Ma. Esther Jiménez-Capdeville

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease with important disability accumulation. Early-onset NMOSD, defined as disease onset before age 50, exhibits distinct clinical characteristics compared to late-onset disease. We present a case series of patients with first symptom onset before age 30. Methods: A retrospective review of 10 patients diagnosed with NMOSD at our center in San Luis Potosí, Mexico, with disease onset before age 30. Clinical presentation, imaging findings, AQP4 antibody status, treatment response, and disability outcomes were analyzed. Results: The mean age at onset was 18.6 years (range 6–30). Area postrema syndrome was the most common presentation (40%), followed by acute myelitis and optic neuritis (30% each). All tested patients were AQP4-positive. The mean EDSS at follow-up was 6.6, indicating severe disability. Most patients received rituximab with variable response rates. Conclusions: Our cohort showed higher disability than reported in other early-onset series, emphasizing the need for prompt diagnosis and aggressive treatment in this population.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease with important disability accumulation. Early-onset NMOSD, defined as disease onset before age 50, exhibits distinct clinical characteristics compared to late-onset disease. We present a case series of patients with first symptom onset before age 30. Methods: Retrospective review of 10 patients diagnosed with NMOSD at our center in San Luis Potosí, Mexico, with disease onset before age 30. Clinical presentation, imaging findings, AQP4 antibody status, treatment response, and disability outcomes were analyzed. Results: Mean age at onset was 18.6 years (range 6-30). Area postrema syndrome was the most common presentation (40%), followed by acute myelitis and optic neuritis (30% each). All tested patients were AQP4-positive. Mean EDSS at follow-up was 6.6, indicating severe disability. Most patients received rituximab with variable response rates. Conclusions: Our cohort showed higher disability than reported in other early-onset series, emphasizing the need for prompt diagnosis and aggressive treatment in this population.

The Montreal Cognitive Assessment (MoCA) is the most accurate cognitive screening tool for early diagnoses of mild cognitive impairment (MCI). However, the majority of research on the correlation between MCI and periodontitis has been conducted using the Mini-Mental State Examination (MMSE). The study aimed to determine a possible correlation between the gingival index (GI), periodontitis staging and MCI as evaluated by the MoCA in adults aged ≥55 years. A total of 120 Mexican patients with or without periodontal disease who met the selection criteria were included in this cross-sectional study. A comprehensive clinical and radiographic evaluation was conducted to determine the periodontal status of all patients. The MoCA was applied to assess cognitive impairment. Descriptive statistics and logistic model-based multivariate statistical analyses were performed to identify variables associated with MCI. The cognitive status of subjects aged ≥55 years with and without periodontitis was mildly impaired in more than half of the studied sample. Thirty-four patients were diagnosed as periodontally healthy (group 1), 48 were diagnosed with mild to moderate periodontitis (group 2; stages I and II), and 38 had severe periodontitis (group 3; stages III and IV); 54% of the subjects exhibited MCI, mostly in groups 2 and 3. A negative correlation was observed between GI and MCI (p = 0.025). Other prognostic variables associated with MCI were loss of clinical attachment level (CAL) (odds ratio (OR) = 1.68 (95% confidence interval (CI): 1.06-2.68)), sex and education level. These findings highlight the potential clinical relevance of gingival and periodontal parameters, such as GI and CAL, and their association with MCI in patients of advanced age.

