase the safety of corneal transplants. All 7950 samples of corneal donor brain tissue examined were negative for the presence of deposits of pathologically conformed prion protein.
Creutzfeldt-Jakob disease (CJD), the most common human prion disorder, may occur as "pure" neurodegeneration with isolated prion deposits in the brain tissue; however, comorbid cases with different concomitant neurodegenerative diseases have been reported. This retrospective study examined correlations of clinical, neuropathological, molecular-genetic, immunological, and neuroimaging biomarkers in pure and comorbid CJD. A total of 215 patients have been diagnosed with CJD during the last ten years by the Czech National Center for Prion Disorder Surveillance. Data were collected from all patients with respect to diagnostic criteria for probable CJD, including clinical description, EEG, MRI, and CSF findings. A detailed neuropathological analysis uncovered that only 11.16% were "pure" CJD, while 62.79% had comorbid tauopathy, 20.47% had Alzheimer's disease, 3.26% had frontotemporal lobar degeneration, and 2.33% had synucleinopathy. The comorbid subgroup analysis revealed that tauopathy was linked to putaminal hyperintensity on MRIs, and AD mainly impacted the age of onset, hippocampal atrophy on MRIs, and beta-amyloid levels in the CSF. The retrospective data analysis found a surprisingly high proportion of comorbid neuropathologies; only 11% of cases were verified as "pure" CJD, i.e., lacking hallmarks of other neurodegenerations. Comorbid neuropathologies can impact disease manifestation and can complicate the clinical diagnosis of CJD.
- Publikační typ
- časopisecké články MeSH
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other pathogenic proteins related to other neurodegenerations. Hippocampal regions of nine clinically, neuropathologically, and genetically confirmed GSS subjects were investigated using immunohistochemistry and multichannel confocal fluorescent microscopy. Most pathognomic prion protein plaques were small (2-10 μm), condensed, globous, and did not contain any of the other investigated proteinaceous components, particularly dystrophic neurites. Equally rare (in two cases out of nine) were plaques over 50 μm having predominantly fibrillar structure and exhibit the presence of dystrophic neuritic structures; in one case, the plaques also included bulbous dystrophic neurites. Co-expression with hyperphosphorylated protein tau protein or amyloid beta-peptide (Aβ) in GSS PrP plaques is generally a rare observation, even in cases with comorbid neuropathology. The dominant picture of the GSS brain is small, condensed plaques, often multicentric, while presence of dystrophic neuritic changes accumulating hyperphosphorylated protein tau or Aβ in the PrP plaques are rare and, thus, their presence probably constitutes a trivial observation without any relationship to GSS development and progression.
- MeSH
- dospělí MeSH
- Gerstmannova-Strausslerova-Scheinkerova nemoc * genetika metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- missense mutace * MeSH
- patologická konformace proteinů * genetika metabolismus patologie MeSH
- prionová bílkovina * genetika metabolismus MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Human prion disorders (transmissible spongiform encephalopathies, TSEs) are unique, progressive, and fatal neurodegenerative diseases caused by aggregation of misfolded prion protein in neuronal tissue. Due to the potential transmission, human TSEs are under active surveillance in a majority of countries; in the Czech Republic data are centralized at the National surveillance center (NRL) which has a clinical and a neuropathological subdivision. The aim of our article is to review current knowledge about human TSEs and summarize the experience of active surveillance of human prion diseases in the Czech Republic during the last 20 years. Possible or probable TSEs undergo a mandatory autopsy using a standardized protocol. From 2001 to 2020, 305 cases of sporadic and genetic TSEs including 8 rare cases of Gerstmann-Sträussler-Scheinker syndrome (GSS) were confirmed. Additionally, in the Czech Republic, brain samples from all corneal donors have been tested by the NRL immunology laboratory to increase the safety of corneal transplants since January 2007. All tested 6590 corneal donor brain tissue samples were negative for prion protein deposits. Moreover, the routine use of diagnostic criteria including biomarkers are robust enough, and not even the COVID-19 pandemic has negatively impacted TSEs surveillance in the Czech Republic.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Despite an early understanding of amyotrophic lateral sclerosis (ALS) as a disease affecting the motor system, including motoneurons in the motor cortex, brainstem, and spinal cord, today, many cases involving dementia and behavioral disorders are reported. Therefore, we currently divide ALS not only based on genetic predisposition into the most common sporadic variant (90% of cases) and the familial variant (10%), but also based on cognitive and/or behavioral symptoms, with five specific subgroups of clinical manifestation-ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, the fully developed behavioral variant of frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer's disease (AD). Generally, these cases are referred to as amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD). Clinical behaviors and the presence of the same pathognomonic deposits suggest that FTLD and ALS could be a continuum of one entity. This review was designed primarily to compare neuropathological findings in different types of ALS relative to their characteristic locations as well as the immunoreactivity of the inclusions, and thus, foster a better understanding of the immunoreactivity, distribution, and morphology of the pathological deposits in relation to genetic mutations, which can be useful in specifying the final diagnosis.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Alzheimer's disease (AD) and sporadic Creutzfeldt-Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins-amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and "compound" plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer's association guidelines, and prion protein subtype with codon 129 methionine-valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.
- MeSH
- Alzheimerova nemoc patologie MeSH
- amyloidní beta-protein genetika metabolismus MeSH
- amyloidní plaky patologie MeSH
- Creutzfeldtova-Jakobova nemoc patologie MeSH
- extracelulární prostor chemie MeSH
- jednonukleotidový polymorfismus genetika MeSH
- kodon genetika MeSH
- komorbidita MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozek patologie MeSH
- neurony patologie MeSH
- pilotní projekty MeSH
- proteinové agregáty * MeSH
- proteiny tau metabolismus MeSH
- PrPSc proteiny genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer's disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term "amyloid" refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer's disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.
- MeSH
- Alzheimerova nemoc metabolismus MeSH
- amyloid metabolismus MeSH
- amyloidní beta-protein metabolismus MeSH
- amyloidní plaky metabolismus MeSH
- amyloidogenní proteiny metabolismus MeSH
- amyloidóza metabolismus MeSH
- Creutzfeldtova-Jakobova nemoc metabolismus MeSH
- lidé MeSH
- mozek metabolismus patologie MeSH
- neurity metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
