Introduction: Research into the pathogenic mechanisms behind frontotemporal dementia (FTD) has yielded several new targets for therapeutic intervention; such targets include specific new pathways uncovered by mutations as well as targets involving the modulation, formation and degradation of protein aggregates.Areas covered: Herein, the authors outline the principal molecular causes underlying FTD to date and the research that has been performed in these areas with respect to an eventual corrective strategy.Expert opinion: While it is worthwhile targeting pathways affected by specific mutations with a causative loss of function linked to FTD, research still has to contend with issues including the remaining presence of protein aggregates or that treatments are rarely universally applicable. Aiming to recover function in a downstream target caused by the protein aggregates will likely be insufficient due to the large cascade of events affected. It is our belief that the clearance of these aggregates and the inhibition of protein misfolding are more appropriate and direct routes to an eventual therapy. 相似文献
Introduction: Progranulin (PGRN) is an acrosomal glycoprotein that is synthesized during spermatogenesis. It is overexpressed in tumors and has anti-inflammatory properties. The protein may be cleaved into granulins which display pro-inflammatory properties. In 2006, mutations in progranulin gene (GRN) that cause haploinsufficiency were found in familial cases of frontotemporal dementia (FTD). Patients with null mutations in GRN display very low-plasma PGRN levels; this analysis is useful for identifying mutation carriers, independent of the clinical presentation, and in those before the appearance of symptoms.
Areas covered: Here, we review the current knowledge of PGRN physiological functions and GRN mutations associated with FTD; we also summarize state of the art clinical trials and those compounds able to replace PGRN loss in preclinical models.
Expert opinion: PGRN represents a promising therapeutic target for FTD. Cohorts suitable for treatment, ideally at the preclinical stage, where pathogenic mechanisms ongoing in the brain are targeted, are available. However, PGRN may have side effects, such as the risk of tumorigenesis, and the risk/benefit ratio of any intervention cannot be predicted. Furthermore, at present, the situation is complicated by the absence of adequate outcome measures. 相似文献
目的:探究稳定期慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)频繁急性加重的影响因素及其与血清分泌型卷曲相关蛋白1(secreted frizzled-related protein 1,SFRP1)、颗粒蛋白前体(progranulin,PGRN)水平的相关性。方法:选取2020年4月至2021年2月于汕头市大峰医院呼吸内科就诊的稳定期COPD患者为研究对象,根据患者既往12个月内症状急性加重的情况,将其分为频繁急性加重组和非频繁急性加重组。采集所有患者一般资料,进行肺功能检查、常规生化指标及血清SFRP1、PGRN水平测定,并行改良英国医学研究委员会呼吸困难量表(modified Medical Research Council Dyspnea Scale,mMRC)、临床慢性阻塞性肺病问卷(Clinical COPD Questionnaire,CCQ)、Charlson合并症指数(Charlson Comorbidity Index,CCI)、汉密尔顿焦虑量表(Hamilton Anxiety Scale,HAMA)评估。采用logistic回归模型分析相关指标与COPD频繁急性加重的关系。结果:共入组160例,其中频繁急性加重组为92例,非频繁急性加重组68例。与非频繁急性加重组相比,频繁急性加重组的体重指数(body mass index,BMI)、第1秒用力呼气容积(forced expiratory volume in one second,FEV1)、FEV1/用力肺活量(forced vital capacity,F VC)及血清肾小球滤过率(glomerular filtration rate,GFR)、血红蛋白(haemoglobin,Hb)水平均明显更低(P<0.05),血清总免疫球蛋白E(immunoglobulin E,IgE)、SFRP1、PGRN水平及慢性阻塞性肺病评估测试(COPD assessment test,CAT)、HAMA评分则均明显更高(P<0.05)。Logistic回归分析显示:BMI[优势比(odds ratio,OR)=0.973]、FEV1(OR=0.963)、GFR(OR=0.865)、血清总IgE(OR=3.473)、SFRP1(OR=2.081)、PGRN(OR=2.612)及CAT评分(OR=1.101)、HAMA评分(OR=1.134)均为稳定期COPD频繁急性加重的独立影响因素(P<0.05)。结论:相比非频繁急性加重患者,COPD频繁急性加重患者存在BMI较低、肺功能较差等特点,且血清SFRP1、PGRN水平与频繁急性加重具有明显相关性。 相似文献
Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD. 相似文献
Introduction: Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility.
Areas covered: This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs.
Expert opinion: There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options. 相似文献