晚期梅毒血清学变化和血清固定的隐性梅毒认知功能相关研究
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摘要
(一)晚期梅毒治疗后的血清学反应研究
[背景和目的]近20年来梅毒再度死灰复燃,全球每年有1200万新发梅毒病例,超过90%的患者在发展中国家。梅毒患者确诊后按正规驱梅治疗,大部分能达到临床治愈和血清学治愈的效果。然而由于抗生素的广泛使用和耐药性的挑战,神经梅毒日益增多。治疗反应有相当大的差异。早期梅毒给予规范性治疗后,血清学有效反应约75%-100%。也有报道经治疗有效的早期梅毒仍然有部分患者进展为神经梅毒,普遍认为神经梅毒的治疗有效性不如早期梅毒。但是晚期梅毒的血清学相关报道极少。本课题对晚期梅毒患者进行了前瞻性队列研究,观察梅毒患者的血清学和脑脊液梅毒抗体滴度特征；比较梅毒治疗前后的改变情况；分析远期预后的影响因素。旨在为晚期梅毒的治疗和随访提供参考依据；也给及早根治早期梅毒提供依据。
[方法]
1.设计方法：采用前瞻性队列研究。
2.研究对象：资料来自于2006年1月-2012年1月期间连续性在广州市脑科医院住院或门诊诊治的梅毒患者。A：纳入标准：①符合美国CDC晚期梅毒的诊断标准；②既往从未驱梅治疗；③所有患者均知情同意。B：排除标准：①HIV抗体试验阳性；②基线RPR(-)③随访不充分,不到1年者。
3.治疗方法：所有患者诊断明确后根据美国CDC推荐的梅毒治疗方案进行规范驱梅治疗。
3.1随访治疗后定期复查TPPA和RPR试验滴度,分别于治疗前和治疗后2周或1个月、6个月和1年。1年以后每半年或一年复查一次。定期复查腰穿,测脑脊液(CSF)白细胞数、蛋白含量以及RPR滴度。在治疗前和治疗后1年时分别完成MMSE检测。
3.2观察指标
(1)1年时血清学反应,即治疗后1年的血清RPR滴度变化情况。①治疗有效/治愈(Serological success):血清RPR滴度比基线时下降4倍或4倍以上/RPR转(-)；②治疗失败(Serological failure):指的是血清RPR滴度比基线时上升4倍或4倍以上(在没有明确的再暴露史情况下)。③血清学无反应或血清固定(Serological nonresponse or serofast status):指的是血清RPR滴度比基线下降或上升2倍以内。④血清RPR转阴率：根据转阴的例数计算出转阴率。
(2)最终结局和治疗反应时间：在随访期间血清学反应结局(同上①②③)。并记录从治疗开始到治疗有效的时间,以天计算。
(3)脑脊液正常化：CSF-RPR滴度下降4倍或以上或转阴性；白细胞从≥10个/uL下降到<10个/uL; CSF-蛋白从≥0.45g/L下降到<0.45g/L。
(4)亚组分析：神经梅毒患者中血清固定和有效组治疗前后MMSE分值的比较。
3.3统计学处理采用SPSS18.0统计软件包进行数据的统计分析。定量资料采用均数±标准差(x±s)或中位数(四分位间距)[M(IQR)]表示：定性资料采用例数(n)和百分率(%)表示。两组之间的比较采用t检验,治疗前后比较采用配对t检验。采用多因素Logistic回归方程分析影响1年时结局的因素；有效时间的生存分析采用Cox比例风险分析；P<0.05有统计学意义。
[结果]
1一般资料
最后共纳入172例梅毒患者,男性127例,占73.8%。平均年龄(50.29±9.21)岁。所有患者随访中位天数是666.50天。其中有症状的神经梅毒138例(80.23%),89.9%是男性；无症状神经梅毒10例(5.82%),80%是女性；隐性梅毒24例(13.95%),几乎是女性(95.8%)。
2治疗前RPR分析
所有患者治疗前血清RPR中位滴度数1：8(IQR1:4-1:32)。神经梅毒(有症状和无症状)的血清RPR滴度为1：8,而隐性梅毒为1：4。神经梅毒(包括有症状和无症状)的CSF-TPHA均(+),RPR中位滴度数1：2(IQR0-1:4)。36.8%的神经梅毒CSF-RPR反应呈阴性。
31月内RPR滴度变化情况
治疗后1个月内有32.0%血清RPR滴度升高,以升高2倍为主。只有6.25%脑脊液RPR滴度升高,6.25%在治疗后1月内转阴,70.3%滴度不变。
4治疗后1年时预后
4.11年时血清学反应
1年时95例(55.2%)治疗有效／治愈；3例(1.7%)失败；74例(43.0%)血清固定。神经梅毒(有症状和无症状的)患者中,52.7%治疗有效,45.3%血清固定。1年时只有21例血清RPR转为阴性,转阴率12.2%。当继续随访至2年,血清RPR转阴率增加到16.1%。
4.2治疗1年时脑脊液变化情况
64例神经梅毒患者在1年时复查了腰穿。有18例(28.1%)脑脊液蛋白未正常化；1年后复查脑脊液RPR滴度有58例(90.6%)均呈阴性。
4.3有症状的神经梅毒患者治疗前后MMSE比较的亚组分析
138例有症状的神经梅毒中,1年时有63例(45.7%)血清学固定,72例(52.2%)血清学有效。两组之间治疗前MMSE评分无统计学差异(t=0.429,P=0.669)。经过治疗后1年两组患者MMSE均有一定程度改善(P<0.001)；但血清固定组改善程度更小,治疗1年时分值明显低于血清学有效组(t=2.947,P=0.004)。
4.4影响预后的多因素分析
多因素Logistic逐步回归分析结果显示：独立影响1年时血清学有效/治愈的有首次脑脊液蛋白含量(OR=0.241,95%CI0.122-0.475,P<0.001)和1月内血清滴度是否升高(OR=0.397,95%CI0.195-0.808,P=0.011)。首次CSF蛋白增高和1月内血清RPR滴度升高者,1年时血清学有效反应的可能性就越小。
4.5发生有效反应时间的Cox生存分析
治疗有效患者的中位天数212.0天(IQR150.5-388.0)天。独立影响血清学有效反应时间的因素是首次血清RPR滴度、首次CSF蛋白含量和年龄。首次血清RPR滴度每增加1倍,发生有效血清学反应的机会是1.193倍(RR=1.193,95%CI1.061-1.341,P=0.003),有统计学意义。也就是首次滴度越高者,滴度下降越快,越快达到有效反应。首次脑脊液蛋白含量超过0.45g/L的患者达到血清学有效反应的中位天数大于低于0.45g/L者,差异达统计学意义(RR=0.513,95%CI0.343-0.770,P=0.001)。年龄每增加1个阶段,发生有效血清学反应的机会是0.721倍(RR=0.721,95%CI0.544-0.956,P=0.023),有统计学意义。年龄越大,血RPR滴度下降越慢,越晚达到有效。
[结论]
1.神经梅毒患者年龄主要集中在36-59岁之间,平均在50岁左右,神经梅毒大多为男性患者；而隐性梅毒几乎是女性患者,女性更容易被选择性发现隐性梅毒。
2.神经梅毒和不明病期的隐性梅毒患者的治疗前血清RPR滴度均偏低,中位数为1：8,尤以不明病期的隐性梅毒更多仅1：2—1：4。
3.治疗后1月内有32.%患者血清RPR滴度上升；CSF-RPR滴度仅6.25%上升。1年时血清学有效／治愈率55.2%,失败1.7%,血清固定43.0%；神经梅毒(有症状和无症状的)患者中,52.7%治疗有效,45.3%血清固定。1年时血清RPR转阴率仅12.2%,神经梅毒有89.1%均不能转阴。部分患者复查脑脊液,71.9%脑脊液蛋白正常化,90.6%脑脊液RPR(-)。
4.独立影响血清学有效反应和时间的有：首次血清RPR滴度、首次脑脊液蛋白含量和年龄。血清RPR滴度越高、脑脊液蛋白正常和年纪更轻的RPR滴度下降更快,更容易达到有效/治愈。
5.和早期梅毒相比,晚期梅毒治疗1年的血清学有效率更低,发生血清固定更多,反应更慢。血清固定的神经梅毒患者认知功能恢复更慢,损害更明显。
(二)血清固定的隐性梅毒患者神经认知功能和脑白质微结构研究
[背景和目的]第一部分研究显示晚期神经梅毒的血清固定现象发生率高(45.3%),有报道隐性梅毒的血清固定发生率也高,约40.8%,而隐性梅毒中血清固定者约35%可出现病情复发,应引起高度重视。梅毒有40%在感染早期就可能侵入中枢神经系统。我们的研究中还提示血清固定在神经梅毒的认知功能可能有一定的影响,在血清固定的隐性梅毒长期潜伏过程中,是否也已经发生了难以察觉的认知功能损害?目前还处于假设与推测中。为了及早发现梅毒慢性感染过程中的认知损害,阻止发展到晚期神经梅毒,我们进一步探索性地对血清固定的隐性梅毒患者进行神经认知测验,选用目前国际上较为公认的认知工具。并设立与患者年龄、性别、教育年限相匹配的正常对照组进行了同样的神经认知测验,对其中部分自愿受试者完成了磁共振弥散张量成像(DTI),定量检测脑白质微结构改变,在活体评估白质的完整性。以明确：1)血清固定的隐性梅毒患者认知功能；2)血清固定的隐性梅毒脑白质微结构改变；3)认知功能改变与白质微结构改变的关系。
[方法]
1.设计方法采用病例-对照试验设计方法。
2.研究对象患者组均来自2009年10月至2012年5月广州市脑科医院住院或门诊患者。对照组来自于广州市脑科医院周边的社区健康志愿者及健康配偶。
隐性梅毒组：梅毒螺旋体明胶凝集试验(TPPA)和快速血浆反应素(RPR)试验阳性的隐性梅毒患者。A纳入标准：①符合美国CDC潜伏梅毒的诊断标准；②年龄25-70岁,小学毕业以上文化,志愿参加本研究；③就诊前HIV抗体试验呈阴性；④无梅毒的临床表现：无明显的神经系统症状和体征；⑤接受正规梅毒治疗后1年的血清RPR滴度比基线变化在2倍以内；⑥简易精神状态量表(MMSE)评分>24分。B排除标准①有神经系统临床表现；②近3月内用过激素及免疫抑制剂；③伴有可致生物学假阳性的急、慢性疾病,如结核、麻风病,结缔组织疾病,及肿瘤者；④患有脑器质性疾病(如脑外伤、脑血管疾病、多发性硬化、痴呆、癫痫等)、内分泌或代谢性疾病(如甲状腺功能减退、糖尿病等)；明显躯体疾病、酒精或药物滥用者；⑤有视听力障碍影响测试者；⑥无法完成磁共振检查者(体内有金属植入物或有幽闭恐惧症等)--针对行弥散张量磁共振检查者。
健康对照组：经血清检测TPPA阴性且询问病史和体格检查后的健康者。A纳入标准：①年龄25-70岁,小学毕业以上文化,志愿参加本研究；②血清检测TPPA、RPR、HIV抗体阴性； B排除标准：同病例组。
3.研究方法
3.1一般资料：详细记录患者的一般资料,如年龄、性别、教育年限、职业、现病史、既往史。
3.2神经心理学背景测试：包括简易精神状态量表(Mini-Mental State Examination, MMSE)、词汇流畅性试验(verbal fluency test, VFT)、数字广度试验(Digital Span, DS)、Stroop测验、听觉词汇学习测验(auditory vocabulary learning test, AVLT)。
3.3前瞻性记忆(prospective memory, PM)研究：采用Einstein和汪凯等人设计的前瞻性记忆检查方法,分别测查基于事件的前瞻性记忆(event-based prospective memory, EBPM)和基于时间的前瞻性记忆(time-based prospective memory, TBPM)成绩。
3.4模糊决策认知研究：采用爱荷华博弈实验(Iowa Gambling Task, IGT)。记录受试者总有利选择数,每阶段有利选择数。计算每个阶段(有利选择—不利选择)的差值。
3.5脑白质微结构研究：使用GE3.0T MR仪行头颅常规MRI检查和弥散张量成像(DTI)。在工作站上运用Functool软件包进行图像后处理,测量不同感兴趣区白质纤维的各向异性(FA)值。分别在额叶白质、顶叶白质、颞叶白质、枕叶白质、胼胝体膝部和压部、锥体束、前扣带束、后扣带束区域左右对称部位选取感兴趣区(ROI)。
3.6统计学处理：采用SPSS18.0软件包进行统计分析。定量资料采用均数±标准差(x±s)或中位数(四分位间距)[M(IQR)]表示；定性资料采用例数(n)和百分率(%)表示。两组之间的比较采用t检验或x2检验,不同组别不同时间点的比较采用重复测量方差分析(repeated measures ANOVAs).相关分析采用线性Logistic回归分析。以P<0.05为差异有统计学意义。
[结果]
1.PM测试结果
1.1一般资料
本研究共纳入隐性梅毒患者30例,男性6例(20%)。平均年龄(48.83±11.37)岁,平均受教育年限(9.67±3.46)年；MMSE平均(27.87±1.41)分。对照组30例,两组在年龄、性别、受教育年数和MMSE评分的差异均无统计学意义(P>0.05)。
1.2隐性梅毒和对照组神经心理学背景测试结果
和正常对照组相比,隐性梅毒组仅有AVLT-延迟10分钟成绩更差,差异有统计学意义(p<0.05)。其余的测试DS.stroop字色测试、VFT.AVLT6即刻回忆和延迟5分钟回忆及再认差异无统计学意义(P>0.05)。
1.3隐性梅毒和对照组PM测试结果
与健康对照组相比(EBPM,6.13±1.252；TBPM,4.67±0.922)相比,隐性梅毒组的EBPM(4.33±2.057)和TBPM(3.80±1.400)均较对照组差(t=-4.095,p<0.001；t=6.902,p<0.05)。PM中的回溯成分,两组的RM1和RM2均无显著性差异(P>0.05)。
2.IGT测试结果
2.1一般资料
纳入PM研究的受试者中有47例同时完成了该测试,其中隐性梅毒患者26例,对照组21例。两组在年龄、性别、受教育年数和MMSE评分的差异均无统计学意义(P>0.05)。隐性梅毒组的AVLT延迟回忆成绩比对照组差(p<0.05)。DS、stroop、AVLT即刻回忆、VFT的差异无统计学意义(P>0.05)。
2.2隐性梅毒和对照组IGT测试结果
隐性梅毒组100次测试总不利备选数(55.538±7.996)明显多于对照组(47.143±7.683),差异达统计学意义(t=-3.641,P=0.001)；而有利备选数(44.615±7.965)明显少于对照组(52.571±7.379),有统计学意义(t=-3.517,p=0.001)。经重复测量方差分析,结果显示组间差异有显著性(F=11.114,P=0.03)；每组先后各阶段间差异有显著性(F=3.813,P=0.017；F=15.074,P<0.001)；组别与时间之间存在交互效应(F=18.424,P<0.001),提示两组受试者随时间的增加选择次数的增加,都有学习效应。进一步分析单独效应,结果显示各阶段内两组间比较在试验的初期无显著性(P>0.05),随着时间的推移,逐渐表现出两组在选择的显著性差异(P61-80,81-100<0.001)。隐性梅毒组的有利选择趋势不如正常对照组。
2.3IGT成绩与各认知功能相关性分析
所有受试者总选择有利备选数与Stroop呈负相关(r=-0.332,P=0.016),与AVLT延迟10min回忆得分呈正相关(r=0.344,P=0.012),均达统计学意义。
3.DTI检查结果
3.1一般资料
完成了PM测试的部分受试者在自愿情况下接受了DTI检查,其中隐性梅毒患者20例,对照组13例,两组在年龄、性别、受教育年数和MMSE评分的差异均无统计学意义(P>0.05)。隐性梅毒组除了AVLT回忆再认成绩差于对照组且达统计学意义(p=0.022)以外,其余心理学背景测试差异均无统计学意义(P>0.05)。
3.2隐性梅毒和对照组脑白质感兴趣区FA值比较
隐性梅毒患者的右侧额叶白质、双侧颞叶白质和右侧顶叶白质的部分各项异性(FA)值较对照组降低,两组差异有统计学意义(p<0.05)。在其他感兴趣区脑白质FA值两组差异无统计学意义。所有受检者不同兴趣区部分各向异性不同,从大到小的顺序是胼胝体压部、胼胝体膝部、锥体束、额叶白质、扣带束、颞叶白质、枕叶和顶叶白质。
3.3认知功能与脑白质改变相关性分析
双侧颞叶白质FA值与EBPM和AVLT得分呈正相关,左侧颞叶与EBPM得分正相关(r=0.451,p=0.010),与AVLT瞬时记忆得分正相关(r=0.439,p=0.011)；右侧颞叶与EBPM得分正相关(r=0.418,p=0.017),与AVLT瞬时记忆正相关(r=0.366,p=0.036),与AVLT延迟回忆正相关(r=0.383,p=0.028)。右侧额叶白质FA值与EBPM得分正相关(r=0.349,p=0.047)。
[结论]
1.血清固定的隐性梅毒患者EBPM和TBPM均受损,其受损是由于其前瞻性部分受损造成。
2.血清固定的隐性梅毒患者存在模糊决策能力障碍,社会问题解决能力损失。
3.决策能力受损与Stroop和AVLT延迟记忆有独立相关性,提示血清固定隐性梅毒患者的注意抑制和词语记忆在博弈试验中起一定的作用。
4.DTI能够发现常规MRI检查正常的脑白质微结构改变。
5.血清固定的隐性梅毒患者部分脑白质感兴趣区FA值下降,提示在血清固定的隐性梅毒患者虽然没有明显临床表现,但是已经出现了部分脑白质微结构的改变,主要在颞叶和额叶白质。DTI评估隐性梅毒患者脑白质微结构损害可能有助于重新认识隐性梅毒中的血清固定患者及病情监测。
6. EBPM与双侧颞叶和右额叶FA值相关,提示颞叶和额叶白质也可能参与了PM任务的完成。
(一)The sudy of serological response treatment of patients with late syphilis
[Background and Objective] Re-emergence of syphilis, a disease previously believed to be closed to eradication, is a matter of increasing global concern. With12million new cases a year worldwide, syphilis remains a global problem. According to WHO, more than90%of cases occur in developing countries. After standard antisyphilitic treatment, most patients can get resolution of clinical symptom and serological cure. Because of the widespread availability of antibiotic treatment and global challenge to antibiotic-resistant Treponema pallidum, neurosyphilis has gradually increased. Serological cure of early syphilis reach75%-100%after standard treatment. However, some previous studies have found a greater number of serological failures after treatment and a greater risk of developing complications, particularly neurosyphilis. It is widely believed that serological response of neurosyphilis is slower and worse than early syphilis. But there is little report about late syphilis. By prospective cohort design,the goal of our study is to analyse the characteristics of serum and CSF nontreponemal RPR titer; to compare of change of RPR titer after the treatment; to investigate factors affecting long-term prognosis; and to afford reference to the treatment and follow-up of late syphilis.
[Methods]
1Design methods Prospective Cohort study.
2Participants From Jan2006to Jan2012, all the patients with syphilis consecutively admitted to the wards of Guangzhou Brain Hospital or outpatients, were enrolled prospectively.
Inclusion criteria①diagnosis of late syphilis according to CDC;②never accept antisyphilis treatment;゛ll patients were informed consent.
Exclusion criteria①human immunodeficiency virus(HIV) antibody test (+);②the baseline serology showed a nonreactive RPR (-);③follow-up is inadequate to determine serological outcome of treatment, less than one year.
3Procedure Treatment according to standard anti syphilitic regimen according to the United States of America Centers for Disease Control and Prevention(CDC)2010guidelines. Patients returned for follow-up visit at2weeks or1month,6months and1year after treatment. All patients underwent lumbar puncture at baseline and1month, the lumbar puncture was repeated at6and1year only if the previous CSF profile was abnormal. Blood samples were obtained at all follow-up visit. MMSE were scored at pre-treatment and lyear after treatment.
4. Variables of interest and definitions
(1) The serological prognosis at1year after treatment:①Serological success/cure:refers to a4-fold decrease in the RPR titer or reversion to nonreactive by1year after baseline;②Serological failure:refers to a4-fold increase in the RPR, and no evidence of reinfection according to medical records;③Serological nonresponse or Serofast status:refers to increase or decrease no more than a2-fold from baseline.④The rate of seroreversion:refers to the property of number of patients of RPR reversion to negative.
(2) The serological outcome at the end of follow-up and time to serological treatment success:it was defined as the earliest date after treatment documenting a4-fold drop in RPR titers.
(3) Normalization of CSF-RPR test was defined as a4-fold decrease in titer or reversion of the test to nonreaction. Normalization of CSF WBC count was defined as a decrease from>10cell/uL to≤10/uL; and normalization of CSF protein concentration was defined as a decrease from>0.45g/L to≤0.45g/L.
(4) Sub-group analysis:MMSE scores at pre-treatment and1-year after treatment were compared between the serofast and serological success patients with symptomatic neurosyphilis.
5. Statistical Analysis Statistical test were conducted with SPSS version18.0software package. Student's t-test was used to compare differences in normally distributed continuous variables and Pearson's chi-squared test for categorical variables. Multivariate Logistic regression was used to analyse the factors related to prognosis at lyear. Cox proportional Harzard model was used to analyse the time to serological success during follow-up. Results were considered statistically significant at P<0.05(2-tailed).
[Results].
1. General Information
A total of172patients with late syphilis were included in the analysis. Most were male, accounting for73.8%. The mean age was (50.29±9.21) years. The median follow-up time was666.50days. Among those,138symptomatic neurosyphilis accounting for80.23%, and89.9%were men.10asymptomatic neurosyphilis accounting for5.82%, and80%were female;24late latent syphilis accounting for13.95%, and almost were female.
2. RPR titers pre-treatment
Median serum RPR titers pre-treatment of all the patients were1:8(interquartile range[IQR]1:4-1:32). Stratified by diagnosis, Median serum RPR titers of neurosyphilis (symptomatic and asymptomatic) were1:8and late latent syphilis were1:4. CSF-TPHA of neurosyphilis (including asymptomatic and symptomatic) was positive. Median CSF-RPR titers were1:2(IQR0-1:4).36.8%of patients with neurosyphilis had a negative CSF-RPR.
3. Variation of RPR titer within first month after syphilis therapy
Overall,32%of patients showed a serum RPR titer increase in the14days or1month after therapy. Only6.25%of patients showed a CSF-RPR titer increase,6.25%of patients reverted to negative of CSF-RPR within the first month after therapy, and70.3%remained unchanged.
4Prognosis at1year after treatment
172patients were followed for at least one year. At1year of these,95(55.2%) had serological success,3(1.7%) had serological failure, and74(43.0%) had serofast. Among those patients with symptomatic and asymptomatic neurosyphilis,52.7%had serological success,45.3%had serofast. Only21patients had seroreverted to negative in RPR, accounting for12.2%. The proportion of seroreverted to negative in RPR increased to16.1%at2years after treatment.
64neurosyphilis were repeated lumbar puncture at1year after treatment.28.1%of CSF protein concentration was also abnormal;90.6%of patients had seroreverted to negative in CSF-RPR at1year after treatment.
Sub-group analysis was conducted with the MMSE scores of thel38patients with symptomatic neurosyphilis. The MMSE scores at pre-treatment were both lower than normal between the serofast group and serological success group(t=0.429, P=0.669); At1year after treatment, both the MMSE scores of the two groups increased, but the patients with serofast were lower significantly than those with serological success (t=2.947,P=0.004).
5. Logistic regression analysis factors related to prognosis at1year
By multivariate Logistic regression analysis, the independent factors related to prognosis at1year were:pre-treatment CSF protein concentration (OR=0.275,95%CI0.124-0.608, P=0.001) and a rise in serum RPR titer within the first month (OR=0.394,95%CI0.185-0.841, P=0.016).
6. Cox survival analysis of reaction time
The estimated median time to treatment response was212.0days (IQR150.5-388.0) days. The independent factors associated with time to serological success were:higher baseline serum RPR titer(RR=1.193,95%CI1.061-1.341, P=0.003), CSF protein concentration(RR=0.513,95%CI0.343-0.770, P=0.001) and young age(RR=0.721,95%CI0.544-0.956, P=0.023).
[Conclusion]
1. Most of patients with neurosyphilis are36-59years old, the mean age is50years or so, and mostly neurosyphilis patients are male. While, latent syphilis patients are almost female. Female are more likely to be found the disorder selectively.
2. Pre-treatment syphilis titers of late syphilis are very low, and median RPR titer is1:8, especially for latent syphilis of unknown duration(1:2-1:4).
3.32%of patients show a serum RPR titer increase in the14days or1month after therapy. Only6.25%of patients show a CSF-RPR titer increase.55.2% had serological success,1.7%serological failure,and43.0%serofast at1year after treatment. Only12.2%of patients has seroreverted to negative in RPR,89.1%of the serum RPR titers couldn't revert to negative in patients with neurosyphilis.28.1%of CSF protein concentration was also abnormal;90.6%of patients had seroreverted to negative in CSF-RPR at1year after treatment.
4. The independent factors related to serological success are:baseline serum RPR titer, CSF protein concentration and age. The higher the baseline serum RPR titer, and the younger, the patients with late syphilis have the higher proportion of serological success. The higher of CSF protein concentration, the patients have the lower proportion of serological success.
