Chronic effects of inflammation on tauopathies

The Lancet Neurology, Journal Year: 2023, Volume and Issue: 22(5), P. 430 - 442

Published: April 13, 2023

Language: Английский

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Neurovascular unit dysfunction as a mechanism of seizures and epilepsy during aging

Epilepsia, Journal Year: 2022, Volume and Issue: 63(6), P. 1297 - 1313

Published: Feb. 25, 2022

The term neurovascular unit (NVU) describes the structural and functional liaison between specialized brain endothelium, glial mural cells, neurons. Within NVU, blood-brain barrier (BBB) is microvascular structure regulating neuronal physiology immune cross-talk, its properties adapt to aging. Here, we analyze a research framework where NVU dysfunction, caused by acute insults or disease progression in aging brain, represents converging mechanism underlying late-onset seizures epilepsy neurological neurodegenerative sequelae. Furthermore, seizure activity may accelerate sustaining regional cerebrovascular pathology link comorbidities. Next, focus on diagnostic approaches that could be tailored conditions elderly. We also examine impending disease-modifying strategies based restoration of and, more general, homeostatic control anti- pro-inflammatory players. conclude with an outlook current pre-clinical knowledge gaps clinical challenges pertinent onset population.

Language: Английский

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Alzheimer Disease and Epilepsy

Neurology, Journal Year: 2023, Volume and Issue: 101(4)

Published: May 24, 2023

Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether in which direction causal association exists. This study aims to explore the genetic predisposition AD, CSF biomarkers of AD (β-amyloid [Aβ] 42 phosphorylated tau [pTau]), epilepsies with 2-sample, Mendelian randomization (MR) method.Genetic instruments were obtained from large-scale genome-wide meta-analysis (Ncase/proxy = 111,326, Ncontrol 677,663), (Aβ42 pTau, N 13,116), epilepsy (Ncase 15,212, 29,677) European ancestry. Epilepsy phenotypes included all epilepsy, generalized focal childhood absence juvenile myoclonic tonic-clonic seizures, hippocampal sclerosis (focal HS), lesion-negative epilepsy. Main analyses performed using summary data-based MR. Sensitivity inverse variance weighted, MR pleiotropy residual sum outlier, MR-Egger, weighted mode, median.For forward analysis, was associated an increased risk (odds ratio [OR] 1.053, 95% CI 1.002-1.105, p 0.038) HS (OR 1.013, 1.004-1.022, 0.004). These associations consistent across sensitivity replicated separate set another study. For reverse there suggestive effect on 3.994, 1.172-13.613, 0.027). In addition, genetically predicted lower Aβ42 (β 0.090, 0.022-0.158, 0.010).This supports link amyloid pathology, also indicates close HS. More effort should be made screen seizure unravel its clinical implications, role as putative modifiable factor.

Language: Английский

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Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease

Autophagy, Journal Year: 2023, Volume and Issue: 19(8), P. 2386 - 2390

Published: Feb. 2, 2023

In 2019 we summarized work relating to the potential use of rapamycin for treating Alzheimer disease (AD). We considered commentary necessary because in people with AD is a very real prospect and wanted present balanced view likely consequences MTOR (mechanistic target kinase) inhibition brain. concluded that rapamycin, an inhibitor increases macroautophagy/autophagy, could hold promise prevention if used early enough. However, appeared ineffectual resolving existing amyloid pathology mouse models. this View article, update these observations new studies have models provide evidence both against its AD. also discuss light research describes rapamycin-induced autophagic stress aging brain as origin plaque itself. conclude will complex effects on Further, hypothesize lysosomal degradative capacity determine how effective or detrimental be treatment

Language: Английский

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Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Frontiers in Neurology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 8, 2024

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) stand as the prevailing sources of neurodegenerative dementia, impacting over 55 million individuals across globe. Patients AD DLB exhibit a higher prevalence epileptic activity compared to those other forms dementia. Seizures can accompany in early stages, associated contribute cognitive symptoms exacerbate decline. Aberrant neuronal may be caused by several mechanisms that are not yet understood. Hyperexcitability could biomarker for detection or before onset In this review, we compare contrast network hyperexcitability DLB. We examine contributions genetic risk factors, Ca 2+ dysregulation, glutamate, AMPA NMDA receptors, mTOR, pathological amyloid beta, tau α-synuclein, altered microglial astrocytic activity, impaired inhibitory interneuron function. By gaining deeper understanding molecular cause hyperexcitability, might uncover therapeutic approaches effectively ease slow down advancement

Language: Английский

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Bidirectional relationship between late-onset epilepsy (LOE) and dementia: A systematic review and meta-analysis of cohort studies

Epilepsy & Behavior, Journal Year: 2024, Volume and Issue: 153, P. 109723 - 109723

Published: March 14, 2024

Language: Английский

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Diagnostic and therapeutic approaches in refractory insular epilepsy

