Longitudinal Study of CSF Biomarkers in Patients with Alzheimer's Disease

Background

The CSF biomarkers tau and Aβ42 can identify patients with AD, even during the preclinical stages. However, previous studies on longitudinal changes of tau and Aβ42 in individual patients with AD and elderly controls report somewhat inconsistent results.

Methodology/Principal Findings

We investigated the levels of tau and Aβ42 at baseline and after 1 year in 100 patients with AD. In a second cohort of 45 AD patients we measured the CSF biomarkers at baseline and after 2 years. Moreover, in 34 healthy elderly controls the CSF biomarkers were followed for 4 years. The baseline levels of tau were increased with >60% in AD patients compared to controls (p<0.001), while baseline Aβ42 levels were decreased with >50% (p<0.001). In the AD group followed for 2 years, tau increased with 16% compared to the baseline levels (p<0.05). However, the levels of tau were stable over 4 years in the controls. The levels of Aβ42 did not change significantly over time in any of the groups. In the patients with AD, tau was moderately associated with worse cognitive performance already at baseline (p<0.05).

Conclusions/Significance

Tau and Aβ42 in CSF seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in the patients with AD is modest when compared to the relatively large difference in absolute tau levels between AD patients and controls. Therefore, these markers maintain their usefulness as state markers over time and might serve as surrogate markers for treatment efficacy in clinical trials.     

The Prepared Tau Exon-Specific Antibodies Revealed Distinct Profiles of Tau in CSF of the Patients with Creutzfeldt-Jakob Disease

Background

The diagnostic value of CSF tau for Creutzfeldt-Jakob disease (CJD) has been widely evaluated, showing a markedly disease-relative manner. However, the profiles of tau isoforms in CSF of CJD patients remain unknown. Here, we prepared the exon-specific antibodies against the peptides encoded by exon-2, exon-3 and exon-10 of human tau protein and evaluated the reactive profiles of tau in CSF samples from the patients with probable CJD.

Methodology/Principal Findings

Sequences encoding exon-2, exon-3 and exon-10 of human tau protein were cloned into a prokaryotic expression vector pGEX-2T. Using recombinant fusion proteins GST-E2, GST-E3 and GST-E10, three tau exon-specific antibodies were elicited. Reliable specificities of the prepared antibodies were obtained after a serial of purification processes, not only in recognizing the tau peptides encoded by exon-2, -3 and -10, but also in distinguishing six recombinant tau isoforms by Western blot and ELISA. Three predominant tau-specific bands were observed in CSF samples with the exon-specific and the commercial tau antibodies, respectively, showing different reactive profiles between the groups of probable CJD and non-CJD. A 65 KD band was detected only in the CSF samples from probable CJD patients, especially with the antibodies against exon-2 (Anti-tE2) and exon-10 (Anit-tE10). The appearances of 65 KD band in CSF correlated well with positive 14-3-3 in CSF and typical abnormality in EEG. Such band was not observed in the CSF samples of six tested genetic CJD patients.

Conclusions/Significance

Three exon-specific polyclonal antibodies were successfully prepared. Based on these antibodies, different CSF tau profiles in Western blots were observed between the groups of probable CJD and non-CJD. A disease-specific tau band emerged in the CSF samples from probable sporadic CJD, which may supply a new biomarker for screening sporadic CJD.     

Identification of Biomarkers of Impaired Sensory Profiles among Autistic Patients

