• Publikační typ
• časopisecké články MeSH

BackgroundKLOTHO-VS heterozygosity (KL-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) KL-VSHET is associated with lower AD biomarker burden (Aβ42, Aβ42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by APOE ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). KLOTHO genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between KL-VSHET, sαKl levels, and biomarkers, stratified by APOE ε4 status and clinical subgroup.ResultsOverall, the associations between KL-VSHET and higher CSF Aβ42 and Aβ42/40 ratio were non-significant (ps ≥ 0.059) except when restricted to APOE ε4 carriers only (β = 0.11, p = 0.008 and β = 0.16, p = 0.033, respectively). Within clinical subgroups, KL-VSHET was positively associated with Aβ42/40 ratio only in aMCI-AD (β = 0.23, p = 0.034). No significant associations were observed between KL-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ42/40 ratio in APOE ε4 non-carriers (β = 0.24 p = 0.047).ConclusionsKL-VSHET may help protect against amyloid pathology, particularly in the presence of APOE ε4, and regardless of APOE status in aMCI-AD.

• MeSH
• Alzheimerova nemoc * mozkomíšní mok   genetika   MeSH
• amyloidní beta-protein mozkomíšní mok   MeSH
• apolipoprotein E4 genetika   MeSH
• biologické markery mozkomíšní mok   MeSH
• glukuronidasa * genetika   MeSH
• heterozygot MeSH
• kognitivní dysfunkce mozkomíšní mok   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty mozkomíšní mok   MeSH
• proteiny Klotho genetika   MeSH
• proteiny tau mozkomíšní mok   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

Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.

• MeSH
• Alzheimerova nemoc * krev   patologie   mozkomíšní mok   MeSH
• autofagie * fyziologie   MeSH
• biologické markery * mozkomíšní mok   krev   MeSH
• frontotemporální lobární degenerace * patologie   mozkomíšní mok   krev   MeSH
• homolog Atg1 metabolismus   MeSH
• intracelulární signální peptidy a proteiny MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitofagie * MeSH
• proteinkinasy metabolismus   krev   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

Předpokládá se, že rozpustné formy Amyloidu beta (Aß) a tau proteinu narušují neuronální aktivitu u Alzheimerovy nemoci (AN) a způsobují poruchy paměti. Brain-derived neurotrophic factor (BDNF) je protein regulující neuronální aktivitu a je syntetizován z prekurzoru pro-BDNF. BDNF posiluje synaptickou aktivitu mezi neurony a tím zvyšuje dlouhodobou potenciaci. Pro-BDNF naopak synaptickou aktivitu snižuje a zvyšuje tak dlouhodobou depresi mezi neurony. Maturace BDNF je regulována tkáňovým aktivátorem plazminogenu (tPA) a inhibitorem aktivátoru plazminogenu (tPA). Z toho vyplývá, že osa tPA/PAI-1 rozhoduje o extracelulárním poměru pro-BDNF/BDNF. U pacientů a AN byly pozorovány zvýšené hladiny PAI-1 v plasmě. Nicméně není známo, zda u pacientů s AN dochází k narušení procesu zrání BDNF. Tuto hypotézy budeme testovat pomocí měření poměru hladin pro-BDNF/BDNF a tPA/PAI-1 v krevním séru a mozkomíšním moku u pacientů s AN a budeme zjišťovat, zda tyto hladiny korelují s výsledky neuropsychologických testů a neurozobrazovacích metod. Výstupem projektu bude zavedení nových biomarkerů neuronové aktivity.; It has been hypothesized that soluble forms of amyloid beta (Aß) and tau proteins in Alzheimer’s Disease (AD) interfere with neuronal activity causing memory deficits. Brain-derived neurotrophic factor (BDNF) is a protein regulating neuronal activity and is synthesized as a precursor pro-BDNF. BDNF regulates activity-dependent forms of synaptic plasticity such as long-term potentiation. Pro-BDNF downregulates synaptic activity and enhances long-term depression. Maturation of BDNF is regulated by tissue-type plasminogen activator (tPA) and by plasminogen activator inhibitor-1 (PAI-1). Thus, tPA/PAI-1 axis arbitrates the extracellular pro-BDNF/BDNF ratio. Plasma levels of PAI-1 are increased in AD patients. However, whether the process of BDNF maturation is altered in AD is not known. To verify this hypothesis, we will measure pro-BDNF/BDNF and tPA/PAI-1 ratios in serum and cerebrospinal fluid from AD patients and explore whether these changes correlate to those of neuropsychological and neuroimaging data. The outcome will be that of adding new biomarkers related to neuronal activity.

