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Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

El fenotipo de muchas enfermedades neurológicas, ocasionadas por mutaciones genéticas deletéreas, puede manifestarse con variaciones drásticas en el momento de aparición, la severidad y prototipo de síntomas y signos, y en muchos casos el cuadro clínico es tan disímil que produce entidades diferentes, aun cuando la mutación ocurra en el mismo nucleótido de un gen particular. Aunque este fenómeno es supremamente complejo, ha recibido nombres como pleiotropía, entre otros. Nosotros hemos usado el término tautología para denotar el efecto de mutaciones en contextos genéticos particulares capaces de producir fenotipos de enfermedad con una alta variabilidad sindromática. Este fenómeno ha sido descrito en diversas enfermedades autoinmunes que, aunque afectan células blanco y órganos diferentes, comparten los mismos mecanismos de daño o factores predisponentes. Fenómeno denominado síndromes autoinmunes múltiples.

Dysfunction in the neurovascular unit (NVU) is a key component in the progressive deterioration of Alzheimer’s disease (AD) and is critical in vascular dementia. Recent studies have shown that inflammation plays early and perhaps causal roles in the pathogenesis of AD related to NVU damage, possibly in part by overactivating the aspartic acid protease activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which until now has almost solely been studied in the context of the β-amyloid cascade. In this study, we analyzed the relationship of BACE1 with astrocytes and blood vessels in human brains with sporadic and familial dementia [Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), sporadic Alzheimer’s disease (SAD), and familial Alzheimer’s disease (FAD)] and how BACE1 inhibition affects astrocytes and endothelial cells under conditions of glutamate toxicity. Our results show increased BACE1, PHF (Paired helical filaments)-tau and GFAP (Glial Fibrillary Acid Protein) immunoreactivity (IR) in the CA1 hippocampal regions of FAD and SAD brains. Furthermore, BACE1 immunoprecipitated with GFAP in tissue samples from all study cases, but their immunofluorescence close to (10 μm 3 ) or overlapping blood vessels was only increased in FAD and SAD brains, and PHF-tau was present around the vessels mainly in FAD brains. Interestingly, the increased BACE1 levels were associated with reactive astrocytes, characterized by morphological changes and upregulation of GFAP under pathological and stressful conditions, and endothelial disruption by glutamate excitotoxicity, and these effects were reversed by BACE1 inhibition; further, BACE1-inhibited astrocytes protected endothelial cell integrity by preserving zonula occludens-1 (ZO-1) distribution and decreasing the expression of inflammatory markers. Taken together, these findings suggest that BACE1 dysregulation in astrocytes may have a role in the alterations in NVU integrity implicated in neurodegeneration.

Proteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction.IntroductionProteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction.In this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach.MethodsIn this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach.Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL.ResultsOur findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL.Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids.ConclusionTherefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids.

In the late phase of Trypanosoma cruzi infection, parasite persistence and an exaggerated immune response accompanied by oxidative stress play a crucial role in the genesis of Chronic Chagasic Cardiomyopathy (CCC). Current treatments (Benznidazole (BNZ) and Nifurtimox) can effect only the elimination of the parasite, but are ineffective for late stage treatment and for preventing heart damage and disease progression. In vivo trypanocidal and cardioprotective activity has been reported for Lippia alba essential oils (EOs), ascribed to their two major terpenes, limonene and caryophyllene oxide. To investigate the role of antioxidant and immunomodulatory mechanisms behind these properties, chronic-T. cruzi-infected rats were treated with oral synergistic mixtures of the aforementioned EOs. For this purpose, the EOs were optimized through limonene-enrichment fractioning and by the addition of exogenous caryophyllene oxide (LIMOX) and used alone or in combined therapy with subtherapeutic doses of BNZ (LIMOXBNZ). Clinical, toxicity, inflammatory, oxidative, and parasitological (qPCR) parameters were assessed in cardiac tissue. These therapies demonstrated meaningful antioxidant and immunomodulatory activity on markers involved in CCC pathogenesis (IFN-γ, TNF-α, IL-4, IL-10, and iNOS), which could explain their significant trypanocidal properties and their noteworthy role in preventing, and even reversing, the progression of cardiac damage in chronic Chagas disease.