BackgroundAutism is a neurodevelopmental disorder that displays significant heterogeneity. Comparison of subgroups within autism, and analyses of selected biomarkers as measure of the variation of the severity of autistic features such as cognitive dysfunction, social interaction impairment, and sensory abnormalities might help in understanding the pathophysiology of autism.ResultsWhile none of the studied markers correlated with CARS and SRS as measure of cognitive and social impairments, six markers significantly correlated with sensory profiles of autistic patients. Multiple regression analysis identifies a combination of PGES, mPGES-1, and PE as best predictors of the degree of sensory profile impairment. Library identification resulted in 100% correct assignments of both autistic and control participants based on either set 1 or 2 biomarkers together with a satisfactory rate of assignments in case of sensory profile impairment using different sets of biomarkers.ConclusionThe two selected sets of biomarkers were effective to separate autistic from healthy control subjects, demonstarting the possibility to accurately predict the severity of autism using the selected biomarkers. The effectiveness of the identified libraries lied in the fact that they were helpful in correctly assigning the study population as control or autistic patients and in classifying autistic patients with different degree of sensory profile impairment.     

帕金森病患者血清氧化应激标志物的变化特点

目的:探索帕金森病(Parkinson's disease,PD)患者血清中氧化应激标志物变化情况。方法:募集2014年4月至2015年4月来我院就诊的PD患者62例,正常对照人群59例,采集两组人群的基本临床信息,测定两组血浆中活性氧和丙二醛含量,超氧化物歧化酶、谷胱甘肽过氧化物酶及过氧化氢酶的活性,同时测定血清清除羟自由基的能力,比较两组之间的差异。结果:与正常对照组比较,PD患者血清中活性氧和丙二醛含量,超氧化物歧化酶、谷胱甘肽过氧化物酶及过氧化氢酶的活性,及血清清除羟自由基的能力无明显差异(P0.05)。而Hoehn/Yahr分级≥4 PD患者与正常对照组血清氧化应激标志物比较发现,Hoehn/Yahr分级≥4 PD患者血清丙二醛含量显著高于对照组(P=0.018),其他指标两组之间无显著变化(P0.05)。结论:PD患者血清中氧化应激水平与正常对照组比较无显著差异,运动功能障碍严重的PD患者血清脂质过氧化产物水平高于正常对照组。该研究为PD与氧化应激相关性的研究提供了一定的参考。     

Neuropsychological and behavioural correlates of CSF biomarkers in dementia

To improve clinical, neuropsychological and behavioural characterisation of the cerebrospinal fluid (CSF) biomarkers beta-amyloid((1-42)) protein (Abeta42), protein tau (tau) and tau phosphorylated at threonine 181 (P-tau181) across diagnostic dementia categories, a prospective study was set up. Patients with probable Alzheimer's disease (AD) (n=201), AD with cerebrovascular disease (CVD) (AD+CVD) (n=33), frontotemporal dementia (FTD) (n=27), dementia with Lewy bodies (DLB) (n=22) and healthy controls (n=148) were included. All patients underwent neuropsychological examination and behavioural assessment by means of a battery of behavioural assessment scales. CSF was obtained by lumbar puncture and levels of Abeta42, tau and P-tau181 were determined with commercially available ELISA kits. Negative correlations between CSF Abeta42 levels and aggressiveness (Spearman: r=-0.223; p=0.002) and positive correlations with age at inclusion (r=0.195; p=0.006), age at onset (r=0.205; p=0.003) and MMSE scores (r=0.198; p=0.005) were found in AD. In AD+CVD, CSF Abeta42 levels were correlated with MMSE (r=0.482; p=0.006), Hierarchic Dementia Scale (r=0.503; p=0.017) and Boston Naming Test (r=0.516; p=0.012) scores. In controls, age was positively correlated with CSF tau (r=0.465; p<0.001) and P-tau181 levels (r=0.312; p<0.001). CSF tau and P-tau181 levels correlated significantly in all groups, whereas CSF Abeta42 correlated with tau and P-tau181 levels in healthy controls only. Negative correlations between CSF Abeta42 levels and aggressiveness were found in AD patients. CSF Abeta42 seems to be a stage marker for AD (+/-CVD) given the positive correlations with neuropsychological test results suggesting that CSF Abeta42 might be of help for monitoring disease progression. Different correlations between age and CSF biomarker levels were obtained in healthy controls compared to AD patients, indicating that AD-induced pathophysiological processes change age-dependent regulation of CSF biomarker levels.     

