BACKGROUND AND PURPOSE: Globular glial tauopathies (GGTs) have heterogeneous presentations; little evidence regarding typical clinical and magnetic resonance imaging (MRI) presentations are available. METHODS: We retrospectively assessed MRIs from three postmortem-confirmed GGT cases, in two patients with atypical progressive aphasia and one with corticobasal syndrome. RESULTS: We suggest that four principal concomitant MRI findings characterize GGT type I: a sagittal callosal hyperintense band, marked focal callosal atrophy suggesting white matter degeneration originating in cortical areas responsible for symptoms (anterior atrophy in predominantly language manifestations and posterior atrophy in predominantly apraxia), periventricular white matter lesions, and mild-to-moderate brain stem atrophy. CONCLUSIONS: We observed four concomitant MRI abnormalities in patients with atypical dementia, parkinsonism, and late incomplete supranuclear gaze palsy. Two patients had atypical progressive aphasia and one had corticobasal syndrome.
BACKGROUND: Obesity leads to low-grade inflammation in the adipose tissue and liver and neuroinflammation in the brain. Obesity-induced insulin resistance (IR) and neuroinflammation seem to intensify neurodegeneration including Alzheimer's disease. In this study, the impact of high-fat (HF) diet-induced obesity on potential neuroinflammation and peripheral IR was tested separately in males and females of THY-Tau22 mice, a model of tau pathology expressing mutated human tau protein. METHODS: Three-, 7-, and 11-month-old THY-Tau22 and wild-type males and females were tested for mobility, anxiety-like behavior, and short-term spatial memory in open-field and Y-maze tests. Plasma insulin, free fatty acid, cholesterol, and leptin were evaluated with commercial assays. Liver was stained with hematoxylin and eosin for histology. Brain sections were 3',3'-diaminobenzidine (DAB) and/or fluorescently detected for ionized calcium-binding adapter molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and tau phosphorylated at T231 (pTau (T231)), and analyzed. Insulin signaling cascade, pTau, extracellular signal-regulated kinase 1/2 (ERK1/2), and protein phosphatase 2A (PP2A) were quantified by western blotting of hippocampi of 11-month-old mice. Data are mean ± SEM and were subjected to Mann-Whitney t test within age and sex and mixed-effects analysis and Bonferroni's post hoc test for age comparison. RESULTS: Increased age most potently decreased mobility and increased anxiety in all mice. THY-Tau22 males showed impaired short-term spatial memory. HF diet increased body, fat, and liver weights and peripheral IR. HF diet-fed THY-Tau22 males showed massive Iba1+ microgliosis and GFAP+ astrocytosis in the hippocampus and amygdala. Activated astrocytes colocalized with pTau (T231) in THY-Tau22, although no significant difference in hippocampal tau phosphorylation was observed between 11-month-old HF and standard diet-fed THY-Tau22 mice. Eleven-month-old THY-Tau22 females, but not males, on both diets showed decreased synaptic and postsynaptic plasticity. CONCLUSIONS: Significant sex differences in neurodegenerative signs were found in THY-Tau22. Impaired short-term spatial memory was observed in 11-month-old THY-tau22 males but not females, which corresponded to increased neuroinflammation colocalized with pTau(T231) in the hippocampi and amygdalae of THY-Tau22 males. A robust decrease in synaptic and postsynaptic plasticity was observed in 11-month-old females but not males. HF diet caused peripheral but not central IR in mice of both sexes.
- MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- fosforylace MeSH
- hipokampus metabolismus MeSH
- inzulinová rezistence * MeSH
- krátkodobá paměť MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus patofyziologie MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- obezita komplikace etiologie MeSH
- omezení pohyblivosti MeSH
- proteiny tau MeSH
- sexuální faktory MeSH
- stárnutí metabolismus MeSH
- tauopatie komplikace genetika MeSH
- zánět MeSH
- ztučnělá játra metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders.