Abstract C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to identify case reports with genetic variants in CTBP1 and CTBP2 associated with brain development syndromes.We screened different databases (PubMed, Scopus, Google Scholar, LILACS) by systematically searching journals and checking reference lists and citations of background papers. We found fourteen cases (10 males) from five papers carrying two pathogenic, heterozygous variants in the CTBP1 gene (13 individuals carried the missense mutation c.991C T, p.Arg342Trp, and one subject carrying the 2-base pair deletion c.1315_1316delCA, p.Gln439ValfsTer84). These mutations were de novo in 13 cases and one case of maternal germinal mosaicism. Two variants are in the same domain of the protein: Pro-Leu-Asp-Leu-Ser (PLDLS) C terminal. Patients with these mutations exhibit a phenotype with intellectual disability, HADDTS syndrome (hypotonia, ataxia, developmental delay, and tooth enamel defects), and cerebellar volume loss. We did not identify reported cases associated with homozygous mutations harbored in CTBP1. We did not identify any report of neurodevelopment phenotypes associated with heterozygous or homozygous CTBP2 mutations. Due to CTBP2/RIBEYE being a gene with dual function, identifying and interpreting the potential pathogenic variants is challenging.Further, homozygous mutations in the CTBP2 gene may be lethal. The mechanisms involved in the pathogenesis of neurodevelopment due to variants of these proteins have not yet been elucidated, despite some functional evidence. Further studies should be conducted to understand these transcription factors and their interaction with each other and their partners.

Dying brain cells release DNA fragments, which can be found circulating free of the cell (cfDNA) in the bloodstream. Plasma cfDNA carries a unique cell-type specific DNA methylation (DNAmeth) signature that could provide information about which specific cells are dying, thus serving as a potential liquid biopsy of the brain (Figure 1). We aimed to perform a pilot study to determine the feasibility of, firstly, identifying DNAmeth patterns specific to brain regions typically degenerated in AD and FTD. Secondly, to identify plasma methylation signatures to differentiate AD and FTD patients from controls. In Aim 1, we investigated DNAmeth patterns in post-mortem brain samples across 5 regions (hippocampus, cerebellum, and frontotemporal, occipital, and parietal lobe), from 9 donors diagnosed with AD, FTD, and controls (in a 1:1:1 ratio). In Aim 2, we tested the value of cfDNA methylation in plasma to distinguish diagnoses. Here, we obtained plasma from 15 living participants diagnosed with AD, FTD, and controls (1:1:1). For brain and plasma assessments, we used the novel MeDSeq technique, which can detect methylation at CpG sites in trace amounts of DNA. This is especially suitable due to the lower quantity of cfDNA in plasma samples. Bioinformatic analyses revealed 353 differentially methylated regions (DMRs) hypermethylated in the hippocampus, while 35 were hypermethylated in the frontotemporal lobe (FDR<0.05). Furthermore, the analysis in plasma cfDNA identified specific methylation signatures across study groups. Specifically, we identified one DMR on chromosome 16q24.2 when comparing dementia cases (AD+FTD) versus controls. Variants at this location have been previously associated with small vessel stroke. Furthermore, we compared AD versus FTD cfDNAmeth, and found 5 significant DMRs close to genes enriched for several lipid- and fatty acid-related processes. These results demonstrate the feasibility of DNAmeth biomarkers, assessed using MedSeq, in identifying unique DNA regions that are differentially methylated in brain regions relevant to dementia. They also suggest the potential value of cfDNAmeth in plasma as a liquid biopsy biomarker to differentiate dementia types, potentially allowing early AD and FTD diagnosis after clinical validations.