5. Serological response of neurosyphilis is slower and worse than early syphilis.
6. Among the neurosyphilis patients with serofast, the cognitive function recover more slowly.
(二)The study of neurocognitive function and cerebral white matter micro-structure on patients with serum-resistant Latent Syphilis
[Background and objective] According to the first part of our study, the proportion of serofast on late neurosyphilis patients was quite high(45.3%). It was reported that latent syphilis patients (including early and late latent syphilis) was also rather high, about40.8%. Among those serofast patients,46.3%of them are impaired partly on central nervous system, cardiovascular and skeletal systems. So, the serofast latent syphilis should be paid more attention. Although current recommended therapeutic regimens remain highly effective for early syphilis, concerns have been raised because invasion of T.pallidum into central nervous system occurs in about40%of early syphilis. From report in the first part of our study, the cognitive function recovered more slowly among the neurosyphilis patients with serofast.There are little report about the cognitive function of patients with latent syphilis. During the chronic infection of syphilis,when and how to happen the impairment of cognition and the mechanism is still a hypothesis. In order to recognize the subtle cognitive impairment of chronic infection of syphilis as soon as possibly, we further explore cognition and cerebral white matter microstructure in serofast patients with latent syphilis. Our study selects the neurocognitive tools recognized internationally. Neuropsychological tests were conducted on patients with serofast latent syphilis, and normal control group with age, sex, years of education matched. combine with quantitative measurement of cerebral white matter by diffusion tensor magnetic resonance imaging to assess the integrity of white matter in vivo.The goal of our study is to investigate:1) the cognitive function of patients with serofast latent syphilis;2) the changes of cerebral white matter microstructure of patients with serofast latent syphilis;3) the relationship between the changes of cognitive function change and microstructural white matter.
[Methods]
1. Design methods Case-Control design.
2. Participants The patients group came from in-hospital or clinic patients of Guangzhou brain hospital from October2009to May2012. The controls group comprised of health volunteers and health spouse of syphilis.
Latent syphilis(LS) group:Serum treponema pallidum particle agglutination test (TPPA) and rapid plasma reagin (RPR) test was positive in patients with latent syphilis.(1) Inclusion criteria:①diagnosis of latent syphilis according to CDC;②age between25and70years, at least primary education and ability to understand the requirements of the study, volunteer to participate in this study;③HIV antibody test negative;④at least1year after standard treatment, the titer increase or decrease no more than a2-fold from baseline;⑤the Mini-Mental State Examination (MMSE) score>24.(2) Exclusion criteria:①evidence of clinical manifestations of nervous system;②used hormones and immune inhibitor in past3months;③accompanied with disease which can cause biological false positive;④history of mental illness, serious physical diseases, brain injury, alcohol or drug abuse;⑤hearing and vision impairment.
Healthy control(HC) group:serum TPPA test negative and without history of syphilis and psychiatric, neurological disorder approximately matched according to age,sex,and education level. Exclusion criteria were same to syphilis group.
3Task and Procedure
3.1General information:Socio-demographic and clinical factors were recorded, such as age, gender, education, occupation, present illness, past history,et al.
3.2Neuropsychological battery tests:Including MMSE, verbal fluency test (VFT), digital span test (DS), Stroop test, and auditory verbal learning test (AVLT).
3.3Prospective Memory study:Using the methods designed by Einstein and Wang K et al, including event-based prospective memory (EBPM) and time-based prospective memory (TBPM) performance.
3.4Decision-making under ambiguity cognitive function:Using the Iowa game task (IGT). Calculation the total number of cards chosen from a "safe" deck the number of cards chosen from a "safe" deck minus the number of cards chosen from a "risky" deck.
3.5Cerebral white-matter microstructure study:All MRI scans and diffusion tensor imaging (DTI) were acquired using the same GE3.0Tesla clinical scanner. Images were post-processed using a program of the Functool image analysis software on a AW4.4workstation. Fractional anisotropy (FA value) from various white matter regions on the DTI scan using regions of interest (ROIs). ROIs setting and measurement of FA values were performed by an experienced neuroradiologist blinded to the information of patients. ROIs selected as follows:frontal white matter, parietal white matter, temporal white matter, occipital white matter, genu and splenium of the corpus callosum, pyramidal tract, anterior cingulate bundle, posterior cingulate bundle region.
4. Statistical Analysis SPSS18.0software was used for statistical analysis. The chi-square test, Fisher's were used to compare independent proportions and the independent t test was used to compare mean values. Repeated measures ANOVAs was used to compare the numbers selected of different group and different time. Linear Logistic regression was used to analyse the factors related to the cognitive impairment. Results were considered statistically significant at P<0.05(2-tailed).
[Results]
1. Results of PM
1.1Socio-demographic data
The study included a sample of30patients with serofast Latent Syphilis and30healthy controls. Among the syphils group, the mean age was (48.83±11.37) years, and80.0%were female. The mean education was (9.67±3.46) years, mean MMSE scores (27.87±1.41). There were no significant differences between two groups in demographic data and general cognitive status (P>0.05).
1.2Neuropsychological battery tests
Compared with healthy controls, Latent syphilis perfomed worse on AVLT-lOmin (P<0.05). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate memory and VFT (P>0.05).
1.3EBPM and TBPM
Compared with Health controls ([EBPM]6.13±1.252,[TBPM]4.67±0.922), the patients with latent syphilis were significantly impaired in EBPM (4.33±2.057) as well as in TBPM (3.80±1.400)(t=-4.095, P<0.001; t=6.902, P<0.05). There were no significant difference in the retrospective component of PM (RM1and RM2) between the two groups (P>0.05).
2Results of IGT
2.1Socio-demographic data and Neuropsychological battery tests
There was no significant differences in demographic data and general cognitive status between26latent syphilis and21healthy controls. Latent syphilis group perfomed worse than the control group on AVLT-10min (P<0.05). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate memory and VFT (P>0.05).
2.2IGT tests
On the overall performation measure (decks [C+D] minus decks [A+B]),there was a significant difference between groups (tblock4=-4.102; tblock5=-5.060; P<0.001),with the latent syphilis group showing more risky performance compared to the health control group. Latent syphilis patients chosed more "risky" decks (55.538±7.996) than that of control group (47.143±7.683), the difference was statistically significant (t=3.641, P=0.001). Of course, syphilis patients chosed less "safe"decks (44.615±7.965) than that of the control group (52.571±7.379), there is statistical significance (t=-3.517, P=0.001).
2.3Correlation analysis between IGT scores and other cognitive function
To all subjects, there were independent correlations between the number chosen from "safe" deck and stroop performation (B=-0.332, P=0.016) and AVLT-10min memory scores (B=0.344, P=0.012) significantly.
3the results of DTI
3.1Socio-demographicdata and Neuropsychological battery tests
There were no significant differences in demographic data and general cognitive status between20latent syphilis patients and13healthy controls. Latent syphilis group perfomed worse than the control group on AVLT-recognition (P=0.022). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate and delay memory and VFT (P>0.05).
3.2FA value of the cerebral white matter
Compared with health control group, FA value of patients with latent syphilis showed a significant reduction in the right frontal white matter and bilateral temporal white matter and right parietal white matter (P<0.05). There was no significant difference between two groups of FA value in other ROIs.
3.3Correlation analysis between FA and other cognitive function
There were positive correlations between FAvalue of Bilateral temporal lobe white matter and EBPM and AVLT score. Among those, FA value of left temporal lobe was correlated with EBPM score (r=0.451, P=0.010), and AVLT (immediate memory) score (r=0.439, P=0.011); FAvalue of right temporal lobe was correlated with EBPM score (r=0.418, P=0.017), and the AVLT (immediate memory) score (r=0.366, p=0.036), and AVLT(delayed memory) score (r=0.383, P=0.028). There were positive correlations between FAvalue of right frontal white matter and EBPM score (r=0.349, P=0.047). All the correlations were significant (P<0.05).
[Conclusion]
1. Both EBPM and TBPM are imaged obviously in patients with serofast Latent Syphilis, due to the impairement of prospective part of PM.
