RESUMEN
BACKGROUND: In Alzheimer's disease (AD) diagnosis, a cerebrospinal fluid (CSF) biomarker panel is commonly interpreted with binary cutoff values. However, these values are not generic and do not reflect the disease continuum. We explored the use of interval-specific likelihood ratios (LRs) and probability-based models for AD using a CSF biomarker panel. METHODS: CSF biomarker (Aß1-42, tTau and pTau181) data for both a clinical discovery cohort of 241 patients (measured with INNOTEST) and a clinical validation cohort of 129 patients (measured with EUROIMMUN), both including AD and non-AD dementia/cognitive complaints were retrospectively retrieved in a single-center study. Interval-specific LRs for AD were calculated and validated for univariate and combined (Aß1-42/tTau and pTau181) biomarkers, and a continuous bivariate probability-based model for AD, plotting Aß1-42/tTau versus pTau181 was constructed and validated. RESULTS: LR for AD increased as individual CSF biomarker values deviated from normal. Interval-specific LRs of a combined biomarker model showed that once one biomarker became abnormal, LRs increased even further when another biomarker largely deviated from normal, as replicated in the validation cohort. A bivariate probability-based model predicted AD with a validated accuracy of 88% on a continuous scale. CONCLUSIONS: Interval-specific LRs in a combined biomarker model and prediction of AD using a continuous bivariate biomarker probability-based model, offer a more meaningful interpretation of CSF AD biomarkers on a (semi-)continuous scale with respect to the post-test probability of AD across different assays and cohorts.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Probabilidad , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Humanos , Biomarcadores/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Funciones de Verosimilitud , Persona de Mediana Edad , Proteínas tau/líquido cefalorraquídeo , Estudios Retrospectivos , Fragmentos de Péptidos/líquido cefalorraquídeo , Estudios de CohortesRESUMEN
The launch of lecanemab (an anti-Aß antibody) has introduced a new treatment for Alzheimer's disease. In contrast to conventional therapeutic approaches to dementia, this drug requires new concepts in diagnosis, evaluation, and adverse effects. Specifically, evaluation of the efficacy of lecanemab is extremely important because this drug does not prevent but only slows the rate of disease progression. In this report, I have discussed future issues, including my personal viewpoint and also described the guidelines for promotion of the optimal use of lecanemab issued by the Ministry of Health, Labour, and Welfare.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Amyloid-related imaging abnormalities (ARIA) represent the most frequent adverse effect of lecanemab, a monoclonal antibody drug that targets amyloid beta. ARIA is observed in approximately 20% of patients who receive lecanemab. Most patients are asymptomatic; however, some develop serious neurological symptoms, and optimal management remains clinically challenging in such cases. In this review, I summarize the pathomechanism underlying ARIA and associated disorders, in addition to countermeasures for ARIA.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificaciónRESUMEN
Alzheimer's disease (AD) is a common dementia disorder in the elderly individuals, accounting for approximately 60-70% of all dementia cases. Recently, significant progress has been made in developing and approving anti-amyloid antibody drugs as one of the disease-modifying therapies (DMT) that aim to slow the progression of AD by targeting amyloid-beta accumulation in the brain. Notable drugs such as aducanumab, lecanemab, and donanemab have shown potential in clinical trials, leading to the approval of aducanumab and lecanemab, and approval is also expected for donanemab. Other anti-amyloid drugs such as remternetug and trontinemab are also under development. However, challenges remain, including adverse effects like amyloid-related imaging abnormalities (ARIA) and the need for addressing healthcare preparedness to support their use. This paper outlines the current status of DMT for AD, including the clinical trial results and current applications of these drugs. It also discusses the existing challenges to improve the safety and accessibility of DMTs.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/inmunología , Péptidos beta-Amiloides/antagonistas & inhibidores , Ensayos Clínicos como AsuntoRESUMEN
Blood biomarkers are minimally invasive, are available at a relatively low cost, and are easily accessible; therefore, they are expected to play a pivotal role in the diagnosis of dementia. Measurement of the amyloid-ß ratio and phosphorylated tau in plasma has shown high potential for accurate detection of brain pathology in patients with Alzheimer's disease. Studies have investigated blood biomarkers that reflect neurodegeneration and neuroinflammation in patients with dementia. Challenges associated with blood biomarker use include the lack of robustness of the test and the role of confounders that potentially prevent their immediate clinical application. Further real-world studies are warranted to validate the usefulness of blood biomarkers in dementia management. Appropriate recommendations for the use of blood biomarkers for dementia have been published for physicians and investigators, both in Japan and overseas. Considering the versatility of blood biomarkers, they should be cautiously introduced for clinical use.
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Enfermedad de Alzheimer , Biomarcadores , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/sangre , Humanos , Biomarcadores/sangre , Péptidos beta-Amiloides/sangre , Proteínas tau/sangreRESUMEN
The molecular pathogenesis of Alzheimer's disease (AD) has been elucidated through the biochemical analysis of senile plaques, neurofibrillary tangles, and pathological features of the brains of patients with AD. Genetic analysis, initiated with familial AD investigation, has revealed that Aß aggregation and accumulation are crucial processes in AD pathogenesis. The success of lecanemab against aggregated Aß is the result of these efforts. Meanwhile, research on tau as a causative molecule in AD and various other tauopathies is advancing gradually. Furthermore, genetic analysis has revealed that the inflammatory response of glial cells modifies AD pathophysiology; a novel therapeutic strategy for inflammation control is thus currently under consideration. This article summarizes the latest discoveries related to these new therapeutic strategies for AD.
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Enfermedad de Alzheimer , Proteínas tau , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , InflamaciónRESUMEN
Conventionally, APOE genetic testing has not been recommended as a component of the standard diagnostic and management practices for Alzheimer's disease. However, recent research highlights the importance of this test, particularly for assessment of the safety profile of anti-amyloid-ß therapies. Therefore, the current United States guidelines for the administration of lecanemab explicitly advise APOE genetic testing. However, integration of this testing into clinical practice is associated with many clinical, ethical, legal, and economic challenges. It is important to initiate comprehensive discussions to address these multifaceted issues in Japan.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Apolipoproteínas E , Pruebas Genéticas , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico , Apolipoproteínas E/genéticaRESUMEN
Alzheimer's disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-ß (Aß) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.
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Enfermedad de Alzheimer , Sistemas de Liberación de Medicamentos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Sistemas de Liberación de Medicamentos/métodos , Animales , Biomarcadores/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aß) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aß plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aß oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. METHODS: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aß1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aß-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aß-treated HEBSCs. RESULTS: Neurotoxicity induced by soluble Aß1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aß-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aß neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aß as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aß-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aß-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. CONCLUSION: Microglia are key mediators of both protection and neurodegeneration in response to Aß. Polarizing microglia toward a protective state could be used as a preventative strategy against Aß-induced neurotoxicity.
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Péptidos beta-Amiloides , Microglía , Fragmentos de Péptidos , Ligando Inductor de Apoptosis Relacionado con TNF , Microglía/metabolismo , Microglía/efectos de los fármacos , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Animales , Fragmentos de Péptidos/toxicidad , Fragmentos de Péptidos/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/toxicidad , Ratones , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Corteza Entorrinal/metabolismo , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Técnicas de Cultivo de ÓrganosRESUMEN
Tannic acid (TA)-derived carbon dots (TACDs) were synthesized for the first time via a solvothermal method using TA as one of the raw materials, which may effectively inhibit amyloid fibril aggregation and disaggregate mature fibril. The fluorescent property of TACDs were modulated by adjusting the ratio of TA to o-phenylenediamine (oPD), and TACDs fabricated with the precursor ratio as 1:1 showed the best fluorescent property. Circular dichroism spectra (CD) showed that the structure of ß-sheet decreased as the concentration of TACDs increased. The inhibition efficiency, as confirmed by thioflavin T (ThT) and transmission electron microscopy (TEM), is extraordinary at 98.16%, whereas disaggregation efficiency is noteworthy at 97.97%, and the disaggregated lysozyme fibrils did not reaggregate after 7 days. More critically, TACDs can also alleviate the cellular toxicity caused by Aß fibrils and improve cell viability. This work offers a new perspective on the design of scavengers for amyloid plaques.
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Carbono , Agregado de Proteínas , Taninos , Taninos/química , Taninos/farmacología , Carbono/química , Humanos , Agregado de Proteínas/efectos de los fármacos , Muramidasa/química , Muramidasa/metabolismo , Supervivencia Celular/efectos de los fármacos , Puntos Cuánticos/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Amiloide/química , Amiloide/metabolismo , Fenilendiaminas/química , Fenilendiaminas/farmacología , Animales , PolifenolesRESUMEN
Alzheimer's disease (AD) is a common neurodegenerative disease with the main manifestations of progressive cognitive dysfunction,behavioral disorders,and gradual decline of living ability.The etiology of AD is complex,and the pathogenesis of this disease remains controversial.Calcium signaling plays an important role in regulating neuronal activities,including neurotransmitter release,synaptic plasticity,memory storage,and neuronal apoptosis.Increasing studies have shown that neuronal calcium dyshomeostasis is a major pathological factor in the occurrence and development of AD.This article reviews the role and research progress in intracellular calcium dyshomeostasis in AD,including the relationship between calcium homeostasis and amyloid ß,the role of calcium/calmodulin-dependent protein kinases in tau phosphorylation,calcium signaling pathways,the relationship between calcium homeostasis and mitochondrial function,autophagy,and neuroinflammation.
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Enfermedad de Alzheimer , Calcio , Homeostasis , Enfermedad de Alzheimer/metabolismo , Humanos , Calcio/metabolismo , Péptidos beta-Amiloides/metabolismo , Señalización del Calcio/fisiología , Mitocondrias/metabolismo , Proteínas tau/metabolismo , Autofagia/fisiología , Animales , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Neuronas/metabolismo , FosforilaciónRESUMEN
OBJECTIVES: Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. ß-Amyloid (Aß) accumulation evidenced by amyloid PET positivity or CSF Aß decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aß and tau in iCAA and sCAA cohorts. METHODS: Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aß40, Aß42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. RESULTS: 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aß40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aß42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aß40 (p = 0.08, 95% CI 181-222), Aß42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aß40, 95% CI 153-193; Aß42, 95% CI 6-7 and total tau, 95% CI 2-4). DISCUSSION: Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aß and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.
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Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral , Enfermedad Iatrogénica , Fragmentos de Péptidos , Proteínas tau , Humanos , Masculino , Femenino , Angiopatía Amiloide Cerebral/sangre , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/sangre , Anciano , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Estudios Prospectivos , Anciano de 80 o más AñosRESUMEN
BACKGROUND AND OBJECTIVES: There is a clear need to characterize and validate molecular biomarkers of cerebral amyloid angiopathy (CAA), in an effort to improve diagnostics, especially in the context of patients with Alzheimer disease (AD) receiving immunotherapies (for whom underlying CAA is the driver of amyloid-related imaging abnormalities). We performed an updated meta-analysis of 5 core CSF biomarkers (Aß42, Aß40, Aß438, total tau [T-tau], and phosphorylated tau [P-tau]) to assess which of these are most altered in sporadic CAA. METHODS: We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting APP metabolism (Aß42, Aß40, Aß38), neurodegeneration (T-tau), and tangle pathology (P-tau), in symptomatic sporadic CAA cohorts (based on the Boston criteria) vs control groups and/or vs patients with AD. Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations in (1) patients with CAA to controls and (2) CAA to patients with AD. RoM >1 indicates higher biomarker concentration in CAA vs comparison population, and RoM <1 indicates higher concentration in comparison groups. RESULTS: 8 studies met inclusion criteria: a total of 11 CAA cohorts (n = 289), 9 control cohorts (n = 310), and 8 AD cohorts (n = 339). Overall included studies were of medium quality based on our assessment tools. CAA to controls had lower mean level of all amyloid markers with CSF Aß42, Aß40, and Aß38 RoMs of 0.46 (95% CI 0.38-0.55, p < 0.0001), 0.70 (95% CI 0.63-0.78, p < 0.0001), and 0.71 (95% CI 0.56-0.89, p = 0.003), respectively. CSF T-tau and P-tau RoMs of patients with CAA to controls were both greater than 1: 1.56 (95% CI 1.32-1.84, p < 0.0001) and 1.31 (95% CI 1.13-1.51, p < 0.0001), respectively. Differentiation between CAA and AD was strong for CSF Aß40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001) and Aß38 (RoM 0.55, 95% CI 0.38-0.81, p < 0.0001), but not Aß42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For T-tau and P-tau, average CSF ratios in patients with CAA vs AD were 0.64 (95% CI 0.58-0.71, p < 0.0001) and 0.64 (95% CI 0.58-0.71, p < 0.0001), respectively. DISCUSSION: Specific CSF patterns of Aß42, Aß40, Aß38, T-tau, and P-tau might serve as molecular biomarkers of CAA, in research and clinical settings, offering the potential to improve the clinical diagnostic approach pathway in specific scenarios.