Epilepsia, Journal Year: 2023, Volume and Issue: 64(6), P. 1409 - 1423

Published: March 4, 2023

Due to heterogenous seizure semiology and poor contribution of scalp electroencephalography (EEG) signals, insular epilepsy requires use the appropriate diagnostic tools for its diagnosis characterization. The deep location insula also presents surgical challenges. aim this article is review current therapeutic their management epilepsy. Magnetic resonance imaging (MRI), isotopic imaging, neurophysiological genetic testing should be used interpretated with caution. Isotopic EEG have demonstrated a lower value in from compared temporal origin, which increases interest functional MRI magnetoencephalography. Intracranial recording stereo-electroencephalography (SEEG) often required. cortex, being highly connected deeply located under areas, difficult reach, ablative surgery raises issues. Tailored resection based on SEEG or alternative curative treatments, such as radiofrequency thermocoagulation, laser interstitial thermal therapy, stereotactic radiosurgery, produced encouraging results. has benefited major advances last years. Perspectives procedures will contribute better complex form

Language: Английский

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Neuroinflammation: A Common Pathway in Alzheimer’s Disease and Epilepsy

Journal of Alzheimer s Disease, Journal Year: 2023, Volume and Issue: 94(s1), P. S253 - S265

Published: April 17, 2023

Background: Neuroinflammation is an innate immunological response of the central nervous system that may be induced by a brain insult and chronic neurodegenerative conditions. Recent research has shown neuroinflammation contribute to initiation Alzheimer’s disease (AD) pathogenesis associated epileptogenesis. Objective: This systematic review aimed investigate available literature on shared molecular mechanisms in AD epilepsy. Methods: The search included this was obtained from 5 established databases. A total 2,760 articles were screened according inclusion criteria. Articles related modulation inflammatory biomarkers commonly with progression epilepsy all populations review. Results: Only 7 met these criteria chosen for further analysis. Selected studies include both vitro vivo conducted rodents. Several neuroinflammatory reported involved cross-talk between Conclusion: directly advancement compared those either or However, more focusing common are required develop standardized monitoring guidelines prevent manifestation delay patients.

Language: Английский

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Assessment of tau phosphorylation and β‐amyloid pathology in human drug‐resistant epilepsy

Epilepsia Open, Journal Year: 2023, Volume and Issue: 8(2), P. 609 - 622

Published: April 13, 2023

Abstract Objective Epilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that decline in epilepsy may associated mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks AD have been found brain biopsies surgically resected from patients drug‐resistant epilepsies. These include hyperphosphorylation tau protein (p‐tau) aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well presence β‐amyloid (Aβ) deposits. While recent studies agree on these neuropathological findings epilepsy, some contrast their correlation to decline. Thus, further address this question we determined abundance p‐tau and Aβ proteins along association function 12 cases refractory epilepsy. Methods Cortical extracted temporal lobes were processed for immunohistology enzyme‐linked immunoassays assess distribution levels, respectively, (Antibodies: Ser202/Thr205; Thr205; Thr181) proteins. In parallel, measured activation mechanistic target rapamycin (mTOR) via p‐S6 Ser240/244; Ser235/236). Pearson coefficient analysis associations between neurophysiological scores full‐scale intelligence quotient (FSIQ). Results We a robust (Ser202/Thr205)‐related NT NFT pathology, deposits, (Ser240/244; Ser235/236) biopsies. no significant correlations (Thr205; Thr181), Aβ, mTOR markers FSIQ scores, although coefficients modest strong. Significance strongly support existence hyperphosphorylated deposits human However, relation is still unclear requires investigation.

Language: Английский

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Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy

Brain Communications, Journal Year: 2024, Volume and Issue: 6(5)

Published: Jan. 1, 2024

Abstract Epilepsy and Alzheimer’s disease share some common pathologies such as neurodegeneration, seizures impaired cognition. However, the molecular mechanisms of these changes are still largely unknown. Fyn, a Src-family non-receptor tyrosine kinase (SFK), its interaction with tau in mediating brain pathology epilepsy can be potential therapeutic target for modification. Although Fyn occurs both epilepsy, dynamics Fyn-tau PSD95-NR2B interactions affected by their impact on have not been investigated. In this study, we demonstrate significant increase following seizure induction kainate acute chronic rodent models human epilepsy. early phase epileptogenesis, show increased Fyn/tau/NR2B/PSD95/neuronal nitric oxide synthase complexes after status epilepticus postsynaptic phosphorylated (pY18 AT8), (pSFK-Y416), NMDAR (pNR2B-Y1472) neuronal synthase. Hippocampal proximity ligation assay co-immunoprecipitation revealed sustained NR2B-PSD95 complexes/binding rat at 3 months post-status epilepticus. Enhanced strongly correlated frequency spontaneously recurring convulsive epileptiform spikes model. epileptic brains, also identified complexes, phosphorylation AT8) activation implying translational interactions. knockout mice rats treated Fyn/SFK inhibitor saracatinib, found reduction (AT8 saracatinib-treated), NR2B (Fyn-tau saracatinib-treated group; group). The group, contrast to vehicle-treated modification progression These findings from animal provide evidence role seizure-induced suggest that blocking could modify

Language: Английский

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