2. Decision-making ability is impaired in patients with serofast Latent Syphilis, reflecting the partly loss of ability on solving social problem.
3. There is negative correlation between impaired decision-making and stroop.
4. DTI can find the changes of cerebral white matter microstructure of routine MRI examination was normal.
5. FA value of some brain white matter of patients with latent syphilis reduce, mainly in the temporal and frontal white matter. These findings suggest that DTI capture clinical relevant information regarding cognitive performation among patoents with serofast latent syphilis and suggests the importance of subtle white matter changes in examing cognitive performance.
6. There is significant relationship between EBPM and FA values of bilateral temporal and right frontal white matter.This findings suggest temporal and frontal lobe parcitipate in the perfomance of the PM task.
[背景和目的]近20年来梅毒再度死灰复燃,全球每年有1200万新发梅毒病例,超过90%的患者在发展中国家。梅毒患者确诊后按正规驱梅治疗,大部分能达到临床治愈和血清学治愈的效果。然而由于抗生素的广泛使用和耐药性的挑战,神经梅毒日益增多。治疗反应有相当大的差异。早期梅毒给予规范性治疗后,血清学有效反应约75%-100%。也有报道经治疗有效的早期梅毒仍然有部分患者进展为神经梅毒,普遍认为神经梅毒的治疗有效性不如早期梅毒。但是晚期梅毒的血清学相关报道极少。本课题对晚期梅毒患者进行了前瞻性队列研究,观察梅毒患者的血清学和脑脊液梅毒抗体滴度特征；比较梅毒治疗前后的改变情况；分析远期预后的影响因素。旨在为晚期梅毒的治疗和随访提供参考依据；也给及早根治早期梅毒提供依据。
[方法]
1.设计方法：采用前瞻性队列研究。
2.研究对象：资料来自于2006年1月-2012年1月期间连续性在广州市脑科医院住院或门诊诊治的梅毒患者。A：纳入标准：①符合美国CDC晚期梅毒的诊断标准；②既往从未驱梅治疗；③所有患者均知情同意。B：排除标准：①HIV抗体试验阳性；②基线RPR(-)③随访不充分,不到1年者。
3.治疗方法：所有患者诊断明确后根据美国CDC推荐的梅毒治疗方案进行规范驱梅治疗。
3.1随访治疗后定期复查TPPA和RPR试验滴度,分别于治疗前和治疗后2周或1个月、6个月和1年。1年以后每半年或一年复查一次。定期复查腰穿,测脑脊液(CSF)白细胞数、蛋白含量以及RPR滴度。在治疗前和治疗后1年时分别完成MMSE检测。
3.2观察指标
(1)1年时血清学反应,即治疗后1年的血清RPR滴度变化情况。①治疗有效/治愈(Serological success):血清RPR滴度比基线时下降4倍或4倍以上/RPR转(-)；②治疗失败(Serological failure):指的是血清RPR滴度比基线时上升4倍或4倍以上(在没有明确的再暴露史情况下)。③血清学无反应或血清固定(Serological nonresponse or serofast status):指的是血清RPR滴度比基线下降或上升2倍以内。④血清RPR转阴率：根据转阴的例数计算出转阴率。
(2)最终结局和治疗反应时间：在随访期间血清学反应结局(同上①②③)。并记录从治疗开始到治疗有效的时间,以天计算。
(3)脑脊液正常化：CSF-RPR滴度下降4倍或以上或转阴性；白细胞从≥10个/uL下降到<10个/uL; CSF-蛋白从≥0.45g/L下降到<0.45g/L。
(4)亚组分析：神经梅毒患者中血清固定和有效组治疗前后MMSE分值的比较。
3.3统计学处理采用SPSS18.0统计软件包进行数据的统计分析。定量资料采用均数±标准差(x±s)或中位数(四分位间距)[M(IQR)]表示：定性资料采用例数(n)和百分率(%)表示。两组之间的比较采用t检验,治疗前后比较采用配对t检验。采用多因素Logistic回归方程分析影响1年时结局的因素；有效时间的生存分析采用Cox比例风险分析；P<0.05有统计学意义。
[结果]
1一般资料
最后共纳入172例梅毒患者,男性127例,占73.8%。平均年龄(50.29±9.21)岁。所有患者随访中位天数是666.50天。其中有症状的神经梅毒138例(80.23%),89.9%是男性；无症状神经梅毒10例(5.82%),80%是女性；隐性梅毒24例(13.95%),几乎是女性(95.8%)。
2治疗前RPR分析
所有患者治疗前血清RPR中位滴度数1：8(IQR1:4-1:32)。神经梅毒(有症状和无症状)的血清RPR滴度为1：8,而隐性梅毒为1：4。神经梅毒(包括有症状和无症状)的CSF-TPHA均(+),RPR中位滴度数1：2(IQR0-1:4)。36.8%的神经梅毒CSF-RPR反应呈阴性。
31月内RPR滴度变化情况
治疗后1个月内有32.0%血清RPR滴度升高,以升高2倍为主。只有6.25%脑脊液RPR滴度升高,6.25%在治疗后1月内转阴,70.3%滴度不变。
4治疗后1年时预后
4.11年时血清学反应
1年时95例(55.2%)治疗有效／治愈；3例(1.7%)失败；74例(43.0%)血清固定。神经梅毒(有症状和无症状的)患者中,52.7%治疗有效,45.3%血清固定。1年时只有21例血清RPR转为阴性,转阴率12.2%。当继续随访至2年,血清RPR转阴率增加到16.1%。
4.2治疗1年时脑脊液变化情况
64例神经梅毒患者在1年时复查了腰穿。有18例(28.1%)脑脊液蛋白未正常化；1年后复查脑脊液RPR滴度有58例(90.6%)均呈阴性。
4.3有症状的神经梅毒患者治疗前后MMSE比较的亚组分析
138例有症状的神经梅毒中,1年时有63例(45.7%)血清学固定,72例(52.2%)血清学有效。两组之间治疗前MMSE评分无统计学差异(t=0.429,P=0.669)。经过治疗后1年两组患者MMSE均有一定程度改善(P<0.001)；但血清固定组改善程度更小,治疗1年时分值明显低于血清学有效组(t=2.947,P=0.004)。
4.4影响预后的多因素分析
多因素Logistic逐步回归分析结果显示：独立影响1年时血清学有效/治愈的有首次脑脊液蛋白含量(OR=0.241,95%CI0.122-0.475,P<0.001)和1月内血清滴度是否升高(OR=0.397,95%CI0.195-0.808,P=0.011)。首次CSF蛋白增高和1月内血清RPR滴度升高者,1年时血清学有效反应的可能性就越小。
4.5发生有效反应时间的Cox生存分析
治疗有效患者的中位天数212.0天(IQR150.5-388.0)天。独立影响血清学有效反应时间的因素是首次血清RPR滴度、首次CSF蛋白含量和年龄。首次血清RPR滴度每增加1倍,发生有效血清学反应的机会是1.193倍(RR=1.193,95%CI1.061-1.341,P=0.003),有统计学意义。也就是首次滴度越高者,滴度下降越快,越快达到有效反应。首次脑脊液蛋白含量超过0.45g/L的患者达到血清学有效反应的中位天数大于低于0.45g/L者,差异达统计学意义(RR=0.513,95%CI0.343-0.770,P=0.001)。年龄每增加1个阶段,发生有效血清学反应的机会是0.721倍(RR=0.721,95%CI0.544-0.956,P=0.023),有统计学意义。年龄越大,血RPR滴度下降越慢,越晚达到有效。
[结论]
1.神经梅毒患者年龄主要集中在36-59岁之间,平均在50岁左右,神经梅毒大多为男性患者；而隐性梅毒几乎是女性患者,女性更容易被选择性发现隐性梅毒。
2.神经梅毒和不明病期的隐性梅毒患者的治疗前血清RPR滴度均偏低,中位数为1：8,尤以不明病期的隐性梅毒更多仅1：2—1：4。
3.治疗后1月内有32.%患者血清RPR滴度上升；CSF-RPR滴度仅6.25%上升。1年时血清学有效／治愈率55.2%,失败1.7%,血清固定43.0%；神经梅毒(有症状和无症状的)患者中,52.7%治疗有效,45.3%血清固定。1年时血清RPR转阴率仅12.2%,神经梅毒有89.1%均不能转阴。部分患者复查脑脊液,71.9%脑脊液蛋白正常化,90.6%脑脊液RPR(-)。
4.独立影响血清学有效反应和时间的有：首次血清RPR滴度、首次脑脊液蛋白含量和年龄。血清RPR滴度越高、脑脊液蛋白正常和年纪更轻的RPR滴度下降更快,更容易达到有效/治愈。
5.和早期梅毒相比,晚期梅毒治疗1年的血清学有效率更低,发生血清固定更多,反应更慢。血清固定的神经梅毒患者认知功能恢复更慢,损害更明显。
(二)血清固定的隐性梅毒患者神经认知功能和脑白质微结构研究
[背景和目的]第一部分研究显示晚期神经梅毒的血清固定现象发生率高(45.3%),有报道隐性梅毒的血清固定发生率也高,约40.8%,而隐性梅毒中血清固定者约35%可出现病情复发,应引起高度重视。梅毒有40%在感染早期就可能侵入中枢神经系统。我们的研究中还提示血清固定在神经梅毒的认知功能可能有一定的影响,在血清固定的隐性梅毒长期潜伏过程中,是否也已经发生了难以察觉的认知功能损害?目前还处于假设与推测中。为了及早发现梅毒慢性感染过程中的认知损害,阻止发展到晚期神经梅毒,我们进一步探索性地对血清固定的隐性梅毒患者进行神经认知测验,选用目前国际上较为公认的认知工具。并设立与患者年龄、性别、教育年限相匹配的正常对照组进行了同样的神经认知测验,对其中部分自愿受试者完成了磁共振弥散张量成像(DTI),定量检测脑白质微结构改变,在活体评估白质的完整性。以明确：1)血清固定的隐性梅毒患者认知功能；2)血清固定的隐性梅毒脑白质微结构改变；3)认知功能改变与白质微结构改变的关系。
[方法]
1.设计方法采用病例-对照试验设计方法。
2.研究对象患者组均来自2009年10月至2012年5月广州市脑科医院住院或门诊患者。对照组来自于广州市脑科医院周边的社区健康志愿者及健康配偶。
隐性梅毒组：梅毒螺旋体明胶凝集试验(TPPA)和快速血浆反应素(RPR)试验阳性的隐性梅毒患者。A纳入标准：①符合美国CDC潜伏梅毒的诊断标准；②年龄25-70岁,小学毕业以上文化,志愿参加本研究；③就诊前HIV抗体试验呈阴性；④无梅毒的临床表现：无明显的神经系统症状和体征；⑤接受正规梅毒治疗后1年的血清RPR滴度比基线变化在2倍以内；⑥简易精神状态量表(MMSE)评分>24分。B排除标准①有神经系统临床表现；②近3月内用过激素及免疫抑制剂；③伴有可致生物学假阳性的急、慢性疾病,如结核、麻风病,结缔组织疾病,及肿瘤者；④患有脑器质性疾病(如脑外伤、脑血管疾病、多发性硬化、痴呆、癫痫等)、内分泌或代谢性疾病(如甲状腺功能减退、糖尿病等)；明显躯体疾病、酒精或药物滥用者；⑤有视听力障碍影响测试者；⑥无法完成磁共振检查者(体内有金属植入物或有幽闭恐惧症等)--针对行弥散张量磁共振检查者。
健康对照组：经血清检测TPPA阴性且询问病史和体格检查后的健康者。A纳入标准：①年龄25-70岁,小学毕业以上文化,志愿参加本研究；②血清检测TPPA、RPR、HIV抗体阴性； B排除标准：同病例组。
3.研究方法
3.1一般资料：详细记录患者的一般资料,如年龄、性别、教育年限、职业、现病史、既往史。
3.2神经心理学背景测试：包括简易精神状态量表(Mini-Mental State Examination, MMSE)、词汇流畅性试验(verbal fluency test, VFT)、数字广度试验(Digital Span, DS)、Stroop测验、听觉词汇学习测验(auditory vocabulary learning test, AVLT)。
3.3前瞻性记忆(prospective memory, PM)研究：采用Einstein和汪凯等人设计的前瞻性记忆检查方法,分别测查基于事件的前瞻性记忆(event-based prospective memory, EBPM)和基于时间的前瞻性记忆(time-based prospective memory, TBPM)成绩。
3.4模糊决策认知研究：采用爱荷华博弈实验(Iowa Gambling Task, IGT)。记录受试者总有利选择数,每阶段有利选择数。计算每个阶段(有利选择—不利选择)的差值。
3.5脑白质微结构研究：使用GE3.0T MR仪行头颅常规MRI检查和弥散张量成像(DTI)。在工作站上运用Functool软件包进行图像后处理,测量不同感兴趣区白质纤维的各向异性(FA)值。分别在额叶白质、顶叶白质、颞叶白质、枕叶白质、胼胝体膝部和压部、锥体束、前扣带束、后扣带束区域左右对称部位选取感兴趣区(ROI)。
3.6统计学处理：采用SPSS18.0软件包进行统计分析。定量资料采用均数±标准差(x±s)或中位数(四分位间距)[M(IQR)]表示；定性资料采用例数(n)和百分率(%)表示。两组之间的比较采用t检验或x2检验,不同组别不同时间点的比较采用重复测量方差分析(repeated measures ANOVAs).相关分析采用线性Logistic回归分析。以P<0.05为差异有统计学意义。
[结果]
1.PM测试结果
1.1一般资料
本研究共纳入隐性梅毒患者30例,男性6例(20%)。平均年龄(48.83±11.37)岁,平均受教育年限(9.67±3.46)年；MMSE平均(27.87±1.41)分。对照组30例,两组在年龄、性别、受教育年数和MMSE评分的差异均无统计学意义(P>0.05)。
1.2隐性梅毒和对照组神经心理学背景测试结果
和正常对照组相比,隐性梅毒组仅有AVLT-延迟10分钟成绩更差,差异有统计学意义(p<0.05)。其余的测试DS.stroop字色测试、VFT.AVLT6即刻回忆和延迟5分钟回忆及再认差异无统计学意义(P>0.05)。
1.3隐性梅毒和对照组PM测试结果
与健康对照组相比(EBPM,6.13±1.252；TBPM,4.67±0.922)相比,隐性梅毒组的EBPM(4.33±2.057)和TBPM(3.80±1.400)均较对照组差(t=-4.095,p<0.001；t=6.902,p<0.05)。PM中的回溯成分,两组的RM1和RM2均无显著性差异(P>0.05)。
2.IGT测试结果
2.1一般资料
纳入PM研究的受试者中有47例同时完成了该测试,其中隐性梅毒患者26例,对照组21例。两组在年龄、性别、受教育年数和MMSE评分的差异均无统计学意义(P>0.05)。隐性梅毒组的AVLT延迟回忆成绩比对照组差(p<0.05)。DS、stroop、AVLT即刻回忆、VFT的差异无统计学意义(P>0.05)。
2.2隐性梅毒和对照组IGT测试结果
隐性梅毒组100次测试总不利备选数(55.538±7.996)明显多于对照组(47.143±7.683),差异达统计学意义(t=-3.641,P=0.001)；而有利备选数(44.615±7.965)明显少于对照组(52.571±7.379),有统计学意义(t=-3.517,p=0.001)。经重复测量方差分析,结果显示组间差异有显著性(F=11.114,P=0.03)；每组先后各阶段间差异有显著性(F=3.813,P=0.017；F=15.074,P<0.001)；组别与时间之间存在交互效应(F=18.424,P<0.001),提示两组受试者随时间的增加选择次数的增加,都有学习效应。进一步分析单独效应,结果显示各阶段内两组间比较在试验的初期无显著性(P>0.05),随着时间的推移,逐渐表现出两组在选择的显著性差异(P61-80,81-100<0.001)。隐性梅毒组的有利选择趋势不如正常对照组。
2.3IGT成绩与各认知功能相关性分析
所有受试者总选择有利备选数与Stroop呈负相关(r=-0.332,P=0.016),与AVLT延迟10min回忆得分呈正相关(r=0.344,P=0.012),均达统计学意义。
3.DTI检查结果
3.1一般资料
完成了PM测试的部分受试者在自愿情况下接受了DTI检查,其中隐性梅毒患者20例,对照组13例,两组在年龄、性别、受教育年数和MMSE评分的差异均无统计学意义(P>0.05)。隐性梅毒组除了AVLT回忆再认成绩差于对照组且达统计学意义(p=0.022)以外,其余心理学背景测试差异均无统计学意义(P>0.05)。
3.2隐性梅毒和对照组脑白质感兴趣区FA值比较
隐性梅毒患者的右侧额叶白质、双侧颞叶白质和右侧顶叶白质的部分各项异性(FA)值较对照组降低,两组差异有统计学意义(p<0.05)。在其他感兴趣区脑白质FA值两组差异无统计学意义。所有受检者不同兴趣区部分各向异性不同,从大到小的顺序是胼胝体压部、胼胝体膝部、锥体束、额叶白质、扣带束、颞叶白质、枕叶和顶叶白质。
3.3认知功能与脑白质改变相关性分析
双侧颞叶白质FA值与EBPM和AVLT得分呈正相关,左侧颞叶与EBPM得分正相关(r=0.451,p=0.010),与AVLT瞬时记忆得分正相关(r=0.439,p=0.011)；右侧颞叶与EBPM得分正相关(r=0.418,p=0.017),与AVLT瞬时记忆正相关(r=0.366,p=0.036),与AVLT延迟回忆正相关(r=0.383,p=0.028)。右侧额叶白质FA值与EBPM得分正相关(r=0.349,p=0.047)。
[结论]
1.血清固定的隐性梅毒患者EBPM和TBPM均受损,其受损是由于其前瞻性部分受损造成。
2.血清固定的隐性梅毒患者存在模糊决策能力障碍,社会问题解决能力损失。
3.决策能力受损与Stroop和AVLT延迟记忆有独立相关性,提示血清固定隐性梅毒患者的注意抑制和词语记忆在博弈试验中起一定的作用。
4.DTI能够发现常规MRI检查正常的脑白质微结构改变。
5.血清固定的隐性梅毒患者部分脑白质感兴趣区FA值下降,提示在血清固定的隐性梅毒患者虽然没有明显临床表现,但是已经出现了部分脑白质微结构的改变,主要在颞叶和额叶白质。DTI评估隐性梅毒患者脑白质微结构损害可能有助于重新认识隐性梅毒中的血清固定患者及病情监测。
6. EBPM与双侧颞叶和右额叶FA值相关,提示颞叶和额叶白质也可能参与了PM任务的完成。
(一)The sudy of serological response treatment of patients with late syphilis
[Background and Objective] Re-emergence of syphilis, a disease previously believed to be closed to eradication, is a matter of increasing global concern. With12million new cases a year worldwide, syphilis remains a global problem. According to WHO, more than90%of cases occur in developing countries. After standard antisyphilitic treatment, most patients can get resolution of clinical symptom and serological cure. Because of the widespread availability of antibiotic treatment and global challenge to antibiotic-resistant Treponema pallidum, neurosyphilis has gradually increased. Serological cure of early syphilis reach75%-100%after standard treatment. However, some previous studies have found a greater number of serological failures after treatment and a greater risk of developing complications, particularly neurosyphilis. It is widely believed that serological response of neurosyphilis is slower and worse than early syphilis. But there is little report about late syphilis. By prospective cohort design,the goal of our study is to analyse the characteristics of serum and CSF nontreponemal RPR titer; to compare of change of RPR titer after the treatment; to investigate factors affecting long-term prognosis; and to afford reference to the treatment and follow-up of late syphilis.
[Methods]
1Design methods Prospective Cohort study.
2Participants From Jan2006to Jan2012, all the patients with syphilis consecutively admitted to the wards of Guangzhou Brain Hospital or outpatients, were enrolled prospectively.
Inclusion criteria①diagnosis of late syphilis according to CDC;②never accept antisyphilis treatment;゛ll patients were informed consent.
Exclusion criteria①human immunodeficiency virus(HIV) antibody test (+);②the baseline serology showed a nonreactive RPR (-);③follow-up is inadequate to determine serological outcome of treatment, less than one year.
3Procedure Treatment according to standard anti syphilitic regimen according to the United States of America Centers for Disease Control and Prevention(CDC)2010guidelines. Patients returned for follow-up visit at2weeks or1month,6months and1year after treatment. All patients underwent lumbar puncture at baseline and1month, the lumbar puncture was repeated at6and1year only if the previous CSF profile was abnormal. Blood samples were obtained at all follow-up visit. MMSE were scored at pre-treatment and lyear after treatment.
4. Variables of interest and definitions
(1) The serological prognosis at1year after treatment:①Serological success/cure:refers to a4-fold decrease in the RPR titer or reversion to nonreactive by1year after baseline;②Serological failure:refers to a4-fold increase in the RPR, and no evidence of reinfection according to medical records;③Serological nonresponse or Serofast status:refers to increase or decrease no more than a2-fold from baseline.④The rate of seroreversion:refers to the property of number of patients of RPR reversion to negative.
(2) The serological outcome at the end of follow-up and time to serological treatment success:it was defined as the earliest date after treatment documenting a4-fold drop in RPR titers.
(3) Normalization of CSF-RPR test was defined as a4-fold decrease in titer or reversion of the test to nonreaction. Normalization of CSF WBC count was defined as a decrease from>10cell/uL to≤10/uL; and normalization of CSF protein concentration was defined as a decrease from>0.45g/L to≤0.45g/L.
(4) Sub-group analysis:MMSE scores at pre-treatment and1-year after treatment were compared between the serofast and serological success patients with symptomatic neurosyphilis.
5. Statistical Analysis Statistical test were conducted with SPSS version18.0software package. Student's t-test was used to compare differences in normally distributed continuous variables and Pearson's chi-squared test for categorical variables. Multivariate Logistic regression was used to analyse the factors related to prognosis at lyear. Cox proportional Harzard model was used to analyse the time to serological success during follow-up. Results were considered statistically significant at P<0.05(2-tailed).
[Results].
1. General Information
A total of172patients with late syphilis were included in the analysis. Most were male, accounting for73.8%. The mean age was (50.29±9.21) years. The median follow-up time was666.50days. Among those,138symptomatic neurosyphilis accounting for80.23%, and89.9%were men.10asymptomatic neurosyphilis accounting for5.82%, and80%were female;24late latent syphilis accounting for13.95%, and almost were female.
2. RPR titers pre-treatment
Median serum RPR titers pre-treatment of all the patients were1:8(interquartile range[IQR]1:4-1:32). Stratified by diagnosis, Median serum RPR titers of neurosyphilis (symptomatic and asymptomatic) were1:8and late latent syphilis were1:4. CSF-TPHA of neurosyphilis (including asymptomatic and symptomatic) was positive. Median CSF-RPR titers were1:2(IQR0-1:4).36.8%of patients with neurosyphilis had a negative CSF-RPR.
3. Variation of RPR titer within first month after syphilis therapy
Overall,32%of patients showed a serum RPR titer increase in the14days or1month after therapy. Only6.25%of patients showed a CSF-RPR titer increase,6.25%of patients reverted to negative of CSF-RPR within the first month after therapy, and70.3%remained unchanged.
4Prognosis at1year after treatment
172patients were followed for at least one year. At1year of these,95(55.2%) had serological success,3(1.7%) had serological failure, and74(43.0%) had serofast. Among those patients with symptomatic and asymptomatic neurosyphilis,52.7%had serological success,45.3%had serofast. Only21patients had seroreverted to negative in RPR, accounting for12.2%. The proportion of seroreverted to negative in RPR increased to16.1%at2years after treatment.
64neurosyphilis were repeated lumbar puncture at1year after treatment.28.1%of CSF protein concentration was also abnormal;90.6%of patients had seroreverted to negative in CSF-RPR at1year after treatment.
Sub-group analysis was conducted with the MMSE scores of thel38patients with symptomatic neurosyphilis. The MMSE scores at pre-treatment were both lower than normal between the serofast group and serological success group(t=0.429, P=0.669); At1year after treatment, both the MMSE scores of the two groups increased, but the patients with serofast were lower significantly than those with serological success (t=2.947,P=0.004).
5. Logistic regression analysis factors related to prognosis at1year
By multivariate Logistic regression analysis, the independent factors related to prognosis at1year were:pre-treatment CSF protein concentration (OR=0.275,95%CI0.124-0.608, P=0.001) and a rise in serum RPR titer within the first month (OR=0.394,95%CI0.185-0.841, P=0.016).
6. Cox survival analysis of reaction time
The estimated median time to treatment response was212.0days (IQR150.5-388.0) days. The independent factors associated with time to serological success were:higher baseline serum RPR titer(RR=1.193,95%CI1.061-1.341, P=0.003), CSF protein concentration(RR=0.513,95%CI0.343-0.770, P=0.001) and young age(RR=0.721,95%CI0.544-0.956, P=0.023).
[Conclusion]
1. Most of patients with neurosyphilis are36-59years old, the mean age is50years or so, and mostly neurosyphilis patients are male. While, latent syphilis patients are almost female. Female are more likely to be found the disorder selectively.
2. Pre-treatment syphilis titers of late syphilis are very low, and median RPR titer is1:8, especially for latent syphilis of unknown duration(1:2-1:4).
3.32%of patients show a serum RPR titer increase in the14days or1month after therapy. Only6.25%of patients show a CSF-RPR titer increase.55.2% had serological success,1.7%serological failure,and43.0%serofast at1year after treatment. Only12.2%of patients has seroreverted to negative in RPR,89.1%of the serum RPR titers couldn't revert to negative in patients with neurosyphilis.28.1%of CSF protein concentration was also abnormal;90.6%of patients had seroreverted to negative in CSF-RPR at1year after treatment.
4. The independent factors related to serological success are:baseline serum RPR titer, CSF protein concentration and age. The higher the baseline serum RPR titer, and the younger, the patients with late syphilis have the higher proportion of serological success. The higher of CSF protein concentration, the patients have the lower proportion of serological success.
5. Serological response of neurosyphilis is slower and worse than early syphilis.
6. Among the neurosyphilis patients with serofast, the cognitive function recover more slowly.
(二)The study of neurocognitive function and cerebral white matter micro-structure on patients with serum-resistant Latent Syphilis
[Background and objective] According to the first part of our study, the proportion of serofast on late neurosyphilis patients was quite high(45.3%). It was reported that latent syphilis patients (including early and late latent syphilis) was also rather high, about40.8%. Among those serofast patients,46.3%of them are impaired partly on central nervous system, cardiovascular and skeletal systems. So, the serofast latent syphilis should be paid more attention. Although current recommended therapeutic regimens remain highly effective for early syphilis, concerns have been raised because invasion of T.pallidum into central nervous system occurs in about40%of early syphilis. From report in the first part of our study, the cognitive function recovered more slowly among the neurosyphilis patients with serofast.There are little report about the cognitive function of patients with latent syphilis. During the chronic infection of syphilis,when and how to happen the impairment of cognition and the mechanism is still a hypothesis. In order to recognize the subtle cognitive impairment of chronic infection of syphilis as soon as possibly, we further explore cognition and cerebral white matter microstructure in serofast patients with latent syphilis. Our study selects the neurocognitive tools recognized internationally. Neuropsychological tests were conducted on patients with serofast latent syphilis, and normal control group with age, sex, years of education matched. combine with quantitative measurement of cerebral white matter by diffusion tensor magnetic resonance imaging to assess the integrity of white matter in vivo.The goal of our study is to investigate:1) the cognitive function of patients with serofast latent syphilis;2) the changes of cerebral white matter microstructure of patients with serofast latent syphilis;3) the relationship between the changes of cognitive function change and microstructural white matter.
[Methods]
1. Design methods Case-Control design.
2. Participants The patients group came from in-hospital or clinic patients of Guangzhou brain hospital from October2009to May2012. The controls group comprised of health volunteers and health spouse of syphilis.
Latent syphilis(LS) group:Serum treponema pallidum particle agglutination test (TPPA) and rapid plasma reagin (RPR) test was positive in patients with latent syphilis.(1) Inclusion criteria:①diagnosis of latent syphilis according to CDC;②age between25and70years, at least primary education and ability to understand the requirements of the study, volunteer to participate in this study;③HIV antibody test negative;④at least1year after standard treatment, the titer increase or decrease no more than a2-fold from baseline;⑤the Mini-Mental State Examination (MMSE) score>24.(2) Exclusion criteria:①evidence of clinical manifestations of nervous system;②used hormones and immune inhibitor in past3months;③accompanied with disease which can cause biological false positive;④history of mental illness, serious physical diseases, brain injury, alcohol or drug abuse;⑤hearing and vision impairment.
Healthy control(HC) group:serum TPPA test negative and without history of syphilis and psychiatric, neurological disorder approximately matched according to age,sex,and education level. Exclusion criteria were same to syphilis group.
3Task and Procedure
3.1General information:Socio-demographic and clinical factors were recorded, such as age, gender, education, occupation, present illness, past history,et al.
3.2Neuropsychological battery tests:Including MMSE, verbal fluency test (VFT), digital span test (DS), Stroop test, and auditory verbal learning test (AVLT).
3.3Prospective Memory study:Using the methods designed by Einstein and Wang K et al, including event-based prospective memory (EBPM) and time-based prospective memory (TBPM) performance.
3.4Decision-making under ambiguity cognitive function:Using the Iowa game task (IGT). Calculation the total number of cards chosen from a "safe" deck the number of cards chosen from a "safe" deck minus the number of cards chosen from a "risky" deck.
3.5Cerebral white-matter microstructure study:All MRI scans and diffusion tensor imaging (DTI) were acquired using the same GE3.0Tesla clinical scanner. Images were post-processed using a program of the Functool image analysis software on a AW4.4workstation. Fractional anisotropy (FA value) from various white matter regions on the DTI scan using regions of interest (ROIs). ROIs setting and measurement of FA values were performed by an experienced neuroradiologist blinded to the information of patients. ROIs selected as follows:frontal white matter, parietal white matter, temporal white matter, occipital white matter, genu and splenium of the corpus callosum, pyramidal tract, anterior cingulate bundle, posterior cingulate bundle region.
4. Statistical Analysis SPSS18.0software was used for statistical analysis. The chi-square test, Fisher's were used to compare independent proportions and the independent t test was used to compare mean values. Repeated measures ANOVAs was used to compare the numbers selected of different group and different time. Linear Logistic regression was used to analyse the factors related to the cognitive impairment. Results were considered statistically significant at P<0.05(2-tailed).
[Results]
1. Results of PM
1.1Socio-demographic data
The study included a sample of30patients with serofast Latent Syphilis and30healthy controls. Among the syphils group, the mean age was (48.83±11.37) years, and80.0%were female. The mean education was (9.67±3.46) years, mean MMSE scores (27.87±1.41). There were no significant differences between two groups in demographic data and general cognitive status (P>0.05).
1.2Neuropsychological battery tests
Compared with healthy controls, Latent syphilis perfomed worse on AVLT-lOmin (P<0.05). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate memory and VFT (P>0.05).
1.3EBPM and TBPM
Compared with Health controls ([EBPM]6.13±1.252,[TBPM]4.67±0.922), the patients with latent syphilis were significantly impaired in EBPM (4.33±2.057) as well as in TBPM (3.80±1.400)(t=-4.095, P<0.001; t=6.902, P<0.05). There were no significant difference in the retrospective component of PM (RM1and RM2) between the two groups (P>0.05).
2Results of IGT
2.1Socio-demographic data and Neuropsychological battery tests
There was no significant differences in demographic data and general cognitive status between26latent syphilis and21healthy controls. Latent syphilis group perfomed worse than the control group on AVLT-10min (P<0.05). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate memory and VFT (P>0.05).
2.2IGT tests
On the overall performation measure (decks [C+D] minus decks [A+B]),there was a significant difference between groups (tblock4=-4.102; tblock5=-5.060; P<0.001),with the latent syphilis group showing more risky performance compared to the health control group. Latent syphilis patients chosed more "risky" decks (55.538±7.996) than that of control group (47.143±7.683), the difference was statistically significant (t=3.641, P=0.001). Of course, syphilis patients chosed less "safe"decks (44.615±7.965) than that of the control group (52.571±7.379), there is statistical significance (t=-3.517, P=0.001).
2.3Correlation analysis between IGT scores and other cognitive function
To all subjects, there were independent correlations between the number chosen from "safe" deck and stroop performation (B=-0.332, P=0.016) and AVLT-10min memory scores (B=0.344, P=0.012) significantly.
3the results of DTI
3.1Socio-demographicdata and Neuropsychological battery tests
There were no significant differences in demographic data and general cognitive status between20latent syphilis patients and13healthy controls. Latent syphilis group perfomed worse than the control group on AVLT-recognition (P=0.022). There were no significant differences on most of the other tests, such as DS, Stroop, AVLT immediate and delay memory and VFT (P>0.05).
3.2FA value of the cerebral white matter
Compared with health control group, FA value of patients with latent syphilis showed a significant reduction in the right frontal white matter and bilateral temporal white matter and right parietal white matter (P<0.05). There was no significant difference between two groups of FA value in other ROIs.
3.3Correlation analysis between FA and other cognitive function
There were positive correlations between FAvalue of Bilateral temporal lobe white matter and EBPM and AVLT score. Among those, FA value of left temporal lobe was correlated with EBPM score (r=0.451, P=0.010), and AVLT (immediate memory) score (r=0.439, P=0.011); FAvalue of right temporal lobe was correlated with EBPM score (r=0.418, P=0.017), and the AVLT (immediate memory) score (r=0.366, p=0.036), and AVLT(delayed memory) score (r=0.383, P=0.028). There were positive correlations between FAvalue of right frontal white matter and EBPM score (r=0.349, P=0.047). All the correlations were significant (P<0.05).
[Conclusion]
1. Both EBPM and TBPM are imaged obviously in patients with serofast Latent Syphilis, due to the impairement of prospective part of PM.
2. Decision-making ability is impaired in patients with serofast Latent Syphilis, reflecting the partly loss of ability on solving social problem.
3. There is negative correlation between impaired decision-making and stroop.
4. DTI can find the changes of cerebral white matter microstructure of routine MRI examination was normal.
5. FA value of some brain white matter of patients with latent syphilis reduce, mainly in the temporal and frontal white matter. These findings suggest that DTI capture clinical relevant information regarding cognitive performation among patoents with serofast latent syphilis and suggests the importance of subtle white matter changes in examing cognitive performance.
6. There is significant relationship between EBPM and FA values of bilateral temporal and right frontal white matter.This findings suggest temporal and frontal lobe parcitipate in the perfomance of the PM task.
引文
[1]Cohen MS, Henderson GE, Aiello P,et al. Successful eradication of sexually transmitted diseases in the People's Republic of China:implications for the 21st century[J]. J Infect Dis,1996,174(S2):223-229.
[2]Chen XS, Gong XD, Liang GJ, et al. Epidemiologic trends of sexually transmitted diseases in China[J]. Sex Transm Dis,2000,27(3):138-142.
[3]Beyrer C. Hidden epidemic of sexually transmitted diseases in China:crisis and opportunity[J]. JAMA,2003,289(10):1303-1305.
[4]Knaute DF, Graf N, Lautenschlager S, et al. Serological response to treatment of syphilis according to disease stage and HIV status [J]. Clin infect Dis, 2012,55 (12):1615-1622.
[5]柯吴坚,车雅敏,刘原君等。性病门诊性传播疾病病原体感染情况调查[J]。天津医科大学学报,2010,4：655-658.
[6]Wang QQ, Chen XS, Yin YP, et al. HIV/STD pattern and its associated risk factors among male STD clinic attendees in China:a foci for HIV intervention[J]. BMC Public Health,2011,11:955.
[7]龚向东,叶顺章,张君炎等.1999-2001年我国性病流行病学分析[J].中华皮肤科杂志,2002,35(3)：178-182.
[8]Hook EW. A syphilis wish list-better data, better tests[J]. Clin infect Dis,2012, 55(12):1623-1624.
[9]Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines:2010[J]. MMWR,2010,59(RR-12):1-110.
[10]World Health Organization. Sexually transmitted infections management guidelines 2012. Geneva:WHO,2012[http://www.who.int/HIV_AIDS
[11]Hayes R, Watson-Jones D, Celum C, et al. Treatment of sexually transmitted infections for HIV prevention:End of the road or new beginning[J]? AIDS 2010,24(s4):15-26.
[12]Lukehart SA, Hook EW, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum:implications for diagnosis and treatment[J]. Ann Intern Med,1988,109(11):855-862.
[13]Ducas J, Robson HG. Cerebrospinal fluid penicillin levels during therapy for latent syphilis[J]. JAMA,1981,246(22):2583-2584.
[14]Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis:association with clinical and laboratory features[J]. J Infect Dis,2004,189(3):369-376.
[15]龙振华.实用梅毒病学[M].北京：北京科学技术出版社,2009,56-57.
[16]Holman KM, Wolff M, Sena AC, et al. Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy[J]. Sex Transm Dis,2012,39 (8):645-647.
[17]Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals [J]. Clin Infect Dis,2000,30(3): 540-544.
[18]Bai ZG, Yang KH, Liu YL,et al. Azithromycin vs. benzathine penicillin G for early syphilis:a meta- analysis of randomized clinical trials[J]. Int J STD AIDS,2008,19(4):217-221.
[19]Sena AC, Wolff M, Martin DH, et al. Predictors of Serological Cure and Serofast StateAfter Treatment in HIV-Negative Persons With Early Syphilis[J]. Clin Infect Dis,2011,53(11):1092-1099.
[20]Gonzalez-Lopez JJ, Fernandez Guerre ML, Lujan R,et al. Factors determining serologic response to treatment in patients with syphili[J]. Clin Infect Dis,2009, 49(10):1505-1511.
[21]Marra CM, Longstreth WT Jr, Maxwell CL,et al. Resolution of serum and cerebro-spinal fluid abnormalities after treatment of neurosyphilis:influence of concomitant human immunodeficiency virus infection[J]. Sex Transm Dis, 1996,23(3):184-189.
[1]Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines:2010[J].MMWR,2010,59(RR-12):1-110.
[2]Stoner, BP. Current controversies in the management of adult syphilis[J].Clin Infect Dis,2007,44(S3):S130-146.
[3]Stamm LV. Global challenge of antibiotic-resistant treponema pallidum[J]. Antimicrob Agents Chemother,2010,54(2):583-589.
[4]Bai ZG, Yang KH, Liu YL,et al. Azithromycin vs. benzathine penicillin G for early syphilis:a meta- analysis of randomized clinical trials[J]. Int J STD AIDS,2008,19(4):217-221.
[5]Ison CA. Antimicrobial resistance in sexually transmitted infections in the developed world:implications for rational treatment[J]. Curr Opin Infect Dis, 2012,25(1):73-78.
[6]Ghanem KG, Erbelding EJ, Cheng WW,et al. Doxycycline compared with benzathine penicillin for treatment of early syphilis[J]. Clin Infect Dis,2006, 42 (6):e45-49.
[7]Wong T, Singh AE, De P. Primary syphilis:serological treatment response to doxycycline/tetracycline versus benzathine penicillin[J]. Am J Med,2008,121 (10):903-908.
[8]Mitchell SJ, Engelman J, Kent CK,et al. Azithromycin-resistant syphilis infection:San Francisco, California,2000-2004[J]. Clin Infect Dis,2006,42 (3):337-345.
[9]Rekart M L, Patrick DM, Chakraborty B,et al. Targeted mass treatment for syphilis with oral azithromycin[J]. Lancet,2003,361(9354):313-314.
[10]Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group[J]. N Engl J Med,1997,337 (5):307-314.
[11]Myint M, Bashiri H,Harrington RD,et al. Relapse of secondary syphilis after benzathine penicillin G. Molecular analysis[J]. Sex Transm Dis,2004,31(3): 196-199.
[12]Marra CM, Maxwell CL,Tantalo LC,et al. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis[J]. Clin Infect Dis,2008,47(7): 893-899.
[13]Sena AC, Wolff M, Martin DH, et al. Predictors of serological cure and serofast State after treatment in HIV-negative persons with early syphilis[J]. Clin Infect Dis,2011,53(11):1092-1099.
[14]Gordon S, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high- dose intravenous penicillin G in patients with human immunodeficiency virus infection[J]. N Engl J Med,1994,331(22):1469-1473.
[15]Walter T, Lebouche B, Miailhes P,et al. Symptomatic relapse of neurologic syphilis after benzathine penicillin G therapy for primary or secondary syphilis in HIV-infected patients[J]. Clin Infect Dis,2006,43(6):787-790.
[16]Zhou P, Gu X, Lu H,et al.Re-evaluation of serological criteria for early syphilis treatment efficacy:progression to neurosyphilis despite therapy [J]. Sex Transm Infect,2012,88(5):342-345.
[17]Lukehart SA, Hook EW, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum:implications for diagnosis and treatment[J]. Ann Intern Med,1988,109(11):855-862.
[18]Ghanem KG, Erbelding EJ, Wiener ZS.Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases[J].Sex Transm Infect,2007,83(2):97-101.
[19]Spornraft-Ragaller P, Abraham S, Lueck C,et al. Response of HIV-infected patients with syphilis to therapy with penicillin or intravenous ceftriaxone[J]. Eur J Med Res,2011,16(2):47-51.
[20]Douglas JM Jr. Penicillin treatment of syphilis-clearing away the shadow on the land[J]. JAMA,2009,301(7):769-771.
[21]Fowler VG Jr, Maxwell GL,Myers SA,et al. Failure of benzathine penicillin in a case of seronegative secondary syphilis in a patient with acquired immunodeficiency syndrome:case report and review of the literature[J]. Arch Dermatol,2001,137 (10):1374-1376.
[22]Gonzalez-Lopez JJ, Fernandez Guerre ML, Lujan R,et al. Factors determining serologic response to treatment in patients with syphili[J]. Clin Infect Dis,2009, 49(10):1505-1511.
[23]Holman KM, Mark Wolff M, Sena AC, et al.Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy[J]. Sex Transm Dis,2012,39(8): 645-647.
[24]Dowell ME, Ross PG, Musher DM, et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus[J]. Am J Med,1992,93(5):481-488.
[25]Marra CM, Longstreth WT Jr, Maxwell CL,et al. Resolution of serum and cerebro- spinal fluid abnormalities after treatment of neurosyphilis:influence of concomitant human immunodeficiency virus infection[J]. Sex Transm Dis, 1996,23(3):184-189.
[26]Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals[J]. Clin Infect Dis,2000,30(3): 540-544.
[27]Horberg MA, Ranatunga DK, Quesenberry C, et al.Syphilis epidemiology and clinical outcomes in HIV-infected and HIVuninfected patients in Kaiser Permanente Northern California[J]. SexTransm Dis,2010,37(1):53-58.
[28]Marra CM, Tantalo LC, Maxwell CL, et al. The rapid plasma regain test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis. Sex Transm Dis,2012,39(6):453-457.
[29]Samoff E, Koumans EH, Gibson JJ,et al. Pre-treatment syphilis titers: distribution and evaluation of their use to distinguish early from late latent syphilis and to prioritize contact investigations[J]. Sex Transm Dis,2009, 36(12):789-793.
[30]Muller I, Brade V, Hagedorn HJ,et al. Is serological testing a reliable tool in laboratory diagnosis of syphilis? meta-analysis of eight external quality control surveys performed by the German infection serology proficiency testing program[J]. J Clin Microbiol,2006,44(4):1335-1341.
[31]Creegan L, Bauer HM, Samuel MC,et al. An evaluation of the relative sensitivities of the venereal disease research laboratory test and the Treponema pallidum particle agglutination test among patients diagnosed with primary syphili[J]. Sex Transm Dis,2007,34(12):1016-1018.
[32]Janier M, Chastang C, Spindler E, et al. A prospective study of the influence of HIV status on the seroreversion of serological tests for syphilis [J]. Dermatology,1999,198(4):362-369.
[33]Knaute DF,Graf N, Lautenschlager S, et al. Serological response to treatment of syphilis according to disease stage and HIV Status[J].Clin Infect Dis, 2012,55 (12):1615-1622.
[34]Castro R, Prieto ES, da Luz Martins Pereira F. Nontreponemal tests in the diagnosis of neurosyphilis:an evaluation of the Venereal Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR) tests[J]. J Clin Lab Anal 2008,22(4):257-261.
[35]Jiang Y, Chen X, Ma X, et al. The usefulness of toluidine red unheated serum test in the diagnosis of HIV-negative neurosyphilis [J]. Sex Transm Dis,2011, 38 (3):244-245.
[36]Hart G. Syphilis tests in diagnostic and therapeutic decisionmaking[J].Ann Intern Med,1986,104(3):368-376.
[37]Jaffe HW, Larsen SA, Peters M, et al. Tests for treponemal antibody in CSF[J]. Arch Intern Med,1978,138(2):252-255.
[38]Harding AS, Ghanem KG. The Performance of cerebrospinal fluid treponemal-pecific antibody tests in neurosyphilis:a systematic review[J].Sex Transm Dis, 2012,39(4):291-297.
[39]Izzat NN, Bartruff JK, Glicksman JM, et al. Validity of the VDRL test on cerebrospinal fluid contaminated by blood[J]. Br J Vener Dis,1971,47(3): 162-164.
[40]Lee JW, Wilck M, Venna N. Dementia due to neurosyphilis with persistently negative CSF-VDRL[J]. Neurology,2005,65(10):1838-1840.
[41]Castro R'Prieto ES, da Luz Martins Pereim E. Nontreponemat tests in the diagnosis of neurosyphilis:all evaluation of the Venereal Disease Research Laboratory(VDRL) and the Rapid Plasma Reagin(RPR) tests[J]. J Clin Lab Anal,2008,22(4):257-261.
[42]Dunlop EM. Survival of treponemes after treatment, comments, clinical conclusions and recommendations [J]. Genitourin Med,1985,61(5):293-301.
[43]Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretationof tests for syphilis[J]. Clin Microbiol Rev,1995,8(1):1-21.
[44]Romanowski B, Sutherland R, Fick GH, et al. Serologic response to treatment of infectious syphilis[J]. Ann Intern Med.1991,114(12):1005-1009.
[45]Lukehart SA. Serologica testing after therapy for syphilis:is there a test for cure[J]? Ann Intern Med,1991,114(12):1057-1058.
[46]Haas JS,Bolan QLarsen SA,et al. Sensitivity of treponemal tests for detecting prior treated syphilis during human immunodeficiency virus infection[J].J Infect Dis,1990,162(4):862-866.
[47]French P, Gomberg M, Janier M,et al. IUSTI:2008 European guidelines on the management of syphilis[J]. Int J STD AIDS,2009,20(5):300-309.
[48]Ghanem KG, Moore RD, Rompalo AM,et al. Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-Infected patients[J]. Clin Infect Dis,2008,47(2):258-265.
[49]Moore JE. The modern treatment of syphilis [M].2nd ed. Baltimore, MD: Charles C Thomas Books,1941.
[50]龙振华.实用梅毒病学[M].北京：北京科学技术出版社,2009,56-57.
[51]Guinan ME.Treatment of primary and secondary syphilis:defining failure at three- and six-month follow-up[J]. JAMA,1987,257(3):359-360.
[52]Manavi K, McMillan A.The outcome of treatment of early latent syphilis and syphilis with undetermined duration in HIV-infected and HIV-uninfected patients[J]. Int J STD AIDS,2007,18(12):814-818.
[53]Smith NH, Musher DM, Huang DB, et al. Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin[J]. Int J STD AIDS,2004,15(5):328-332.
[54]Brown ST, Zaidi A, Larsen SA, et al. Serological response to syphilis treatment:a new analysis of old data[J]. JAMA,1985,253(9):1296-1299.
[55]Knaute DF, Graf N, Lautenschlager S,et al. Serological response to treatment of syphilis according to disease stage and HIVstatus[J]. Clin infect Dis,2012, 55 (12):1615-1622.
[56]Fiumara NJ. Treatment of seropositive primary syphilis:an evaluation of 196 patients[J]. Sex Transm Dis,1977,4(3):92-95.
[57]Fiumara NJ. Treatment of secondary syphilis:an evaluation of 204 patients. Sex Transm Dis,1977,4(3):96-99.
[58]Hook EW, Behets F, van Damm K, et al. A phase III equivalence trial of azithromycin vs benzathine penicillin for treatment of early syphilis [J]. J Infect Dis,2010,201(11):1729-1735.
[59]Hook EW 3rd, Martin DH, Stephens J,et al. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis[J]. Sex Transm Dis,2002,29(8):486-490.
[60]Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy:does HIV status matter[J]? Clin Infect Dis,2004,38(7):1001-1006.
[61]Rose MS, Fick GH, Romanowski B, et al.First year serologic response to treatment for syphilis:a model for predictiom of seroreversion[J]. Stat Med, 1997,16(18):2103-2115.
[62]Kim JH, Psevdos G, Suh J,et al. Factors influencing syphilis treatment failure and/or re-infection in HIV co-infected patients:immunosuppression or behaviors[J]. Chin Med J(Engl),2011,124(14):2123-2126.
[63]Baker-Zander SA, Shaffer JM, Lukehart SA. VDRL antibodies enhance phagocytosis of treponema pallidum by macrophages[J]. J Infect Dis,1993, 167(5):1100-1105.
[64]Kovaiou RD, Grubeck-Loebenstein B. Age-associated changes within CD4+T cells[J]. Immunol Lett,2006,107(1):8-14.
[65]Engelhart DA, Jenkins AJ. Comparison of drug concentrations in postmortem cerebrospinal fluid and blood specimens[J]. J Anal Toxicol,2007,31(9): 581-587.
[66]Mealey KL, Greene S, Bagley R, et al.P-glycoprotein contributes to the blood-brain, but not blood-CSF, barrier in a spontaneous canine P-glycoprotein knockout model [J]. Drug Metab Dispos,2008,36(6):1073-1079.
[67]Mori S, Takanaga H, Ohtsuki S, et al. Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells[J]. J Cereb Blood Flow Metab, 2003;23(4):432-440.
[68]Rousselle C, Clair P, Temsamani J, Scherrmann JM. Proved brain delivery of benzylpenicillin with a peptide-vector-mediated strategy [J]. J Drug Target, 2002,10(4):309-315.
[69]Serragui S, Yahyaoui M, Hassar M,et al. A comparison study of two therapeutic protocols for neurosyphilis[J]. Therapie,1999,54(5):613-621.
[70]Azimi PH, Janner D, Berne P, et al.Concentrations of procaine and aqueous penicillin in the cerebrospinal fluid of infants treated for congenital syphilis [J]. J Pediatr,1994,124(4):649-653.
[1]Lynn WA, Lightman S. Syphilis and HIV:a dangerous combination[J]. Lancet Infect Dis,2004,4(7):456-466.
[2]de Almeida SM, Bhatt A, Riggs PK, et al. Cerebrospinal fluid human immunodeficiency virus viral load in patients with neuro syphilis [J]. J Neurovirol,2010,16(1):6-12.
[3]Chen XS, Gong XD, Liang GJ, et al. Epidemiologic trends of sexually transmitted diseases in China[J]. Sex Transm Dis,2000,27(3):138-142.
[4]杨文林,杨健,黄新宇。近10年梅毒血清固定患者临床分析[J].临床皮肤科杂志,2005,34(11)：719-721.
[5]吴志华,现代皮肤性病学[M].广州：广东人民出版社,1999,350.
[6]杨文林,杨健,许教雄等。梅毒血清固定的系统受累状况[J].临床皮肤科杂志,2012,41(7)：406-408.
[7]Wohrl S, Geusau A. Neurosyphilis is unlikely in patients with late latent syphilis and anegative blood VDRL test[J]. Acta Derm Venereol,2006,86(4): 335-339.
[8]陈玲玲,季孙平,施辛等。梅毒血清固定患者的抑郁情绪调查和生活质量评估[J]。苏州医学,2011,34(1)：33-35.
[9]Chan DJ. Syphilis and HIV co-infection:when is lumbar puncture indicated[J]? Curr HIV Res,2005,3(1):95-98.
[10]Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus[J]. N Engl J Med,1987,316(25):1569-1572.
[11]Thomaidis L, Bertou G, Critselis E, et al. Cognitive and psychosocial development of HIV pediatric patients receiving highly active anti-retroviral therapy:a case-control study[J]. BMC Pediatr,2010,10:99.
[12]Al-Khindi T, Zakzanis KK, van Gorp WG. Does Antiretroviral Therapy Improve HIV-Associated Cognitive Impairment? A Quantitative Review of the Literature[J]. J Int. Neuropsychol. Soc,2011,17(6):956-969.
[13]Burgess PW, Gonen-Yaacovi G, Volle E. Functional neuroimaging studies of prospective memory:What have we learnt so far[J]? Neuropsychologia,2011, 49 (8):2246-2257.
[14]Woods SP, Iudicello JE, Moran LM, et al. HIV-associated prospective memory impairment increases risk of dependence in everyday functioning [J]. Neuropsychology,2008,22(1):110-117.
[15]McDaniel MA, Glisky EL, Rubin SR, et al. Prospective memory:a neuropsy-chological study[J]. Neuropsychology,1999,13:103-110.
[16]Lui SS, Wang Y, Liu AC, et al. Prospective memory in patients with first-onset schizophrenia and their non-psychotic siblings [J]. Neuropsycholo-gia,2011,49(8):2217-2224.
[17]Zhuo K, Lu Y, Yang ZL, et al.Prospective memory performance in patients with drug-naive, first-episode psychosis [J]. Schizophr Res.,2013,143(2-3) 285-290.
[18]Lee E, Xiang YT, Man D, et al. Prospective memory deficits in patients with bipolar disorder:a preliminary study[J]. Arch Of Clin Neuropsych,2010,25 (7):640-647.
[19]Albinski R, Kliegel M, Sedek G,etal. Positive effects of subclinical depression in prospective memory and ongoing tasks in young and old adult[J], Neuropsychol Dev Cogn B Aging Neuropsychol Cogn,2012,19 (1-2):35-57.
[20]Foster ER, McDaniel MA, Repovs G, et al. Prospective memory in parkinson disease across laboratory and self-reported everyday performance[J]. Neuropsychology,2009,23(3):347-358.
[21]Kliegel M, Altgassen M, Hering A, et al.A process-model based approach to prospective memory impairment in Parkinson's disease[J]. Neuropsychologia, 2011,49(8):2166-2177.
[22]Shum D,Levin H, Chan RC. Prospective memory in patients with closed head injury:A review[J]. Neuropsychologia,2011,49(8):2156-2165.
[23]van den Berg E, Kant N, Postma A Remember to buy milk on the way home! A meta-analytic review of prospective memory in mild cognitive impairment and dementia[J]. J Int Neuropsychol Soc,2012,18(4):706-716.
[24]Woods SP, Moran LM, Carey CL, et al. Prospective memory in HIV infection: Is "remembering to remember" a unique predictor of self-reported medication management[J]? Arch Clin Neuropsychol,2008,23(3):257-270.
[25]Gupta S, Woods SP, Weber E,et al.Is prospective memory a dissociable cognitive function in HIV infection[J]? J Clin Exp Neuropsychol,2010,32 (8): 898-908.
[26]Einstein GO, McDaniel MA. Normal aging and prospective memory[J]. J Exp Psychol Learn Mem Cogn,1990,16(4):717-726.
[27]程怀东,汪凯,孟玉,等。老年人前瞻性记忆损害的研究[J]。中华神经科杂志,2006,39(9)：600-603.
[28]杨文林,杨健,黄新宇。近10年梅毒血清固定患者临床分析[J].临床皮肤科杂志,2005,34(11)：719-721.
[29]French P, Gomberg M, Janier M, IUSTI:2008 European guidelines on the management of syphilis[J]. Int J STD AIDS,2009,20(5):300-309.
[30]Lin LR,Tong ML,Fu ZG, et al. Evaluation of a colloidalgold immunochro mato- graphy assay in the detection of treponema pallidum specific IgM antibody in syphilis serofast reaction patients:a serologic marker for the relapse and infection of syphilis[J]. Diagn Microbiol Infect Dis,2011,70 (1):10-16.
[31]Agmon-Levin N, Elbirt D, Asher I,et al. Syphilis and hiv co-infection in an Israeli hiv clinic:incidence and outcome [J].Int J STD AIDS,2010,21(4):249-252.
[32]Wang J, Guo Q, Zhou P,et al. Cognitive impairment in mild general paresis of the insane:AD-like pattern[J]. Dement Geriatr Cogn Discord,2011,31(4):284-290.
[33]Miklossy J. Alzheimer's disease-a neurospirochetosis.analysis of the evidence following Koch's and Hill's criteria[J]. J Neuroinflammation,2011, 8:90.
[34]Miklossy J. Emerging roles of pathogens in Alzheimer disease[J]. Expert Rev Mol Med,2011,13:e30.
[35]Paraskevas GP, Kapaki E, Kararizou, et al. cerebrospinal fluid tau protein is increased in neurosyphilis:discrimination from syphilis without nervous system involvement[J]? Sex Transm Dis,2007,34(4):220-223.
[36]Maylor EA, Smith G, Della Sala S, et al. Prospective and retrospective memory in normal aging and dementia:an experimental study[J]. Mem Cognit, 2002,30(6):871-884.
[37]Barban F, Carlesimo GA, Macaluso E,et al. Functional brain activity within the medial and lateral portion of BA10 during a prospective memory task[J]. Behav Neurol,2013,26(3):207-209.
[38]Reynolds JR, West R, Braver T. Distinct neural circuits support transient and sustained processes in prospective memory and working memory [J]. Cereb Cortex,2009,19(5):1208-1221.
[39]Burgess N, Maguire EA, O'Keefe J. The human hippocampus and spatial and episodic memory[J]. Neuron,2002,35(4):625-641.
[40]Gordon BA,Shelton JT, Bugg JM, et al. Structural correlates of prospective memory[J]. Neuropsychologia,2011,49(14):3795-3800.
[41]Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain[J]. Nat Rev Neurosci,2002,3(3):201-215
[42]Mattei PL, Beachkofsky TM, Gilson RT, et al. Syphilis:a reemerging infection [J]. Am Fam Physician,2012,86(5):433-440.