- MeSH
- Alzheimerova nemoc farmakoterapie etiologie patofyziologie psychologie MeSH
- antigeny imunologie metabolismus fyziologie MeSH
- cílená molekulární terapie MeSH
- extracelulární matrix metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- neurodegenerativní nemoci farmakoterapie etiologie patofyziologie psychologie MeSH
- neuroplasticita MeSH
- neutralizující protilátky terapeutické užití MeSH
- paměť fyziologie MeSH
- potkani Sprague-Dawley MeSH
- proteoglykany imunologie metabolismus fyziologie MeSH
- protilátky aplikace a dávkování MeSH
- reakční čas MeSH
- tauopatie komplikace MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Neuropatologická diagnostická kritéria neurodegenerací jsou založena na průkazu specifických změn v parenchymu korelujících s klinickým obrazem. Souběžná neuropatologicky definovaná onemocnění odpovídají kombinaci dvou (i více) odlišných, plně rozvinutých postižení u téhož pacienta. U souběžné patologie více entit v ohraničených oblastech mozku vedle primární nozologické jednotky nacházíme zároveň depozita proteinu specifického pro jinou neurodegeneraci. Častá je kombinace Alzheimerovy nemoci (AN) s inkluzemi alfa‑synukleinu. U AN se může zároveň ukládat i protein TDP‑43, není ale jasné, zda se jedná o atypicky probíhající AN nebo kombinaci atypické AN s frontotemporální lobární degenerací. Komorbidity AN a tauopatií jsou relativně vzácné. U pacientů s Creutzfeldtovou‑Jakobovou nemocí lze diagnostikovat doprovodnou AN nebo demenci s Lewyho tělísky. Kombinace vaskulární patologie s primární neurodegenerací (nejčastěji AN nebo demencí s Lewyho tělísky) se historicky označuje jako smíšená demence. Kombinace neuropatologicky potvrzených neurodegenerací může vést k atypickým klinickým projevům, které ilustrujeme na příkladech s odkazy na publikované kazuistiky ze souboru našich pacientů. Klíčová slova: neurodegenerace – Alzheimerova nemoc - tauopatie – protein TDP-43 – synukleinopatie – smíšená demence
Neuropathological diagnostic criteria of neurodegenerative disorders are based on the presence of specific lesions in the brain tissue that correlate with clinical symptoms. Concomitant neurodegenerative disorders correspond to a combination of two (or more) different fully developed diseases in one patient. Concomitant neurodegenerative pathology stays for the presence of a definite neurodegeneration and deposits specific for another, but not fully developed, disease. Frequent overlaps include Alzheimer’s disease (AD) and alpha-synuclein inclusions. In AD, protein TDP-43 may co-aggregate but it is not clear whether this is an atypical but isolated AD, or an overlap of AD with early frontotemporal lobar degeneration. Comorbidities of AD and tauopathies are relatively rare. In Creutzfeldt-Jakob disease, concomitant AD or Lewy body dementia may occur. A combination of vascular pathology with a primary neurodegeneration (mostly Alzheimer’s disease or Lewy body dementia) is historically called mixed dementia. Overlap of neuropathologically confirmed neurodegenerations may lead to atypical and unusual clinical presentations, illustrated with examples and references to published case reports from our patient cohort. Key words: neurodegeneration – Alzheimer’s disease – tauopathy – TDP-43 protein – synucleinopathy – mixed dementia The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
- MeSH
- Alzheimerova nemoc diagnóza etiologie komplikace MeSH
- demence s Lewyho tělísky diagnóza etiologie komplikace MeSH
- komorbidita * MeSH
- lidé MeSH
- mezioborová komunikace * MeSH
- neurodegenerativní nemoci * diagnóza etiologie komplikace MeSH
- Parkinsonova nemoc diagnóza etiologie komplikace MeSH
- proteinopatie TDP-43 diagnóza etiologie komplikace MeSH
- statistika jako téma MeSH
- tauopatie diagnóza etiologie komplikace MeSH