Cerebrospinal Fluid (CSF) 25-Hydroxyvitamin D Concentration and CSF Acetylcholinesterase Activity Are Reduced in Patients with Alzheimer's Disease

Background

Little is known of vitamin D concentration in cerebrospinal fluid (CSF) in Alzheimer´s disease (AD) and its relation with CSF acetylcholinesterase (AChE) activity, a marker of cholinergic function.

Methods

A cross-sectional study of 52 consecutive patients under primary evaluation of cognitive impairment and 17 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 28), other dementias (n = 12), and stable MCI (SMCI, n = 12). We determined serum and CSF concentrations of calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), and CSF activities of AChE and butyrylcholinesterase (BuChE).

Findings

CSF 25OHD level was reduced in AD patients (P < 0.05), and CSF AChE activity was decreased both in patients with AD (P < 0.05) and other dementias (P < 0.01) compared to healthy controls. None of the measured variables differed between BuChE K-variant genotypes whereas the participants that were homozygous in terms of the apolipoprotein E (APOE) ε4 allele had decreased CSF AChE activity compared to subjects lacking the APOE ε4 allele (P = 0.01). In AD patients (n=28), CSF AChE activity correlated positively with CSF levels of total tau (T-tau) (r = 0.44, P < 0.05) and phosphorylated tau protein (P-tau) (r = 0.50, P < 0.01), but CSF activities of AChE or BuChE did not correlate with serum or CSF levels of 25OHD.

Conclusions

In this pilot study, both CSF 25OHD level and CSF AChE activity were reduced in AD patients. However, the lack of correlations between 25OHD levels and CSF activities of AChE or BuChE might suggest different mechanisms of action, which could have implications for treatment trials.     

CSF N-Glycan Profiles to Investigate Biomarkers in Brain Developmental Disorders: Application to Leukodystrophies Related to eIF2B Mutations

Background

Primary or secondary abnormalities of glycosylation have been reported in various brain diseases. Decreased asialotransferrin to sialotransferrin ratio in cerebrospinal fluid (CSF) is a diagnostic marker of leukodystrophies related to mutations of genes encoding translation initiation factor, EIF2B. We investigated the CSF glycome of eIF2B-mutated patients and age-matched normal individuals in order to further characterize the glycosylation defect for possible use as a biomarker.

Methodology/Principal Findings

We conducted a differential N-glycan analysis using MALDI-TOF/MS of permethylated N-glycans in CSF and plasma of controls and eIF2B-mutated patients. We found in control CSF that tri-antennary/bisecting and high mannose structures were highly represented in samples obtained between 1 to 5 years of age, whereas fucosylated, sialylated structures were predominant at later age. In CSF, but not in plasma, of eIF2B-mutated patient samples, we found increased relative intensity of bi-antennary structures and decreased tri-antennary/bisecting structures in N-glycan profiles. Four of these structures appeared to be biomarker candidates of glycomic profiles of eIF2B-related disorders.

Conclusion

Our results suggest a dynamic development of normal CSF N-glycan profiles from high mannose type structures to complex sialylated structures that could be correlated with postnatal brain maturation. CSF N-glycome analysis shows relevant quantitative changes associated with eIF2B related disorders. This approach could be applied to other neurological disorders involving developmental gliogenesis/synaptogenesis abnormalities.     

