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3.
Neurotox Res ; 42(3): 28, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38842585

RESUMEN

Parkinson's disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson's disease (PD) and Alzheimer's disease (AD). Although it is assumed that alpha-synuclein ( α -Syn), amyloid beta (A ß ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10 µ M) for 24 h. ROT provokes loss of Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of α -synuclein ( α -Syn, Ser129), induces accumulation of intracellular A ß (iA ß ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin- α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p- α -Syn, iA ß , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.


Asunto(s)
Neuronas Colinérgicas , Rotenona , Rotenona/toxicidad , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/metabolismo , Neuronas Colinérgicas/patología , Animales , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Demencia/patología , Demencia/metabolismo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Humanos , Células Cultivadas
4.
Int J Mol Sci ; 25(11)2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38892378

RESUMEN

Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.


Asunto(s)
Demencia , Regulación de la Expresión Génica , MicroARNs , ARN Circular , ARN Largo no Codificante , ARN no Traducido , Humanos , Demencia/genética , Demencia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo , Animales , Biomarcadores , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo
5.
Genes (Basel) ; 15(5)2024 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-38790197

RESUMEN

Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's Disease and Related Dementias (ADRD) accounts for nearly 60-70% of all those cases. The spread of Alzheimer's Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD's causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs' ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs' transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.


Asunto(s)
Enfermedad de Alzheimer , Estrés del Retículo Endoplásmico , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Tapsigargina/farmacología , Demencia/genética , Demencia/metabolismo , Demencia/patología , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo , Masculino , Factor de Transcripción Activador 6/metabolismo , Factor de Transcripción Activador 6/genética , Neurogénesis , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Femenino , Respuesta de Proteína Desplegada , Factor de Transcripción CHOP
6.
Aging (Albany NY) ; 16(10): 9280-9302, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38805248

RESUMEN

Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress (e.g., reactive oxygen species [ROS]). Emerging evidence suggests that several fundamental aging mechanisms (e.g., "hallmarks" of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction. Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging "hallmarks" to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.


Asunto(s)
Envejecimiento , Encéfalo , Estrés Oxidativo , Humanos , Envejecimiento/fisiología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Enfermedades Vasculares Periféricas/fisiopatología , Especies Reactivas de Oxígeno/metabolismo , Demencia/fisiopatología , Demencia/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Factores de Riesgo , Animales
7.
Medicine (Baltimore) ; 103(18): e38086, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38701247

RESUMEN

BACKGROUND: Dementia is a major public health challenge for aging societies worldwide. Neuroinflammation is thought to be a key factor in dementia development. The aim of this study was to comprehensively assess translocator protein (TSPO) expression by positron emission tomography (PET) imaging to reveal the characteristics of neuroinflammation in dementia. METHODS: We used a meta-analysis to retrieve literature on TSPO expression in dementia using PET imaging technology, including but not limited to the quality of the study design, sample size, and the type of TSPO ligand used in the study. For the included studies, we extracted key data, including TSPO expression levels, clinical characteristics of the study participants, and specific information on brain regions. Meta-analysis was performed using R software to assess the relationship between TSPO expression and dementia. RESULTS: After screening, 12 studies that met the criteria were included. The results of the meta-analysis showed that the expression level of TSPO was significantly elevated in patients with dementia, especially in the hippocampal region. The OR in the hippocampus was 1.50 with a 95% CI of 1.09 to 1.25, indicating a significant increase in the expression of TSPO in this region compared to controls. Elevated levels of inflammation in the prefrontal lobe and cingulate gyrus are associated with cognitive impairment in patients. This was despite an OR of 1.00 in the anterior cingulate gyrus, indicating that TSPO expression in this region did not correlate significantly with the findings. The overall heterogeneity test showed I² = 51%, indicating moderate heterogeneity. CONCLUSION: This study summarizes the existing literature on TSPO expression in specific regions of the brain in patients with dementia, and also provides some preliminary evidence on the possible association between neuroinflammation and dementia. However, the heterogeneity of results and limitations of the study suggest that we need to interpret these findings with caution. Future studies need to adopt a more rigorous and consistent methodological design to more accurately assess the role of neuroinflammation in dementia, thereby providing a more reliable evidence base for understanding pathological mechanisms and developing potential therapeutic strategies.


Asunto(s)
Demencia , Enfermedades Neuroinflamatorias , Tomografía de Emisión de Positrones , Receptores de GABA , Humanos , Tomografía de Emisión de Positrones/métodos , Demencia/diagnóstico por imagen , Demencia/metabolismo , Receptores de GABA/metabolismo , Enfermedades Neuroinflamatorias/diagnóstico por imagen , Enfermedades Neuroinflamatorias/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo
8.
Alzheimers Dement ; 20(5): 3606-3628, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38556838

RESUMEN

INTRODUCTION: Alternative splicing of the human MAPT gene generates six brain-specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations. METHODS: A comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server. RESULTS: While TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive. DISCUSSION: In this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU-associated diseases. HIGHLIGHTS: MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development-, cell-type and brain region specific. The contribution of TAU to neurodegeneration might be isoform-specific. Ineffective TAU-based therapies highlight the need for specific targeting strategies.


Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Isoformas de Proteínas , Proteínas tau , Humanos , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Encéfalo/patología , Tauopatías/genética , Tauopatías/metabolismo , Empalme Alternativo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Animales , Demencia/genética , Demencia/metabolismo
9.
Basic Clin Pharmacol Toxicol ; 134(5): 563-573, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38459754

RESUMEN

Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It is estimated that dementia affects 50 million people worldwide and that Alzheimer's disease (AD) is responsible for up to 75% of cases. Small extracellular senile plaques composed of filamentous aggregates of amyloid ß (Aß) protein tend to bind to neuronal receptors, affecting cholinergic, serotonergic, dopaminergic and noradrenergic neurotransmission, leading to neuroinflammation, among other pathophysiologic processes and subsequent neuronal death, followed by dementia. The amyloid cascade hypothesis points to a pathological process in the cleavage of the amyloid precursor protein (APP), resulting in pathological Aß. There is a close relationship between the pathologies that lead to dementia and depression. It is estimated that depression is prevalent in up to 90% of individuals diagnosed with Parkinson's disease, with varying severity, and in 20 to 30% of cases of Alzheimer's disease. The hypothalamic pituitary adrenal (HPA) axis is the great intermediary between the pathophysiological mechanisms in neurodegenerative diseases and depression. This review discusses the role of Aß protein in the pathophysiological mechanisms of dementia and depression, considering the HPA axis, neuroinflammation, oxidative stress, signalling pathways and neurotransmission.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Demencia , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Depresión , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/patología , Enfermedades Neuroinflamatorias , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/patología , Demencia/metabolismo
10.
Neurosci Res ; 204: 22-33, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38278219

RESUMEN

Altered cholesterol metabolism is implicated in brain ageing and Alzheimer's disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer's disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.


Asunto(s)
Enfermedad de Alzheimer , Colesterol , Demencia , Hidroximetilglutaril-CoA Reductasas , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Humanos , Colesterol/metabolismo , Colesterol/biosíntesis , Masculino , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hidroximetilglutaril-CoA Reductasas/genética , Femenino , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Anciano , Demencia/metabolismo , Demencia/patología , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Cohortes , Neuronas/metabolismo , Colesterol 24-Hidroxilasa/metabolismo , Astrocitos/metabolismo
11.
Exp Neurol ; 374: 114680, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38185314

RESUMEN

Cerebrovascular diseases are a major cause of stroke and dementia, both requiring long-term care. These diseases involve multiple pathophysiologies, with mitochondrial dysfunction being a crucial contributor to the initiation of inflammation, apoptosis, and oxidative stress, resulting in injuries to neurovascular units that include neuronal cell death, endothelial cell death, glial activation, and blood-brain barrier disruption. To maintain brain homeostasis against these pathogenic conditions, brain immune cells, including border-associated macrophages and microglia, play significant roles as brain innate immunity cells in the pathophysiology of cerebrovascular injury. Although microglia have long been recognized as significant contributors to neuroinflammation, attention has recently shifted to border-associated macrophages, such as perivascular macrophages (PVMs), which have been studied based on their crucial roles in the brain. These cells are strategically positioned around the walls of brain vessels, where they mainly perform critical functions, such as perivascular drainage, cerebrovascular flexibility, phagocytic activity, antigen presentation, activation of inflammatory responses, and preservation of blood-brain barrier integrity. Although PVMs act as scavenger and surveillant cells under normal conditions, these cells exert harmful effects under pathological conditions. PVMs detect mitochondrial dysfunction in injured cells and implement pathological changes to regulate brain homeostasis. Therefore, PVMs are promising as they play a significant role in mitochondrial dysfunction and, in turn, disrupt the homeostatic condition. Herein, we summarize the significant roles of PVMs in cerebrovascular diseases, especially ischemic and hemorrhagic stroke and dementia, mainly in correlation with inflammation. A better understanding of the biology and pathobiology of PVMs may lead to new insights on and therapeutic strategies for cerebrovascular diseases.


Asunto(s)
Trastornos Cerebrovasculares , Demencia , Enfermedades Mitocondriales , Humanos , Macrófagos/metabolismo , Encéfalo/metabolismo , Inflamación/metabolismo , Demencia/metabolismo
12.
Open Biol ; 13(12): 230253, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38052249

RESUMEN

The mechanisms underlying neurodegenerative sequelae of traumatic brain injury (TBI) are poorly understood. The normal plasma protein, serum amyloid P component (SAP), which is normally rigorously excluded from the brain, is directly neurocytotoxic for cerebral neurones and also binds to Aß amyloid fibrils and neurofibrillary tangles, promoting formation and persistence of Aß fibrils. Increased brain exposure to SAP is common to many risk factors for dementia, including TBI, and dementia at death in the elderly is significantly associated with neocortical SAP content. Here, in 18 of 30 severe TBI cases, we report immunohistochemical staining for SAP in contused brain tissue with blood-brain barrier disruption. The SAP was localized to neurofilaments in a subset of neurones and their processes, particularly damaged axons and cell bodies, and was present regardless of the time after injury. No SAP was detected on astrocytes, microglia, cerebral capillaries or serotoninergic neurones and was absent from undamaged brain. C-reactive protein, the control plasma protein most closely similar to SAP, was only detected within capillary lumina. The appearance of neurocytotoxic SAP in the brain after TBI, and its persistent, selective deposition in cerebral neurones, are consistent with a potential contribution to subsequent neurodegeneration.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Demencia , Humanos , Anciano , Componente Amiloide P Sérico/química , Componente Amiloide P Sérico/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Encéfalo/metabolismo , Proteínas Sanguíneas/metabolismo , Demencia/metabolismo , Péptidos beta-Amiloides/metabolismo
13.
Int J Mol Sci ; 24(22)2023 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-38003671

RESUMEN

The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a deficit of cognitive capacity. Later, the growing incidence of type 2 diabetes mellitus (T2D) and dementia in aged populations revealed their high association, in which a reduced neuronal glucose supply has also been considered as a key mechanism, despite hyperglycemia. Here, we discuss the role of glucose in neuronal functioning/preservation, and how peripheral blood glucose accesses the neuronal intracellular compartment, including the exquisite glucose flux across the blood-brain barrier (BBB) and the complex network of glucose transporters, in dementia-related areas such as the hippocampus. In addition, insulin resistance-induced abnormalities in the hippocampus of obese/T2D patients, such as inflammatory stress, oxidative stress, and mitochondrial stress, increased generation of advanced glycated end products and BBB dysfunction, as well as their association with dementia/Alzheimer's disease, are addressed. Finally, we discuss how these abnormalities are accompained by the reduction in the expression and translocation of the high capacity insulin-sensitive glucose transporter GLUT4 in hippocampal neurons, which leads to neurocytoglycopenia and eventually to cognitive dysfunction. This knowledge should further encourage investigations into the beneficial effects of promising therapeutic approaches which could improve central insulin sensitivity and GLUT4 expression, to fight diabetes-related cognitive dysfunctions.


Asunto(s)
Demencia , Diabetes Mellitus Tipo 2 , Hiperinsulinismo , Resistencia a la Insulina , Niño , Humanos , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Neurofisiología , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Hipocampo/metabolismo , Hiperinsulinismo/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Demencia/metabolismo , Insulina/metabolismo
14.
J Neuroimaging ; 33(6): 953-959, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37726927

RESUMEN

BACKGROUND AND PURPOSE: The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS: We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS: MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION: PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.


Asunto(s)
Demencia , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Predisposición Genética a la Enfermedad , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Haplotipos , Demencia/genética , Demencia/metabolismo
15.
Int J Mol Sci ; 24(13)2023 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-37445910

RESUMEN

In assessing and managing pain, when obtaining a self-report is impossible, therapeutic decision-making becomes more challenging. This study aimed to investigate whether monocytes and some membrane monocyte proteins, identified as a cluster of differentiation (CD), could be potential non-invasive peripheral biomarkers in identifying and characterizing pain in patients with severe dementia. We used 53 blood samples from non-oncological palliative patients, 44 patients with pain (38 of whom had dementia) and 0 without pain or dementia (controls). We evaluated the levels of monocytes and their subtypes, including classic, intermediate, and non-classic, and characterized the levels of specific phenotypic markers, namely CD11c, CD86, CD163, and CD206. We found that the relative concentrations of monocytes, particularly the percentage of classic monocytes, may be a helpful pain biomarker. Furthermore, the CD11c expression levels were significantly higher in patients with mixed pain, while CD163 and CD206 expression levels were significantly higher in patients with nociceptive pain. These findings suggest that the levels of monocytes, particularly the classic subtype, and their phenotype markers CD11c, CD163, and CD206 could serve as pain biomarkers in patients with severe dementia.


Asunto(s)
Demencia , Monocitos , Humanos , Monocitos/metabolismo , Proyectos Piloto , Antígenos de Diferenciación Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Proteínas de la Membrana/metabolismo , Dolor/metabolismo , Demencia/complicaciones , Demencia/metabolismo
16.
Int J Mol Sci ; 24(12)2023 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-37373216

RESUMEN

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aß aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.


Asunto(s)
Demencia , Diabetes Mellitus , Neuropatías Diabéticas , Hiperglucemia , Humanos , Barrera Hematoencefálica/metabolismo , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Neuropatías Diabéticas/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Demencia/etiología , Demencia/metabolismo , Diabetes Mellitus/metabolismo
17.
Brain Pathol ; 33(6): e13164, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37158450

RESUMEN

Circulating C-reactive protein (pCRP) concentrations rise dramatically during both acute (e.g., following stroke) or chronic infection and disease (e.g., autoimmune conditions such as lupus), providing complement fixation through C1q protein binding. It is now known, that on exposure to the membranes of activated immune cells (and microvesicles and platelets), or damaged/dysfunctional tissue, it undergoes lysophosphocholine (LPC)-phospholipase-C-dependent dissociation to the monomeric form (mCRP), concomitantly becoming biologically active. We review histological, immunohistochemical, and morphological/topological studies of post-mortem brain tissue from individuals with neuroinflammatory disease, showing that mCRP becomes stably distributed within the parenchyma, and resident in the arterial intima and lumen, being "released" from damaged, hemorrhagic vessels into the extracellular matrix. The possible de novo synthesis via neurons, endothelial cells, and glia is also considered. In vitro, in vivo, and human tissue co-localization analyses have linked mCRP to neurovascular dysfunction, vascular activation resulting in increased permeability, and leakage, compromise of blood brain barrier function, buildup of toxic proteins including tau and beta amyloid (Aß), association with and capacity to "manufacture" Aß-mCRP-hybrid plaques, and, greater susceptibility to neurodegeneration and dementia. Recently, several studies linked chronic CRP/mCRP systemic expression in autoimmune disease with increased risk of dementia and the mechanisms through which this occurs are investigated here. The neurovascular unit mediates correct intramural periarterial drainage, evidence is provided here that suggests a critical impact of mCRP on neurovascular elements that could suggest its participation in the earliest stages of dysfunction and conclude that further investigation is warranted. We discuss future therapeutic options aimed at inhibiting the pCRP-LPC mediated dissociation associated with brain pathology, for example, compound 1,6-bis-PC, injected intravenously, prevented mCRP deposition and associated damage, after temporary left anterior descending artery ligation and myocardial infarction in a rat model.