- vaskulární demence diagnóza etiologie komplikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Ochorenie, ktoré dnes označujeme ako frontotemporálna lobárna degenerácia (FTLD), prešlo zložitým vývojom od svojho prvého opisu Arnoldom Pickom a neskôr Aloisom Alzheimerom, cez prvé klinicko‑patologické kritériá predstavené Davidom Nearym a Davidom Mannom, až po dnešné nomenklatúrne vnímanie ako komplexnej klinicko‑patologickej entity. V súčasnosti je frontotemporálna lobárna degenerácia vnímaná ako heterogénny syndróm spôsobený progresívnou degeneráciou frontálnych a temporálnych lalokov mozgu. Klinicky sa môže prejaviť ako tri syndrómy frontotemporálnej demencie (behaviorálny variant FTD, progresívna non‑fluentná afázia a sémantická demencia), ale aj ako tzv. overlap syndrómy zahrňujúce kortikobazálnu degeneráciu a progresívnu supranukleárnu obrnu. Jej výskyt je asi 10 % spomedzi všetkých demencií a 40 % spomedzi demencií so začiatkom medzi 45. a 65. rokom života. Klinická manifestácia jednotlivých subtypov sa líši, spoločným menovateľom sú poruchy správania a postihnutie fatických, gnostických a exekutívnych funkcií. Mnestické a zrakovo‑priestorové funkcie zostávajú síce relatívne dlho zachované, sú však prekryté rozpadom osobnosti, fatickými alebo gnostickými poruchami. V porovnaní s Alzheimerovou chorobou má spravidla skorší vek nástupu, rýchlejší priebeh a devastujúcejšie postihnutie jednotlivých kognitívnych domén. Postihnutí sú spravidla rýchlejšie odkázaní na pomoc inej osoby alebo inštitúcie. V našom príspevku sa snažíme o súhrnný pohľad na túto výrazne heterogénnu klinicko‑patologickú entitu so zameraním sa na klinické, genetické a histopatologické špecifiká. Hlavnú pozornosť venujeme syndrómom frontotemporálnej demencie.
The disease currently known as Frontotemporal Lobar Degeneration (FTLD) underwent a complicated development. From its first description by Arnold Pick and Alois Alzheimer, through the first clinical and pathological criteria introduced by David Neary and David Mann to the current perception of the disease as a complex clinical and pathological entity. At present, the Frontotemporal Lobar Degeneration is understood to be a heterogeneous clinical syndrome caused by degeneration of the frontal and temporal lobes. FTLD can manifest as any of the three clinical syndromes of frontotemporal dementia (behavioural variant of frontotemporal dementia, progressive non‑fluent aphasia and semantic dementia) as well as so called overlap syndromes encompassing corticobasal dementia and progressive supranuclear palsy. FTLD represents approximately 10% of all cases of dementia but 40% of cases of early onset dementia (between the age of 45 and 65 years). Although FTLD subtypes differ in their clinical manifestation, common denominators include behavioural disturbances and impairment of fatic, gnostic and executive functions. Mnestic and visual‑spatial functions are preserved until advanced stages of the disease. Compared to Alzheimer’s disease, the FTLD usually onsets at an earlier age and causes more devastating impairment of cognitive domains. Persons affected by FTLD become more quickly dependent on the help of other person or an institution. In our paper, we provide an overview of this complex entity, focusing mainly on frontotemporal dementia syndromes. Key words: frontotemporal lobar degeneration – frontotemporal dementia – progressive non-fluent aphasia – semantic dementia – tau protein – tautopathy – ubiquitin – TDP-43 protein – behavioural disturbances – speech disorder The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
- Klíčová slova
- progresivní non-fluentní afázie, TDP-43 protein, progranulin,
- MeSH
- biologické markery MeSH
- DNA vazebné proteiny metabolismus MeSH
- duševní poruchy MeSH
- frontotemporální demence * diagnóza patologie MeSH
- frontotemporální lobární degenerace * diagnóza genetika patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mutace MeSH
- Pickova nemoc mozku diagnóza patofyziologie MeSH
- poruchy řeči MeSH
- primární progresivní nonfluentní afázie * diagnóza patologie MeSH
- protein FUS vázající RNA metabolismus MeSH
- proteiny tau genetika metabolismus MeSH
- tauopatie komplikace patofyziologie MeSH
- ubikvitin metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