Background Dying brain cells release DNA fragments, which can be found circulating free of the cell (cfDNA) in the bloodstream. Plasma cfDNA carries a unique cell‐type specific DNA methylation (DNAmeth) signature that could provide information about which specific cells are dying, thus serving as a potential liquid biopsy of the brain (Figure 1). We aimed to perform a pilot study to determine the feasibility of, firstly, identifying DNAmeth patterns specific to brain regions typically degenerated in AD and FTD. Secondly, to identify plasma methylation signatures to differentiate AD and FTD patients from controls. Method In Aim 1, we investigated DNAmeth patterns in post‐mortem brain samples across 5 regions (hippocampus, cerebellum, and frontotemporal, occipital, and parietal lobe), from 9 donors diagnosed with AD, FTD, and controls (in a 1:1:1 ratio). In Aim 2, we tested the value of cfDNA methylation in plasma to distinguish diagnoses. Here, we obtained plasma from 15 living participants diagnosed with AD, FTD, and controls (1:1:1). For brain and plasma assessments, we used the novel MeDSeq technique, which can detect methylation at CpG sites in trace amounts of DNA. This is especially suitable due to the lower quantity of cfDNA in plasma samples. Result Bioinformatic analyses revealed 353 differentially methylated regions (DMRs) hypermethylated in the hippocampus, while 35 were hypermethylated in the frontotemporal lobe (FDR<0.05). Furthermore, the analysis in plasma cfDNA identified specific methylation signatures across study groups. Specifically, we identified one DMR on chromosome 16q24.2 when comparing dementia cases (AD+FTD) versus controls. Variants at this location have been previously associated with small vessel stroke. Furthermore, we compared AD versus FTD cfDNAmeth, and found 5 significant DMRs close to genes enriched for several lipid‐ and fatty acid‐related processes. Conclusion These results demonstrate the feasibility of DNAmeth biomarkers, assessed using MedSeq, in identifying unique DNA regions that are differentially methylated in brain regions relevant to dementia. They also suggest the potential value of cfDNAmeth in plasma as a liquid biopsy biomarker to differentiate dementia types, potentially allowing early AD and FTD diagnosis after clinical validations.

Las enfermedades ocasionadas por priones son también conocidas como encefalitis espongiformes transmisibles o demencias de tipo infeccioso. En humanos las presentaciones clínicas más reconocidas son la enfermedad de Creutzfeldt-Jakob, el síndrome de Gerstmann-Sträussler-Scheinker y el insomnio fatal familiar. Son consideradas patologías poco comunes, pero los descubrimientos en biología molecular de los últimos años muestran que los mecanismos patológicos que llevan a su desarrollo pueden ser comunes a varias enfermedades neurodegenerativas, lo cual puede ampliar el espectro patológico, convirtiéndolas en alteraciones no tan infrecuentes en neurología. Esta revisión pretende dar herramientas al clínico para reconocer estas enfermedades discutiendo las presentaciones clínicas en seres humanos con sus variantes: esporádicas, infecciosas y familiares, comentando además el uso de laboratorios, criterios diagnósticos y aproximación terapéutica.

Las enfermedades ocasionadas por priones son también conocidas como encefalitis espongiformes transmisibles o demencias de tipo infeccioso. En humanos las presentaciones clínicas más reconocidas son la enfermedad de Creutzfeldt-Jakob, el síndrome de Gerstmann-Sträussler-Scheinker y el insomnio fatal familiar. Son consideradas patologías poco comunes, pero los descubrimientos en biología molecular de los últimos años muestran que los mecanismos patológicos que llevan a su desarrollo pueden ser comunes a varias enfermedades neurodegenerativas, lo cual puede ampliar el espectro patológico, convirtiéndolas en alteraciones no tan infrecuentes en neurología. Esta revisión pretende dar herramientas al clínico para reconocer estas enfermedades discutiendo las presentaciones clínicas en seres humanos con sus variantes: esporádicas, infecciosas y familiares, comentando además el uso de laboratorios, criterios diagnósticos y aproximación terapéutica.