Background: Alpha‐synuclein (ASyn), a marker of Parkinson’s disease (PD) and other neurodegenerative processes, plays pivotal roles in neuronal nuclei and synapses. ASyn and its phosphorylated form at Serine 129 (p‐ASyn) are involved in DNA protection and repair, processes altered in aging, neurodegeneration, and cancer. Objective: To analyze the localization of p‐ASyn in skin biopsies of PD patients and melanoma. Methods: Biopsies from 26 PD patients, 20 melanoma patients, and 31 control subjects were probed and analyzed with a p‐ASyn antibody by immunohistochemistry and immunofluorescence. Nuclear positivity was quantified by image analysis. Results: Peripheral nerve endings from healthy subjects show little p‐ASyn immunopositivity but notable axonal presence in PD. Control subjects show immunopositivity to p‐ASyn along all epidermic strata and scarce presence in their cytoplasm. In contrast, its nuclear presence in PD is weaker, with a higher cytoplasmic and intercellular presence. Nuclear p‐ASyn in melanoma varied from similar to control skin in early stage melanoma to a higher rate of empty nuclei in the intermediate stage and total absence of nuclear p‐ASyn in severe cases. Interpretation: These findings support the nuclear localization of p‐ASyn in skin cells and show that its presence decreases PD and almost disappears in the malignant transformation of melanocytes, redistributing to the cytoplasm and intercellular spaces. This confirms the association between PD and melanoma, providing crucial insights into the role of p‐ASyn in both diseases. Trial Registration: ClinicalTrials.gov identifier: NCT01380899 .

The dentate gyrus (DG) of the human hippocampus is a complex and dynamic structure harboring mature and immature granular neurons in diverse proliferative states. While most mammals show persistent neurogenesis through adulthood, human neurogenesis is still under debate. We found nuclear alterations in granular cells in autopsied human brains, detected by immunohistochemistry. These alterations differ from those reported in pyramidal neurons of the hippocampal circuit. Aging and early AD chromatin were clearly differentiated by the increased epigenetic markers H3K9me3 (heterochromatin suppressive mark) and H3K4me3 (transcriptional euchromatin mark). At early AD stages, lamin B2 was redistributed to the nucleoplasm, indicating cell-cycle reactivation, probably induced by hippocampal nuclear pathology. At intermediate and late AD stages, higher lamin B2 immunopositivity in the perinucleus suggests fewer immature neurons, less neurogenesis, and fewer adaptation resources to environmental factors. In addition, senile samples showed increased nuclear Tau interacting with aged chromatin, likely favoring DNA repair and maintaining genomic stability. However, at late AD stages, the progressive disappearance of phosphorylated Tau forms in the nucleus, increased chromatin disorganization, and increased nuclear autophagy support a model of biphasic neurogenesis in AD. Therefore, designing therapies to alleviate the neuronal nuclear pathology might be the only pathway to a true rejuvenation of brain circuits.

Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau–chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.

There is solid epidemiological evidence that arsenic exposure leads to cognitive impairment, while experimental work supports the hypothesis that it also contributes to neurodegeneration. Energy deficit, oxidative stress, demyelination, and defective neurotransmission are demonstrated arsenic effects, but it remains unclear whether synaptic structure is also affected. Employing both a triple-transgenic Alzheimer’s disease model and Wistar rats, the cortical microstructure and synapses were analyzed under chronic arsenic exposure. Male animals were studied at 2 and 4 months of age, after exposure to 3 ppm sodium arsenite in drinking water during gestation, lactation, and postnatal development. Through nuclear magnetic resonance, diffusion-weighted images were acquired and anisotropy (integrity; FA) and apparent diffusion coefficient (dispersion degree; ADC) metrics were derived. Postsynaptic density protein and synaptophysin were analyzed by means of immunoblot and immunohistochemistry, while dendritic spine density and morphology of cortical pyramidal neurons were quantified after Golgi staining. A structural reorganization of the cortex was evidenced through high-ADC and low-FA values in the exposed group. Similar changes in synaptic protein levels in the 2 models suggest a decreased synaptic connectivity at 4 months of age. An abnormal dendritic arborization was observed at 4 months of age, after increased spine density at 2 months. These findings demonstrate alterations of cortical synaptic connectivity and microstructure associated to arsenic exposure appearing in young rodents and adults, and these subtle and non-adaptive plastic changes in dendritic spines and in synaptic markers may further progress to the degeneration observed at older ages.