Altered Hypercoagulability Factors in Patients with Chronic Chagas Disease: Potential Biomarkers of Therapeutic Response

Thromboembolic events were described in patients with Chagas disease without cardiomyopathy. We aim to confirm if there is a hypercoagulable state in these patients and to determine if there is an early normalization of hemostasis factors after antiparasitic treatment. Ninety-nine individuals from Chagas disease-endemic areas were classified in two groups: G1, with T.cruzi infection (n = 56); G2, healthy individuals (n = 43). Twenty-four hemostasis factors were measured at baseline. G1 patients treated with benznidazole were followed for 36 months, recording clinical parameters and performance of conventional serology, chemiluminescent enzyme-linked immunosorbent assay (trypomastigote-derived glycosylphosphatidylinositol-anchored mucins), quantitative polymerase chain reaction, and hemostasis tests every 6-month visits. Prothrombin fragment 1+2 (F1+2) and endogenous thrombin potential (ETP) were abnormally expressed in 77% and 50% of infected patients at baseline but returned to and remained at normal levels shortly after treatment in 76% and 96% of cases, respectively. Plasmin-antiplasmin complexes (PAP) were altered before treatment in 32% of G1 patients but normalized in 94% of cases several months after treatment. None of the patients with normal F1+2 values during follow-up had a positive qRT-PCR result, but 3/24 patients (13%) with normal ETP values did. In a percentage of chronic T. cruzi infected patients treated with benznidazole, altered coagulation markers returned into normal levels. F1+2, ETP and PAP could be useful markers for assessing sustained response to benznidazole.     

非透析慢性肾脏病患者心脏功能生物标记物的临床价值比较

目的:比较非透析慢性肾脏病患者心脏功能生物标记物的临床应用价值。方法:选取122例非透析且无急性冠脉综合征(ACS)的慢性肾脏病患者(CKD),将其分为CKD1-2期组、CKD3-4期组和CKD5期组,同时选择同期确诊急性冠脉综合征的慢性肾脏病患者20例作为对照组,观察并比较各组患者室间隔厚度(IVST)、左室后壁厚度(LVPWT),检测血液中血肌酐(Scr)、尿素氮(BUN)、心型脂肪酸结合蛋白(HFABP)、心肌钙蛋白(cTnI)以及肌酸激酶同功酶(CK-MB)。结果:非ACS的CKD患者HFABP、cTnI、CK-MB水平均呈不同程度增高,且各CKD组中这三个指标的阳性率存在显著差异,其中HFABP阳性率最高(P0.05)。cTnI与e GFR、Scr及年龄无显著相关性(P0.05),但与IVST、LVPWT呈显著正相关(P0.05);CK-MB与e GFR、Scr、年龄、IVST、LVPWT均无相关性(P0.05);HFABP与e GFR呈负相关(P0.05),与Scr和BUN正相关(P0.05),与年龄、IVST、LVPWT无相关性(P0.05)。结论:在非ACS的CKD患者中,HFABP可能不是一个可靠的反映心脏功能的生物标记物,cTnI及CK-MB对于CKD患者而言是较为可靠的心脏标记物。     

新发缺血性脑卒中患者实施单病种质量管理的预后评价

目的 调查分析上海市某三甲医院缺血性脑卒中单病种质量管理实施情况并评价其效果。方法 采用回顾性调查的方法,以NIHSS评分为疗效评价依据,对新发缺血性脑卒中单病种质量管理实施组和未实施组的预后情况进行分析评估。结果 在2组基线资料均衡的情况下,缺血性脑卒中单病种质量管理实施组的疗效显著优于未实施组,尤其是发病初始疾病严重程度一般者的疗效最好。结论 缺血性脑卒中单病种质量管理通过对诊疗过程的质量控制,规范了诊疗行为,改善了新发缺血性脑卒中患者的预后。     

Decision-Making in Patients with Hyperthyroidism: A Neuropsychological Study

Introduction

Cognitive and behavioral impairments are common in patients with abnormal thyroid function; these impairments cause a reduction in their quality of life. The current study investigates the decision making performance in patients with hyperthyroidism to explore the possible mechanism of their cognitive and behavioral impairments.

Methods

Thirty-eight patients with hyperthyroidism and forty healthy control subjects were recruited to perform the Iowa Gambling Task (IGT), which assessed decision making under ambiguous conditions.