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Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral , Proteínas tau , Humanos , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnósticoRESUMEN
BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-ß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. CONCLUSIONS: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.
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Enfermedad de Alzheimer , Atrofia , Tomografía de Emisión de Positrones , Lóbulo Temporal , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Atrofia/patología , Masculino , Femenino , Anciano , Lóbulo Temporal/patología , Lóbulo Temporal/diagnóstico por imagen , Persona de Mediana Edad , Imagen por Resonancia Magnética , Proteínas tau/metabolismo , Edad de Inicio , Péptidos beta-Amiloides/metabolismo , Amnesia/patología , Amnesia/diagnóstico por imagen , Anciano de 80 o más AñosRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized pathologically by extracellular deposition of ß-amyloid (Aß) into senile plaques and intracellular accumulation of hyperphosphorylated tau (pTau) as neurofibrillary tangles. Clinically, AD patients show memory deterioration with varying cognitive dysfunctions. The exact molecular mechanisms underlying AD are still not fully understood, and there are no efficient drugs to stop or reverse the disease progression. In this review, we first provide an update on how the risk factors, including APOE variants, infections and inflammation, contribute to AD; how Aß and tau become abnormally accumulated and how this accumulation plays a role in AD neurodegeneration. Then we summarize the commonly used experimental models, diagnostic and prediction strategies, and advances in periphery biomarkers from high-risk populations for AD. Finally, we introduce current status of development of disease-modifying drugs, including the newly officially approved Aß vaccines, as well as novel and promising strategies to target the abnormal pTau. Together, this paper was aimed to update AD research progress from fundamental mechanisms to the clinical diagnosis and therapies.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Humanos , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Biomarcadores/metabolismo , Biomarcadores/análisisRESUMEN
BACKGROUND: Major depressive disorder (MDD) is characterized by hippocampal volume reduction, impacting cognitive function. Inflammation, particularly elevated tumor necrosis factor-alpha (TNF-α) levels, is consistently implicated in MDD pathophysiology. This study investigates the relationships between TNF-α levels, hippocampal volume, beta-amyloid (Aß) burden, and cognitive abilities in MDD patients, aiming to illuminate the complex interplay among inflammatory markers, pathology indicators, structural brain alterations, and cognitive performance in non-demented MDD individuals. METHOD: Fifty-two non-demented MDD patients, comprising 25 with mild cognitive impairment (MCI), were recruited along with 10 control subjects. Each participant underwent a thorough assessment encompassing TNF-α blood testing, 18F-florbetapir positron emission tomography, magnetic resonance imaging scans, and neuropsychological testing. Statistical analyses, adjusted for age and education, were performed to investigate the associations between TNF-α levels, adjusted hippocampal volume (HVa), global Aß burden, and cognitive performance. RESULTS: MCI MDD patients displayed elevated TNF-α levels and reduced HVa relative to controls. Correlation analyses demonstrated inverse relationships between TNF-α level and HVa in MCI MDD, all MDD, and all subjects groups. Both TNF-α level and HVa exhibited significant correlations with processing speed across all MDD and all subjects. Notably, global 18F-florbetapir standardized uptake value ratio did not exhibit significant correlations with TNF-α level, HVa, and cognitive measures. CONCLUSION: This study highlights elevated TNF-α levels and reduced hippocampal volume in MCI MDD patients, indicating a potential association between peripheral inflammation and structural brain alterations in depression. Furthermore, our results suggest that certain cases of MDD may be affected by non-amyloid-mediated process, which impacts their TNF-α and hippocampal volume. These findings emphasize the importance of further investigating the complex interplay among inflammation, neurodegeneration, and cognitive function in MDD.