• Klíčová slova
• alzheimerova choroba, Alzheimer's disease, mírná kognitivní porucha, mild cognitive impairment, BDNF, Pro-BDNF, BDNF, pro-BDNF, PAI-1, tPA, PAI-1, tPA,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

The application of artificial intelligence (AI) in neurology is a growing field offering opportunities to improve accuracy of diagnosis and treatment of complicated neuronal disorders, plus fostering a deeper understanding of the aetiologies of these diseases through AI-based analyses of large omics data. The most common neurodegenerative disease, Alzheimer's disease (AD), is characterized by brain accumulation of specific pathological proteins, accompanied by cognitive impairment. In this review, we summarize the latest progress on the use of AI in different AD-related fields, such as analysis of neuroimaging data enabling early and accurate AD diagnosis; prediction of AD progression, identification of patients at higher risk and evaluation of new treatments; improvement of the evaluation of drug response using AI algorithms to analyze patient clinical and neuroimaging data; the development of personalized AD therapies; and the use of AI-based techniques to improve the quality of daily life of AD patients and their caregivers.

• MeSH
• Alzheimerova nemoc * diagnóza   farmakoterapie   metabolismus   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• neurozobrazování metody   MeSH
• umělá inteligence * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

• MeSH
• Alzheimerova nemoc * mozkomíšní mok   krev   diagnóza   MeSH
• biologické markery * mozkomíšní mok   krev   metabolismus   MeSH
• kognitivní dysfunkce mozkomíšní mok   krev   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové proteiny mozkomíšní mok   metabolismus   krev   MeSH
• mitofagie * MeSH
• mozek metabolismus   patologie   MeSH
• nádorové supresorové proteiny MeSH
• proteinkinasy metabolismus   MeSH
• proteiny tau mozkomíšní mok   metabolismus   MeSH
• protoonkogenní proteiny mozkomíšní mok   krev   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktory BHLH-Zip metabolismus   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
• práce podpořená grantem MeSH

BACKGROUND: The central vein sign (CVS) has been proposed as a novel MRI biomarker to improve diagnosis of pediatric-onset MS (POMS). However, the role of CVS in POMS progression has yet to be discovered. OBJECTIVES: To investigate the appearance of CVS and its correlation with POMS disease progression. METHODS: One hundred fifty-six POMS from two MS centers in Israel and Czech Republic MS centers were followed for five years. Patient assessment was performed by the Expanded Disability Status Scale (EDSS) and Annual Relapse Rate (ARR). Patients in whom at least 40 % of brain MRI lesions had CVS ("rule of 40") were determined as CVS-positive. RESULTS: The total group of POMS consisted of 96 CVS-negative (61.5 %), aged 14.6 ± 1.9 years, EDSS 2.0, 75 % Interquartile Range (IQR) 1.0-3.0, disease duration (DD) 6.28 ± 0.38 years, and 60 CVS-positive (38.5 %), aged 15.1 ± 0.3 years, EDSS 2.0, IQR 1.5-3.0, DD 5.62 ± 0.13 years, were analyzed. After a three and five-year follow-up, the CVS-positive patients had higher EDSS scores than those who were CVS-negative, 2.0, IQR 1.0-2.5, vs 1.0, IQR 1.0-2.0, (p = 0.009) and 2.0, IQR 1.0-3.25 vs 1.0, IQR 1.0-2.0, (p = 0.0003), respectively. Patients with CVS-positive POMS were characterized by a significantly higher ARR (0.78 ± 0.08 vs 0.57 ± 0.04, p = 0.002). These results were confirmed in subgroups of Disease Modifying Treatments (DMT) untreated and treated patients. CONCLUSION: CVS-positive POMS is characterized by higher disability progression than CVS-negative, indicating the importance of CVS in disease pathogenesis.