Results

Patients with hyperthyroidism had a higher score on the Zung Self-Rating Anxiety Scale (Z-SAS), and exhibited poorer executive function and IGT performance than did healthy control subjects. The patients preferred to choose decks with a high immediate reward, despite a higher future punishment, and were not capable of effectively using feedback information from previous choices. No clinical characteristics were associated with the total net score of the IGT in the current study.

Conclusions

Patients with hyperthyroidism had decision-making impairment under ambiguous conditions. The deficits may result from frontal cortex and limbic system metabolic disorders and dopamine dysfunction.     

不同病因的慢性肾病患者血清氨基酸谱存在显著差异

慢性肾病(chronic kidney disease, CKD)患者血清氨基酸谱发生了显著性变化,但目前并无不同病因的CKD患者血清氨基酸谱的比较研究。本研究主要探究不同病因CKD患者血清氨基酸谱的差异,以及差异氨基酸与肾疾病发生发展的相互关系。选取79例确诊慢性肾病的成年患者,根据其病因,分糖尿病肾病组、高血压肾病组及慢性肾小球肾炎组。另选取25例性别年龄匹配的健康成年人为正常对照组。收集及处理清晨空腹血清标本,采用反相高效液相色谱法（reverse-phase high-performance liquid chromatography, RP-HPLC）测定血清中22种游离氨基酸的水平。结果显示,与正常对照组相比,3组CKD患者血清赖氨酸、丝氨酸、甘氨酸、伽马氨基丁酸(GABA)、色氨酸、亮氨酸以及酪氨酸水平均显著下降（P<0.05）,而血氨水平显著升高（P<0.05）。糖尿病肾病组患者血清苏氨酸水平明显高于其余3组（P<0.05）,而血清天冬氨酸水平显著低于其余3组（P<0.05）。慢性肾小球肾炎患者血清异亮氨酸水平显著低于糖尿病肾病及高血压肾病患者（P<0.05）。上述结果证实,慢性肾病患者血清氨基酸谱较正常对照发生显著变化,且不同病因CKD患者部分血清氨基酸水平存在显著差异。其中,色氨酸水平的差异可能是不同病因CKD患者肾功能恶化速度不一致的原因之一。     

Neuropsychological Investigation in Chinese Patients with Progressive Muscular Atrophy

Background

Progressive muscular atrophy (PMA) is a rare type of degenerative motor neuron disease (MND) of which the onset happens in adult period. Despite its well-defined clinical characteristics, its neuropsychological profile has remained poorly understood, considering the consensus of cognitive and behavioral impairment reached in amyotrophic lateral sclerosis (ALS).

Methods

We conducted a cross-sectional evaluation of Chinese PMA patients with a series of comprehensive batteries emphasizing the executive and attention function, and covering other domains of memory, language, visuospatial function, calculation and behavior as well. Their performances were compared with those of age- and education-matched ALS and healthy controls (HC).

Results

21 patients newly diagnosed with PMA were consecutively enrolled into our ALS and other MND registry platform, accounting for 14.7% of all the incident MND cases registered during the same period. 20 patients who completed the neuropsychological batteries were included into analysis. Compared with HC, PMA performed significantly worse in maintenance function of attention, while they exhibited quantitative similarity to ALS in all behavioral inventories and neuropsychological tests except the time for Stroop interference effect.

Conclusion

PMA could display mild cognitive dysfunction in the same frontal-mediated territory of ALS but in a lesser degree, whereas they did not differ from ALS behaviorally.     