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Péptidos beta-Amiloides , Atrofia , Disfunción Cognitiva , Trastorno Depresivo Mayor , Hipocampo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Factor de Necrosis Tumoral alfa , Humanos , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/metabolismo , Masculino , Femenino , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Anciano , Péptidos beta-Amiloides/metabolismo , Atrofia/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Persona de Mediana Edad , Pruebas Neuropsicológicas , Compuestos de Anilina , Glicoles de EtilenoRESUMEN
Effective cognitive performance often requires the allocation of additional neural resources (i.e. blood-oxygen-level-dependent [BOLD] activation) as task demands increase, and this demand-related modulation is affected by amyloid-beta deposition and normal aging. The present study investigated these complex relationships between amyloid, modulation, and cognitive function (i.e. fluid ability). Participants from the Dallas Lifespan Brain Study (DLBS, n = 252, ages 50-89) completed a semantic judgment task during functional magnetic resonance imaging (fMRI) where the judgments differed in classification difficulty. Amyloid burden was assessed via positron emission tomography (PET) using 18F-florbetapir. A quadratic relationship between amyloid standardized value uptake ratios (SUVRs) and BOLD modulation was observed such that modulation was weaker in those with moderately elevated SUVRs (e.g. just reaching amyloid-positivity), whereas those with very high SUVRs (e.g. SUVR > 1.5) showed strong modulation. Greater modulation was related to better fluid ability, and this relationship was strongest in younger participants and those with lower amyloid burden. These results support the theory that effective demand-related modulation contributes to healthy cognitive aging, especially in the transition from middle age to older adulthood, whereas high modulation may be dysfunctional in those with substantial amyloid deposition.
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Envejecimiento , Encéfalo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Humanos , Anciano , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Anciano de 80 o más Años , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Envejecimiento/fisiología , Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Cognición/fisiología , Oxígeno/sangreRESUMEN
Alzheimer's disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-ß (Aß) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aß phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aß phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aß phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aß phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aß phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aß phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD.
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Péptidos beta-Amiloides , Lipoilación , Ratones Transgénicos , Microglía , Fagocitosis , Canales Catiónicos TRPV , Tirosina , Animales , Ratones , Microglía/metabolismo , Microglía/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Péptidos beta-Amiloides/metabolismo , Fagocitosis/efectos de los fármacos , Humanos , Fosforilación/efectos de los fármacos , Tirosina/metabolismo , Lipoilación/efectos de los fármacos , Células Cultivadas , Enfermedad de Alzheimer/metabolismo , Cannabidiol/farmacología , Ratones Endogámicos C57BL , Canales de CalcioRESUMEN
Beta-amyloid (Aß), the most pivotal pathological hallmark for Alzheimer's disease (AD) diagnosis and drug evaluation, was recognized by TZ095, a high-affinity fluorescent probe developed by rational molecular design. With a TICT mechanism, TZ095 exhibited remarkable affinity with Aß aggregates (Kd = 81.54 nM for oligomers; Kd = 66.70 nM for fibril) and substantial fluorescence enhancement (F/F0 = 44), enabling real-time monitoring of Aß in live cells and nematodes. Significantly, this work used TZ095 to construct a new protocol that can quickly and conveniently monitor Aß changes at the cellular and nematode levels to evaluate the anti-AD efficacy of candidate compounds, and four reported Aß-lowering drug candidates were administrated for validation. Imaging data demonstrated that TZ095 can visually and quantitatively track the effect of Aß elimination after drug treatment. Furthermore, TZ095 excelled in ex vivo histological staining of 12-month-old APP/PS1 mouse brains, accurately visualizing Aß plaques. Integrating CUBIC technology, TZ095 facilitated whole-brain, 3D imaging of Aß distribution in APP/PS1 mice, enabling high-resolution in situ analysis of Aß plaques. Collectively, these innovative applications of TZ095 offer a promising strategy for rapid, convenient, and real-time monitoring of Aß levels in preclinical therapeutic assessments.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Diseño de Fármacos , Colorantes Fluorescentes , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/farmacología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Humanos , Ratones , Estructura Molecular , Ratones Transgénicos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Relación Estructura-Actividad , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Relación Dosis-Respuesta a Droga , Imagen ÓpticaRESUMEN
Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.