Blood Biomarkers and Prognosis of Amyotrophic Lateral Sclerosis.


  • 影响因子:3.37
  • DOI:10.1111/ene.14409
  • 作者列表:"Sun J","Carrero JJ","Zagai U","Evans M","Ingre C","Pawitan Y","Fang F
  • 发表时间:2020-06-17

OBJECTIVE:To assess the ability of eight commonly measured blood markers to serve as prognostic biomarkers in ALS. METHODS:A cohort study of 399 individuals with newly diagnosed ALS between 2006 and 2011 in Stockholm, Sweden was conducted. We collected information on eight blood markers, including creatinine, albumin, haemoglobin, C-reactive protein (CRP), glucose, potassium, sodium, and calcium, measured at or after the date of ALS diagnosis. Cox regression model and joint model were used to explore the associations between biomarkers and risk of mortality. RESULTS:The mean age at ALS diagnosis was 66.25 years and 58% of the patients were male. A lower-than-median level of serum creatinine (Hazard Ratio [HR] =1.67; 95% confidence interval [CI] =1.31-2.12) or albumin (1.49, 1.13-1.96), whereas a higher-than-median level of log-transformed CRP (1.33, 1.04-1.71) or glucose (1.34, 1.01-1.78), at baseline was associated with a higher mortality risk. Taking all available measurements after ALS diagnosis into account, we found an association between per SD decrease in serum creatinine (2.23, 1.81-2.75) or albumin (1.83, 1.43-2.36) as well as per SD increase of log(CRP) (1.96, 1.58-2.43) or glucose (1.61, 1.21-2.12) and a higher mortality risk. No clear association was found for haemoglobin, potassium, sodium, or calcium. CONCLUSIONS:This study suggests that serum creatinine, albumin, CRP and glucose measured at the time of ALS diagnosis as well as their temporal changes after ALS diagnosis could serve as additional prognostic biomarkers for ALS. Their values in routine clinical practice and clinical trials of ALS needs to be investigated further.


目的: 评估 8 种常用的血液标志物作为 ALS 预后生物标志物的能力。 方法: 对瑞典斯德哥尔摩 2006 年至 399 年间新诊断的 2011 例 ALS 患者进行队列研究。我们收集了八种血液标志物的信息,包括肌酐、白蛋白、血红蛋白、 C 反应蛋白 (CRP) 、葡萄糖、钾、钠和钙,在 ALS 诊断日期或之后测量。采用 Cox 回归模型和联合模型探讨生物标志物与死亡风险的相关性。 结果: ALS 诊断的平均年龄为 66.25 岁,58% 的患者为男性。血清肌酐水平低于中位数 (风险比 [HR] = 1.67; 95% 置信区间 [CI] = 1.31-2.12) 或白蛋白 (1.49,1.13-1.96),而基线时高于中位数的对数转化 CRP (1.33,1.04-1.71) 或葡萄糖 (1.34,1.01-1.78) 水平与较高的死亡风险相关。考虑到 ALS 诊断后所有可用的测量结果,我们发现血清肌酐 (2.23,1.81-2.75) 或白蛋白 (1.83,1.43-2.36) 每 SD 降低之间存在关联以及 log(CRP) (1.96,1.58-2.43) 或葡萄糖 (1.61,1.21-2.12) 的每 SD 增加和更高的死亡风险。未发现血红蛋白、钾、钠或钙的明确关联。 结论: 本研究表明,ALS 诊断时测定的血清肌酐、白蛋白、 CRP 和葡萄糖以及 ALS 诊断后的时间变化可作为 ALS 的额外预后生物标志物。它们在 ALS 常规临床实践和临床试验中的价值需要进一步研究。



作者列表:["Aimé P","Karuppagounder SS","Rao A","Chen Y","Burke RE","Ratan RR","Greene LA"]

METHODS::Identifying disease-causing pathways and drugs that target them in Parkinson's disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.

翻译标题与摘要 下载文献
作者列表:["Sebastián-Serrano Á","Simón-García A","Belmonte-Alfaro A","Pose-Utrilla J","Santos-Galindo M","Del Puerto A","García-Guerra L","Hernández IH","Schiavo G","Campanero MR","Lucas JJ","Iglesias T"]

METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

翻译标题与摘要 下载文献
作者列表:["Mendes FR","Leclerc JL","Liu L","Kamat PK","Naziripour A","Hernandez D","Li C","Ahmad AS","Doré S"]

METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.