RESUMEN
AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.
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Péptidos beta-Amiloides , Biomarcadores , Demencia , Progresión de la Enfermedad , Proteínas tau , Humanos , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Masculino , Femenino , Anciano , Persona de Mediana Edad , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Pronóstico , Demencia/diagnóstico , Demencia/sangre , Demencia/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/sangre , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Anciano de 80 o más AñosRESUMEN
Studies have shown that multimorbidity may be associated with the Alzheimer's disease (AD) stages, but it has not been fully characterized in patients without dementia. A total of 1402 Han Chinese older adults without dementia from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were included and grouped according to their multimorbidity patterns, defined by the number of chronic disorders and cluster analysis. Multivariable linear regression models were used to detect the associations with AD-related cerebrospinal fluid (CSF) biomarkers. Multimorbidity and severe multimorbidity (≥4 chronic conditions) were significantly associated with CSF amyloid and tau levels (pFDR < 0.05). Metabolic patterns were significantly associated with higher levels of CSF Aß40 (ß = 0.159, pFDR = 0.036) and tau (P-tau: ß = 0.132, pFDR = 0.035; T-tau: ß = 0.126, pFDR = 0.035). The above associations were only significant in the cognitively normal (CN) group. Multimorbidity was associated with brain AD pathology before any symptomatic evidence of cognitive impairment. Identifying such high-risk groups might allow tailored interventions for AD prevention.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Multimorbilidad , Disfunción Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Estilo de Vida , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Multimorbidity (the presence of two or more long-term conditions [LTCs]) was suggested to exacerbate the neuronal injuries. The impact of multimorbidity on dementia has not been fully elucidated. We aimed to investigate the association between multimorbidity and dementia risk. We used the prospective data from 245,483 UK Biobank participants during a 9-year follow-up. Multimorbidity status was evaluated based on the LTC counts and multimorbidity patterns. Cox regression models adjusted for potential confounders were used to examine the associations of multimorbidity status with all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Participants with multimorbidity at baseline had higher risks of ACD and VD, and the risks were elevated with the increase of LTC counts (ACD: hazard ratios [HR] = 1.15, 95% confidence intervals [CI] = 1.01-1.31 with 2 LTCs; HR = 1.18, CI = 1.01-1.39 with 3 LTCs; HR = 1.65, CI = 1.44-1.88 with ≥4 LTCs; VD: HR = 1. 66, CI = 1.24-2.21 with 2 LTCs; HR = 2.10, CI = 1.53-2.88 with 3 LTCs; HR = 3.17, CI = 2.43-4.13 with ≥4 LTCs). Participants with ≥4 LTCs also had a higher risk of AD (HR = 1.34, CI = 1.08-1.66]. Participants with the cardio-cerebrovascular/respiratory/metabolic/musculoskeletal/depressive multimorbidity were 1.46, 1.28, and 2.50 times more likely to develop ACD (HR = 1.46, 95% CI = 1.28-1.67), AD (HR = 1.28, CI = 1.04-1.58), and VD (HR = 2.50, CI = 1.90-3.27), respectively. Those with tumor/genitourinary/digestive disorders had a 11% higher hazard of ACD (HR = 1.11, CI = 1.00-1.24) and a 73% elevated risk of VD (HR = 1.73, CI = 1.37-2.18). The prevention of LTC accumulation and the identification of specific multimorbidity patterns might be beneficial to the prevention of dementia and its subtypes, AD as well as VD.