• MeSH
• dítě MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mladiství MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• mozkové žíly diagnostické zobrazování   patofyziologie   MeSH
• následné studie MeSH
• posuzování pracovní neschopnosti MeSH
• progrese nemoci * MeSH
• roztroušená skleróza diagnostické zobrazování   patofyziologie   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Česká republika MeSH
• Izrael MeSH

Plasminogen activator inhibitor-1 (PAI-1) impedes brain plasmin synthesis. Reduced plasmin activity facilitates cumulation of amyloid beta (Aβ) in Alzheimer's disease (AD). Since plasmin also regulates the synaptic activity, it is possible that altered PAI-1 is present in other neurodegenerative disorders. We investigated whether PAI-1 and its counter-regulatory tissue plasminogen activator (tPA) are altered in serum of patients with dementia due to frontotemporal lobar degeneration (FTLD). Thirty five FTLD patients (21 in mild cognitive impairment stage (MCI) and 14 in dementia stage) and 10 cognitively healthy controls were recruited. Serum tPA and PAI-1 protein levels were measured by anova. Correlation between biochemical and demographic data were explored by measuring Pearson correlation coefficient. Serum PAI-1 levels were elevated in the FTLD dementia group as compared to FTLD MCI and controls. tPA serum levels and PAI-1/tPA ratio did not significantly differ among groups. There was a negative correlation between PAI-1 serum levels and disease severity measured by MMSE score. No correlations of tPA serum levels and PAI-1/tPA ratio with MMSE were found. Increased PAI-1 serum levels may serve as a marker of dementia in FTLD, suggesting that, besides Aβ pathway, the plasmin system may affect cognition through synaptic activity.

• MeSH
• biologické markery krev   MeSH
• frontotemporální lobární degenerace * krev   MeSH
• inhibitor aktivátoru plazminogenu 1 * krev   MeSH
• kognitivní dysfunkce krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• tkáňový aktivátor plazminogenu krev   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We previously demonstrated that serum levels of plasminogen activator inhibitor-1 (PAI-1), which inhibits both the tissue plasminogen activator (tPA) and plasmin activity, are increased in patients with Alzheimer's disease. tPA/plasmin not only prevents the accumulation of β-amyloid in the brain but also is involved in the synthesis of the brain-derived neurotrophic factor (BDNF), a neurotrophin whose levels are reduced in Alzheimer. In the present study, we compared BDNF serum levels in Alzheimer patients with dementia to those in Alzheimer patients with amnestic mild cognitive impairment and to cognitively healthy controls. Moreover, we examined whether the PAI-1/BDNF ratio correlates with disease severity, as measured by Mini-Mental State Examination. Our results showed that BDNF serum levels are lower (13.7% less) and PAI-1 levels are higher in Alzheimer patients with dementia than in Alzheimer patients with amnestic mild cognitive impairment patients (23% more) or controls (36% more). Furthermore, the PAI-1/BDNF ratio was significantly increased in Alzheimer patients as compared to amnestic mild cognitive impairment (36.4% more) and controls (40% more). Lastly, the PAI-1/BDNF ratio negatively correlated with the Mini-Mental score. Our results suggest that increased PAI-1 levels in Alzheimer, by impairing the production of the BDNF, are implicated in disease progression. They also indicate that the PAI-1/BDNF ratio could be used as a marker of Alzheimer. In support of this hypothesis, a strong negative correlation between the PAI-1/BDNF ratio and the Mini-Mental score was observed.

• Publikační typ
• časopisecké články MeSH

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system (CNS). Currently, MS treatment is limited to several Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved medications that slow disease progression by immunomodulatory action. Fingolimod and siponimod have similar mechanisms of action, and consequently, their therapeutic effects may be comparable. However, while fingolimod is mainly used for relapsing-remitting MS (RRMS), siponimod, according to EMA label, is recommended for active secondary progressive MS (SPMS). Clinicians and scientists are analysing whether patients can switch from fingolimod to siponimod and identifying the advantages or disadvantages of such a switch from a therapeutic point of view. In this review, we aim to discuss the therapeutic effects of these two drugs and the advantages/disadvantages of switching treatment from fingolimod to siponimod in patients with the most common forms of MS, RRMS and SPMS.

• MeSH
• chronicko-progresivní roztroušená skleróza * farmakoterapie   chemicky indukované   MeSH
• fingolimod hydrochlorid škodlivé účinky   MeSH
• hodnocení rizik MeSH
• imunosupresiva škodlivé účinky   MeSH
• lidé MeSH
• neurodegenerativní nemoci * chemicky indukované   farmakoterapie   MeSH
• recidiva MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH