Ethical considerations of biomarker use in neurodegenerative diseases--a case study of Alzheimer's disease

A major issue in current Alzheimer research presents in a growing dysbalance between a swiftly advancing biological marker and diagnostic research field (including advances in genetic research towards genetic profiling), key aspects of which have already found their way into newly proposed diagnostic criteria and international clinical dementia guidelines, and still rather limited and stagnating therapeutic and preventive options for physicians and patients worldwide. While Alzheimer's disease (AD) to date can be diagnosed with high accuracy years ahead of the late stage clinical syndromal dementia manifestation supported by biomarker guided detection of AD-characteristic pathophysiological features, there are currently no approved preventive or disease-modifying therapies available and the existing approved symptomatic therapy options provide only modest effect sizes in already demented patients without affecting the overall course and progression of the chronically progressive and complex brain disease. This unsatisfactory situation brings along a number of important ethical issues that need to be addressed. We outline some of the relevant ethical implications mainly related to the patient's best interest as well as to the patient's autonomy in the specific context of medical, psychological and social consequences of predicting AD using multi-modal biological markers. Consent, disclosure, or failure to disclose, information from genetic and predictive biomarker results raises significant ethical concerns among IRBs, regulators and advocacy groups. With the swift advances in ever earlier detection, diagnosis and classification in AD, a worldwide debate on ethical issues and consensus processes to reach a common ethical framework is warranted to safely and responsibly bring the best possible diagnostic measures as early as possible to patients and to the health care system.     

Phosphorylated tau 231, memory decline and medial temporal atrophy in normal elders

Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau₂₃₁ (p-tau₂₃₁), total tau, the amyloid beta (Aβ) Aβ42/Aβ40, t-tau/Aβ42 and p-tau₂₃₁/Aβ42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau₂₃₁ (Z = −2.2, p = 0.03), lower Aβ42/Aβ40 (t = −2.2 [55], p = 0.04) and greater longitudinal MTL GM reductions (t_[52] = −2.70, p = 0.01). Higher baseline p-tau₂₃₁ was also associated with the absolute decrease in memory scores (rho = −0.30, p = 0.02) and with longitudinal MTL GM reduction (F_[2,52] = 4.4, p = 0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau₂₃₁, a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage.     

Alteration of prolyl oligopeptidase and activated α-2-macroglobulin in multiple sclerosis subtypes and in the clinically isolated syndrome

Prolyl oligopeptidase (PREP) has been considered as a drug target for the treatment of neurodegenerative diseases. In plasma, PREP has been found altered in several disorders of the central nervous system including multiple sclerosis (MS). Oxidative stress and the levels of an endogenous plasma PREP inhibitor have been proposed to decrease PREP activity in MS. In this work, we measured the circulating levels of PREP in patients suffering of relapsing remitting (RR), secondary progressive (SP), primary progressive (PP) MS, and in subjects with clinically isolated syndrome (CIS). We found a significantly lower PREP activity in plasma of RRMS as well as in PPMS patients and a trend to reduced activity in subjects diagnosed with CIS, compared to controls. No signs of oxidative inactivation of PREP, and no correlation with the endogenous PREP inhibitor, identified as activated α-2-macroglobulin (α₂M*), were observed in any of the patients studied. However, a significant decrease of α₂M* was recorded in MS. In cell cultures, we found that PREP specifically stimulates immune active cells possibly by modifying the levels of fibrinogen β, thymosin β4, and collagen. Our results open new lines of research on the role of PREP and α₂M* in MS, aiming to relate them to the diagnosis and prognosis of this devastating disease.     

精神分裂症患者血浆MicroRNA异常表达的对照研究

目的检测microRNA（miRNA或miR）在精神分裂症患者中的异常表达,探究miRNA能否作为精神分裂症的生物标记物。方法连续入组64例精神分裂症患者和64例配对正常对照,使用实时荧光定量RT—PCR技术检测病例组和对照组血浆10种miRNA（miR-30e、miR一34a、miR一181b、miR一195、miR一346、miR一432、miR一7、miR一132、miR一137andmiR一212）的相对表达水平。结果病例组血浆miR一30e、miR一18lb、miR一346、miR一34a和miR一7表达水平（2．99±1．59,2．29±0．77,4．24±1．51,9．94±1．52,11．08±2．24）较对照组（3．74±1．28,2．87±0．90,4．65±0．99,10．90±1．99,12．00±1．95）显著上调（P〈0．05—0．001）。ROC曲线分析显示,5种miRNA作为联合生物标记物对精神分裂症具有较高诊断价值（AUC为0．705,敏感度和特异度分别为34．5％和90．2％）;Logistic回归分析显示miR-181b具有最高相对危险度（OR=2．483）。结论miR一30e、miR一181b、miR一346、miR一34a和miR．7可能成为精神分裂症的联合生物标记物。     