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Demencia , Humanos , Estudios Prospectivos , Demencia/epidemiologíaRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Metabolómica , Biomarcadores , Proteómica , GenómicaRESUMEN
BACKGROUND: Excessive oxidative stress may contribute to neurodegeneration by leading to protein aggregation and mitochondrial dysfunction. Uric acid (UA) is an important endogenous antioxidant that protects against oxidative stress, yet its exact role in neurodegeneration remains unclear. OBJECTIVE: To explore the performance of serum UA in neurodegenerative disorders. METHODS: A total of 839 controls and 840 patients, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), motor neuron disease (MND), Creutzfeldt-Jakob disease (CJD), and mixed dementia (MixD) were enrolled. Fasting serum UA levels were measured in all participants and compared between patients and controls. Linear regression models were utilized to explore possible relationships of serum UA with cognition, disease duration, age, and age of onset. RESULTS: Compared to controls (355.48â±â85.38âµmol/L), serum UA was significantly lower in AD (291.29â±â83.49âµmol/L, pâ<â0.001), PD (286.95â±â81.78âµmol/L, pâ<â0.001), PSP (313.32â±â88.19âµmol/L, pâ<â0.001), FTD (313.89â±â71.18âµmol/L, pâ=â0.001), and DLB (279.23â±â65.51âµmol/L, pâ<â0.001), adjusting for confounding factors including age, gender, education, etc. In addition, serum UA was positively correlated with cognitive levels in all patients (Mini-Mental State Examination: râ=â0.136, pâ=â0.001; and Montreal Cognitive Assessment Scale: râ=â0.108, pâ=â0.009). CONCLUSION: Decreased levels of serum UA were correlated with AD, PD, PSP, FTD, and DLB, offering significant potential as a promisingly relevant, less-invasive marker of multiple neurodegenerative disorders.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Parálisis Supranuclear Progresiva , Humanos , Ácido Úrico , Estudios Transversales , Enfermedad de Alzheimer/psicologíaRESUMEN
The pathogenesis of Alzheimer's disease (AD) is complex. Still it remains unclear, which resulted in all efforts for AD treatments with targeting the pathogenic factors unsuccessful over past decades. It has been evidenced that the innate immune is strongly implicated in the pathogenesis of AD. However, the role of adaptive immune in AD remains mostly unknown and the results obtained were controversial. In the review, we summarized recent studies and showed that the molecular and cellular alterations in AD patients and its animal models involving T cells and B cells as well as immune mediators of adaptive immune occur not only in the peripheral blood but also in the brain and the cerebrospinal fluid. The risk factors that cause AD contribute to AD progress by affecting the adaptive immune, indicating that adaptive immunity proposes a pivotal role in this disease. It may provide a possible basis for applying immunotherapy in AD and further investigates whether the immunotherapies are effective or off-target?
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Animales , Encéfalo/patología , Humanos , Inmunoterapia , Factores de RiesgoRESUMEN
BACKGROUND: Guillain-Barré syndrome (GBS) is an acquired immune-mediated inflammatory peripheral neuropathy. The immune regulation of ginkgolides have been revealed in recent years. We herein investigate the potential therapeutic effects of ginkgolides both on GBS and its animal model, experimental autoimmune neuritis (EAN). METHODS: EAN in C57BL/6 mice induced by subcutaneous injection with peripheral nerve myelin P0 protein peptide 180-199 (P0 peptide) were treated with ginkgolides at three different doses. GBS patients were randomly divided into two groups, the experimental group and the control group. The experimental group were treated with ginkgolides as soon as diagnosed. RESULTS: Our data indicated that ginkgolides administration daily ameliorated the score of EAN and delayed the peak of disease in EAN mice. Ginkgolides also down-regulated the proportions of T helper (Th) 17 cells in EAN spleens. Furthermore, we also found that administration of ginkgolides significantly decreased the levels of interferon (IFN)-γ and interleukin-12 (IL)-12 in GBS patients. CONCLUSIONS: Our results suggested that ginkgolides ameliorated the clinical score of EAN through down-regulating the proportions of Th 17 cells. Ginkgolides also suppressed inflammation response by decreasing pro-inflammatory cytokines IFN-γ and IL-12, suggesting ginkgolides had potential therapeutic effects on GBS patients and EAN in the future.
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Ginkgólidos/farmacología , Síndrome de Guillain-Barré/tratamiento farmacológico , Neuritis Autoinmune Experimental/tratamiento farmacológico , Adulto , Anciano , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Ginkgólidos/metabolismo , Ginkgólidos/uso terapéutico , Síndrome de Guillain-Barré/inmunología , Síndrome de Guillain-Barré/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteína P0 de la Mielina , Neuritis Autoinmune Experimental/inmunología , Neuritis Autoinmune Experimental/metabolismo , Nervios Periféricos , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
The inflammatory immune response (IIR) is a physiological or excessive systemic response, induced by inflammatory immune cells according to changes in the internal and external environments. An excessive IIR is the pathological basis for the generation and development of neurological diseases. Ginkgolides are one of the important medicinal ingredients in Ginkgo biloba. Many studies have verified that ginkgolides have anti-platelet-activating, anti-apoptotic, anti-oxidative, neurotrophic, and neuroimmunomodulatory effects. Inflammatory immunomodulation is mediated by inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. They also inhibit the platelet-activating factor (PAF)-mediated signal transduction to attenuate the inflammatory response. Herein, we reviewed the studies on the roles of ginkgolides in inflammatory immunomodulation and suggested its potential role in novel treatments for neurological diseases.