Asunto(s)
Demencia , Enfermedades Neurodegenerativas , Humanos , Ratas , Animales , Proteína C-Reactiva/química , Proteína C-Reactiva/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Células Endoteliales/patología , Biomarcadores/metabolismo , Demencia/metabolismo , Inflamación/patología
18.
Int J Mol Sci ; 24(7)2023 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-37047057

RESUMEN

Cerebrospinal fluid (CSF) plays an important role in the homeostasis of the brain. We previously reported that CSF major glycoproteins are biosynthesized in the brain, i.e., lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin isoforms carrying unique glycans. Although these glycoproteins are secreted from distinct cell types, their CSF levels have been found to be highly correlated with each other in cases of neurodegenerative disorders. The aim of this study was to examine these marker levels and their correlations in other neurological diseases, such as depression and schizophrenia, and disorders featuring abnormal CSF metabolism, including spontaneous intracranial hypotension (SIH) and idiopathic normal pressure hydrocephalus (iNPH). Brain-derived marker levels were found to be highly correlated with each other in the CSF of depression and schizophrenia patients. SIH is caused by CSF leakage, which is suspected to induce hypovolemia and a compensatory increase in CSF production. In SIH, the brain-derived markers were 2-3-fold higher than in other diseases, and, regardless of their diverse levels, they were found to be correlated with each other. Another abnormality of the CSF metabolism, iNPH, is possibly caused by the reduced absorption of CSF, which secondarily induces CSF accumulation in the ventricle; the excess CSF compresses the brain's parenchyma to induce dementia. One potential treatment is a "shunt operation" to bypass excess CSF from the ventricles to the peritoneal cavity, leading to the attenuation of dementia. After the shunt operation, marker levels began to increase within a week and then further increased by 2-2.5-fold at three, six, and twelve months post-operation, at which point symptoms had gradually attenuated. Notably, the marker levels were found to be correlated with each other in the post-operative period. In conclusion, the brain-derived major glycoprotein markers were highly correlated in the CSF of patients with different neurological diseases, and their correlations were maintained even after surgical intervention. These results suggest that brain-derived proteins could be biomarkers of CSF production.


Asunto(s)
Demencia , Hidrocefalia , Enfermedades del Sistema Nervioso , Humanos , Encéfalo/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Glicoproteínas/metabolismo , Hidrocefalia/metabolismo , Demencia/metabolismo , Biomarcadores/metabolismo
19.
Proc Natl Acad Sci U S A ; 120(13): e2220984120, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36952379

RESUMEN

The amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of Guam is an endemic neurodegenerative disease that features widespread tau tangles, occasional α-synuclein Lewy bodies, and sparse ß-amyloid (Aß) plaques distributed in the central nervous system. Extensive studies of genetic or environmental factors have failed to identify a cause of ALS-PDC. Building on prior work describing the detection of tau and Aß prions in Alzheimer's disease (AD) and Down syndrome brains, we investigated ALS-PDC brain samples for the presence of prions. We obtained postmortem frozen brain tissue from 26 donors from Guam with ALS-PDC or no neurological impairment and 71 non-Guamanian donors with AD or no neurological impairment. We employed cellular bioassays to detect the prion conformers of tau, α-synuclein, and Aß proteins in brain extracts. In ALS-PDC brain samples, we detected high titers of tau and Aß prions, but we did not detect α-synuclein prions in either cohort. The specific activity of tau and Aß prions was increased in Guam ALS-PDC compared with sporadic AD. Applying partial least squares regression to all biochemical and prion infectivity measurements, we demonstrated that the ALS-PDC cohort has a unique molecular signature distinguishable from AD. Our findings argue that Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aß prions.


Asunto(s)
Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Demencia , Enfermedades Neurodegenerativas , Trastornos Parkinsonianos , Enfermedades por Prión , Priones , Humanos , alfa-Sinucleína , Esclerosis Amiotrófica Lateral/metabolismo , Demencia/metabolismo , Trastornos Parkinsonianos/metabolismo , Proteínas tau/metabolismo
20.
Mov Disord ; 38(4): 682-688, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36808643

RESUMEN

BACKGROUND: The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD. OBJECTIVE: To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment. METHODS: In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30). RESULTS: Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances. CONCLUSIONS: The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Demencia , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Demencia/etiología , Demencia/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/química , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Mutación , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/líquido cefalorraquídeo , Trastornos Parkinsonianos/líquido cefalorraquídeo , Trastornos Parkinsonianos/complicaciones , Estudios Retrospectivos
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