Discovery of the cancer stem cell related determinants of radioresistance

Tumors are known to be heterogeneous containing a dynamic mixture of phenotypically and functionally different tumor cells. The two concepts attempting to explain the origin of intratumor heterogeneity are the cancer stem cell hypothesis and the clonal evolution model. The stochastic model argues that tumors are biologically homogenous and all cancer cells within the tumor have equal ability to propagate the tumor growth depending on continuing mutations and selective pressure. By contrast, the stem cells model suggests that cancer heterogeneity is due to the hierarchy that originates from a small population of cancer stem cells (CSCs) which are biologically distinct from the bulk tumor and possesses self-renewal, tumorigenic and multilineage potential. Although these two hypotheses have been discussed for a long time as mutually exclusive explanations of tumor heterogeneity, they are easily reconciled serving as a driving force of cancer evolution and diversity. Recent discovery of the cancer cell plasticity and heterogeneity makes the CSC population a moving target that could be hard to track and eradicate. Understanding the signaling mechanisms regulating CSCs during the course of cancer treatment can be indispensable for the optimization of current treatment strategies.     

Combination of p53(ser15) and p21/p21(thr145) in peripheral blood lymphocytes as potential Alzheimer's disease biomarkers

Alzheimer's disease (AD) is still difficult to be precisely diagnosed in its early stage to date. Establishing of reliable and manageable disease-specific biological markers is required to improve diagnostic accuracy. Based on the hypothesis of cell cycle regulatory failure at the early stage of AD, we tested whether cell cycle regulating proteins p53, p21 and their phosphorylated forms p53(ser15), p21(thr145) were changed in AD patients and whether these proteins could be used as diagnostic biomarkers. Western bolt, Enzyme-linked immunosorbent assay (ELISA), immunofluorescent staining and flow cytometry (FCM) analysis were employed to analyze levels of these proteins in peripheral blood lymphocytes (PBLs) from 95 controls, 94 AD, 12 Parkinson's disease (PD) and 15 vascular dementia (VaD) patients. Compared with controls, p53(ser15) and p21(thr145) levels were significantly increased and p21 level was significantly decreased in PBLs of AD patients but not in PD or VaD, while p53 was increased in both AD and VaD patients. The receiver operating characteristic (ROC) curve analysis showed that the specificity and sensitivity were 76% and 84% for p53, 88% and 82% for p53(ser15), 80% and 75% for p21 and 84% and 68% for p21(thr145) in identifying AD patients. The relatively high diagnostic accuracy support these proteins, especially p53(ser15) and p21 in PBLs may become potential biomarkers for diagnosis of AD.     

Cyclooxygenase-2 -765G>C polymorphism is associated with C-reactive protein levels in resistant smokers but not in chronic obstructive pulmonary disease patients

We sought to investigate whether the serum concentrations of several inflammatory biomarkers are related to the cyclooxygenase-2 (COX2) −765G>C polymorphism in chronic obstructive pulmonary disease (COPD) and a control group of non-COPD smokers. Serum inflammatory markers (CRP, SAA, CXCL8, and sICAM-1) were measured by ELISA in 144 patients with COPD and in 55 control subjects. Genomic DNA was extracted from peripheral blood leukocytes, and the COX2 −765G>C (rs20417) polymorphism was genotyped. After adjustment for age and active smoking, CRP and SAA concentrations were associated with the COX2 polymorphism in controls (p = 0.041 and 0.014, respectively) but not in COPD patients. The CXCL8 and sICAM-1 concentrations were not associated with the COX2 polymorphism for either cases or controls. The results of the present study indicate that there is a relationship between the COX2 −765G>C polymorphism and the concentrations of CRP and SAA in non-COPD smokers and that this relationship does not exist in COPD patients.