Galanin-Like Immunoreactivity Is Increased in the Postmortem Cerebral Cortex from Patients with Alzheimer's Disease

Abstract: Galanin is a peptide that is associated with cholinergic neurons of the basal forebrain and, thus, of interest for the neuropathology of Alzheimer's disease. In the present study, human galanin-like immunoreactivity was measured in postmortem human cerebral cortical tissues by using a homologous radioimmunoassay. In an initial study, six cerebral cortical regions were evaluated from nine elderly controls, 13 neuropathologically verified Alzheimer's disease patients, and 19 elderly schizophrenics. A significant 65% increase in galanin was found in frontal cortex Brodmann area 8 of Alzheimer's disease patients compared with controls. In contrast, cerebral cortical tissues from elderly schizophrenics were not different from those from elderly controls in any region. In a second study, 10 cerebral cortical regions were evaluated from 50 neuropathologically verified Alzheimer's disease patients and nine elderly controls. Concentrations of galanin were increased significantly 26–61% in six of 10 cerebral cortical regions examined (Brodmann areas F8, F44, T20, T21, T36, and P22). Purification of brain extracts by size-exclusion Sephadex G-50 chromatography revealed that human galanin-like immunoreactivity eluted in two peaks of different molecular weights. These studies reveal increased concentrations of galanin in the cerebral cortex of Alzheimer's disease, similar to previous findings in basal forebrain tissue. Because galanin inhibits cholinergic neurotransmission, these findings may have important implications in the understanding of Alzheimer's disease neuropathology and associated cognitive deficits.     

Multiple Sclerosis: MicroRNA Expression Profiles Accurately Differentiate Patients with Relapsing-Remitting Disease from Healthy Controls

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, which is heterogenous with respect to clinical manifestations and response to therapy. Identification of biomarkers appears desirable for an improved diagnosis of MS as well as for monitoring of disease activity and treatment response. MicroRNAs (miRNAs) are short non-coding RNAs, which have been shown to have the potential to serve as biomarkers for different human diseases, most notably cancer. Here, we analyzed the expression profiles of 866 human miRNAs. In detail, we investigated the miRNA expression in blood cells of 20 patients with relapsing-remitting MS (RRMS) and 19 healthy controls using a human miRNA microarray and the Geniom Real Time Analyzer (GRTA) platform. We identified 165 miRNAs that were significantly up- or downregulated in patients with RRMS as compared to healthy controls. The best single miRNA marker, hsa-miR-145, allowed discriminating MS from controls with a specificity of 89.5%, a sensitivity of 90.0%, and an accuracy of 89.7%. A set of 48 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 95%, a sensitivity of 97.6%, and an accuracy of 96.3%. While 43 of the 165 miRNAs deregulated in patients with MS have previously been related to other human diseases, the remaining 122 miRNAs are so far exclusively associated with MS. The implications of our study are twofold. The miRNA expression profiles in blood cells may serve as a biomarker for MS, and deregulation of miRNA expression may play a role in the pathogenesis of MS.     

A Non-Invasive Method to Assess Cerebral Perfusion Pressure in Geriatric Patients with Suspected Cerebrovascular Disease

Background

Cerebral perfusion pressure (CPP) can adversely impact cerebrovascular hemodynamics but cannot be practically measured in most clinical settings. Here, we aimed to establish a representative mathematical model for CPP in geriatric patients with suspected cerebrovascular disease.

Methods

A total of 100 patients (54 males and 46 females between 60–80 years of age) with suspected cerebrovascular disease and no obvious cerebrovascular stenosis were selected for invasive CPP monitoring via catheterization of the middle segment of the common carotid arteries and openings of the vertebral arteries bilaterally. Curves were function-fitted using MATLAB 7.0, and data was statistically processed by SPSS 20.0.

Results

MATLAB 7.0 constructed eighth-order Fourier functions that fit all recorded CPP curves. Since the coefficients of the 100 functions were significantly different, all functions were standardized to derive one representative function. By manipulating the heart rate and maximum/minimum CPP of the representative function, estimated CPP curves can be constructed for patients with differing heart rates, intracranial pressures (ICPs) and blood pressures.

Conclusions

CPP can be well-modeled through an eighth-order Fourier function that can be constructed from a patient’s brachial artery blood pressure (BABP), ICP and heart rate. This function is representative of geriatric patients with cerebrovascular disease and can be used in the future study of cerebral hemodynamics.