[43]Serragui S, Yahyaoui M, Hassar M, et al. A comparison study of two therapeutic protocols for neurosyphilis[J]. Therapie,1999,54(5):613-621.
[1]Adolphs R. Social cognition and the human brain[J]. Trends in Cognitive Sciences,1999,3(12):469-479
[2]Brand M, Labudda K,Markowitsch HJ.Neuropsychological correlates of decision-making in ambiguous and risky situations. Neural Networks,2006, 19 (8):1266-1276.
[3]Rangel A, Camerer C, Montague PR. A framework for studying the neurobiology of value-based decision making[J]. Nat RevNeurosci,2008,9(7): 545-556.
[4]Brand M, Labudda K, Markowitsch HJ. Neuropsychological correlates of decision-making in ambiguous and risky situations [J]. Neural Netw,2006,19 (8):1266-1276.
[5]Ernst M, Paulus MP. Neurobiology of decision making:A selective review from a neurocognitive and clinical perspective [J]. Biol Psychiatry,2005; 58(8): 597-604.
[6]Bechara A, Damasio H, Damasio AR. Emotion, decision making and the orbitofrontal cortex[J]. Cereb Cortex,2000,10(3):295-307.
[7]Bechara A, Damasio AR, Damasio H, et al. Insensitivity to future consequences following damage to human prefrontal cortex [J]. Cognition, 1994,50(1-3),7-15.
[8]Gleichgerrcht E, Ibanez A, Roca M,et al. Decision making cognition in neurodegenerative diseases[J]. Nature Reviews Neurology,2010,6(11):611-623.
[9]Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation:patient EVR[J]. Neurology,198,35 (12):1731-1741.
[10]席春华,汪凯,牛朝诗等。前额叶损伤患者的社会认知障碍[J].中华神经科杂志,2006,39(10)：651-654.
[11]Svaldi J, Philipsen A, Matthies S, et al. Risky decision-making in borderline personality disorder[J]. Psychiatry Re,2012,197(1-2):112-118.
[12]Schuermann B, Kathmann N, Stiglmayr C, et al.Impaired decision making and feedback evaluation in borderline personality disorder [J]. Psychol Med,2011, 41 (9):1917-1927.
[13]Matthies S, Philipsen A Svaldi J. Risky decision making in adults with ADHD[J]. J Behav Ther Exp Psychiatry,2012,43(3):938-946.
[14]Iudicello JE, Woods SP, Cattie JE, et al. Risky decision-making in HIV-associated neurocognitive disorders(HAND) [J]. Clin Neuropsychol, 2013,27(2):256-275.
[15]Dean AC, Altstein LL, Berman ME,et al. Secondary psychopathy, but not primary psychopathy, is associated with risky decision-making in noninstitutionalized young adults [J]. Pers Individ Dif,2013,54(2):272-277.
[16]Larquet M,Coricelli QOpolczynski G, et al. Impaired decision making in schizophrenia and orbitofrontal cortex lesion patients [J]. Schizophr Res,2010, 116(2-3):266-273.
[17]Pignatti R, Brioschi A, Mauro A,et al. Selective IGT decision-making impairment in a patient with juvenile Parkinson'sdisease and pathological gambling:a role for dopaminergic therapy [J]? Neurocase,2012,18(6):503-513.
[18]Oyama G, Shimo Y, Natori S,et al. Acute effects of bilateral subthalamic stimulation on decision-making in Parkinson's disease [J]. Parkinsonism Relat Disord,2011,17(3):189-193.
[19]Zamarian L, Hofler J, Kuchukhidze G.et al. Decision making in juvenile myoclonic epilepsy [J]. J Neurol,2013,260(3):839-846.
[20]Delazer M, Zamarian L, Bonatti E,et al. Decision making under ambiguity in temporal lobe epilepsy:does the location of the underlying structural abnormality matter [J]? Epilepsy Behav,2011,20(1):34-37.
[21]Yamano M, Akamatsu N, Tsuji S, et al. Decision-making in temporal lobe epilepsy examined with the Iowa gambling task [J]. Epilepsy Rev,2011,93(1): 33-38.
[22]Delazer M, Sinz H, Zamarian L, et al. Decision making under risk and under ambiguity in Parkinson's disease [J]. Neuropsychologia,2009,47(8-9):1901-1908.
[23]Hardy DJ, Hinkin CH, Castellon SA, et al. Risky decision making assessed with the Gambling Task in adults with HIV [J]. Neuropsychology,2006,20 (3):355-360.
[24]Wardle MC, Gonzalez R, Bechara A,et al. Iowa Gambling Task performance and emotional distress interact to predict risky sexual behavior in individuals with dual substance and HIV diagnoses[J]. J Clin Exp Neuropsychol,2010,32 (10):1110-1121.
[25]Smith EE, Jonides J. Storage and executive processes in the frontal lobes[J]. Science,1999,283(5408):1657-1661.
[26]Mimura M, Oeda R, Kawamura M. Impaired decision-making in Parkinson's disease[J]. Parkinsonism Relat Disord,2006,12(3):169-175.
[27]Delazer M, Sinz H, Zamarian L, et al. Decision making under risk and under ambiguity in Parkinson's disease[J]. Neuropsychologia,2009,47(8-9):1901-1909.
[28]Iudicello JE, Woods SP, Cattie JE, et al. Risky-decision-making in HIV-associated neurocognitive disorders(HAND)[J]. Clin Neuropsychol,2013,27 (2):256-275.
[29]Gonzalez R, Vassileva J, Bechara A,et al. The influence of executive functions, sensation seeking, and HIV serostatus on the risky sexual practices of substance dependent individuals[J]. J Int Neuropsychol Soc,2005,11(2):121-131.
[30]Duarte NA, Woods SP, Rooney A, et al. Working memory deficits affect risky decision-making in methamphetamine users with attention-deficit /hyperactivity disorder[J]. J Psychiatric Res,2012,46(6):492-499.
[31]Smith B W, Mitchell DG, Hardin MG, et al.Neural substrates of reward magnitude, probability, and risk during a wheel of fortune decision-making task[J]. Neuroimage,2009,44(2):600-609.
[32]Volz KG, Schubotz RI, von Cramon DY. Frontomedian activation depends on both feedback validity and valence:fMRI evidence for contextual feedback evaluation[J]. Neuroimage,2005,27(3):564-571.
[33]Koechlin E, Corrado G, Pietrini P, et al.Dissociating the role of the medial and lateral anterior prefrontal cortex in human planning [J]. Proc Natl Acad Sci USA,2000,97(13):7651-7656.
[34]Christakou A,Brammer M,Giampietro V,et al. Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation [J]. J Neurosci,2009,29(35): 11020-11028.
[35]Rushworth MF, Noonan MP, Boorman ED, et al. Frontal cortex and reward-guided learning and decision-making [J].Neuron,2011,70(6):1054-106.
[1]Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI[J].Nat Rev Neurosci,2003,4(6):469-480.
[2]Abe O, Aoki S,Hayashi N, et al.Normal aging in the central nervous system quantitative MR diffusion tensor analysis[J].Neurobiol Aging,2002,23(3):433-441.
[3]Filippi CG, Ulug AM, Ryan E, et al. Diffusion tensor imaging of patients with HIV and normal-appearing white matter on MR images of the brain[J]. Am J Neuroradiol,2001,22(2):277-283.
[4]Filley CM.White matter and behavioral neurology[J]. Ann N Y Acad Sci,2005, 1064,162-183.
[5]Benes FM, Turtle M, Khan Y,et al. Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood[J]. Arch Gen Psychiatry,1994,51 (6):477-484.
[6]Giedd JN. Structural magnetic resonance imaging of the adolescent brain[J]. Ann NY Acad Sci,2004,1021:77-85.
[7]Bartzokis G, Beckson M, Lu PH,et al. Age-related changes in frontal and temporal lobe volumes in men:a magnetic resonance imaging study[J]. Arch Gen Psychiatry,2001,58(5):461-465.
[8]Bengtsson SL,NagyZ, Skare S,et al. Extensive piano practicing has regionally specific effects on white matter development[J]. Nat Neurosci,2005,8(9): 1148-1150
[9]Chanraud S, Zahr N, Sullivan EV,et al. MR diffusion tensor imaging:a window into white matter integrity of the working brain[J]. Neuropsychol Rev,2010,20(2):209-225.
[10]Basser PJ,Mattiello J, LeBihan D, MR diffusion tensor spectroscopy and imaging[J]. Biophys J,1994,66(1):259-267.
[11]Nicoletetti G, Lodi R, Condino F, et al. Apparent diffusion coefficient measurements of the middle cerebellar peduncle differentiate the Parkinson variatent of MSA from PD and PSP[J].Brain,2006,129(Pt10):2674-2687。
[12]Lafond RE, Lukehart SA. Biological basis for syphilis[J]. Clin Microbiol Rev, 2006,19(1):29-49.
[13]Jantzen SU, Ferrea S, Langebner T,et al. Late-stage neurosyphilis presenting with severe neuropsychiatric deficits:diagnosis, therapy, and course of three patients[J]. J Neurol,2012,259(4):720-728.
[14]江婷陈少琼单鸿等。麻痹性痴呆的MRI表现(附32例报道)[J]。中华神经医学杂志,2011,10(7)：716-720.
[15]Guo Q, Zhao Q, Chen M, et al. A comparison study of mild cognitive impairment with 3 memory tests among Chinese individuals[J]. Alzheimer Dis Assoc Disord,2009,23(3):253-259.
[16]Hook EW. A syphilis wish list-better data, better tests[J]. Clin infect Dis,2012, 55(12):1623-1624.
[17]Vaillancourt DE, Spraker MB, Prodoehl J, et al. High resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease[J]. Neurology,2009,72(16):1378-1384.
[18]Koch K, Wagner G, Schachtzabel C, et al.Neural activation and radial diffusivity in schizophrenia:combined fMRI and diffusion tensor imaging study[J].Br J Psychiatry,2011,198(3):223-229.
[19]Kafantaris V, Kingsley P, Ardekani B et al.Lower orbital frontal white matter integrity in adolescentswith bipolar I disorder[J]. J Am Acad Child Adolesc Psychiatry,2009,48(1):79-86.
[20]Ragin AB, Wu Y, Storey P, et al.Diffusion tensor imaging of subcortical brain injury in patients infected with human immunodeficiency virus [J]. J Neurovirol,2005,11(3):292-298.
[21]Stubbe-Drger B, Deppe M, Mohammadi S, et al.Early microstructural white matter changes in patients with HIV:a diffusion tensor imaging study[J].BMC Neurol,2012,12:23.
[22]Miklossy J.Alzheimer's disease-a neurospirochetosis.Analysis of the evidence following Koch's and Hill's criteria[J]. J Neuroinflammation,2011, 8:90.
[23]Miklossy J. Emerging roles of pathogens in Alzheimer diseas[J]. Expert Rev Mol Med,2011,13:e30.
[24]Rovaris M, Iarnnucci G, Cercignani M, et al. Aged-relatede changes in conventional magnetization transfe and diffusion tensor MR imaging findings: study with whole brain tissue histogram analysis[J]. Radiolog,2003,227(30): 731-738.
[25]Mette RW, Henrik BWL, VanJW. Fiber crossing in human brain depicted with diffusion tensor MR imaging[J]. Radiology,2000,21(7):897-903.
[26]Burgess PW, Quayle A, Frith CD. Brain regions involved in prospective memory as determined by positron emission tomography[J]. Neuropsycholo-gia,2001,39 (6):545-555.
[27]Okuda J, Fujii T, Ohtake H, et al. Differential involvement of regions of rostral prefrontal cortex (Brodmann area 10) in time- and event-based prospective memory[J]. Int J Psychophysiol,2007,64(3):233-246.
[28]Martin T, McDaniel MA, Guyunn MJ, et al. Brain regions and their dynamics in prospective memory retrieval:A MEG study [J]. Int J Psychophysiol, 2007,64 (3):247-258.
[29]Gordon BA, Shelton JT, Bugg JM, et al. Structural Correlates of Prospective Memory[J]. Neuropsychologia,2011,49(14):3795-800.
[30]Burgess PW, Gonen-Yaacovi G, Volle E. Functional neuroimaging studies of prospective memory:What have we learnt so far[J]? Neuropsychologia,2011, 49(8):2246-2257.
[31]Reynolds JR, West R, Braver T. Distinct neural circuits support transient and sustained processes in prospective memory and working memory[J]. Cereb Cortex,2009,19(5):1208-1221.
[32]Barban F, Carlesimo GA, Macaluso E,et al. Functional brain activity within the medial and lateral portion of BA10 during a prospective memory task[J]. Behav Neurol,2013,26(3):207-209.
[2]Chen XS, Gong XD, Liang GJ, et al. Epidemiologic trends of sexually transmitted diseases in China[J]. Sex Transm Dis,2000,27(3):138-142.
[3]Beyrer C. Hidden epidemic of sexually transmitted diseases in China:crisis and opportunity[J]. JAMA,2003,289(10):1303-1305.
[4]Knaute DF, Graf N, Lautenschlager S, et al. Serological response to treatment of syphilis according to disease stage and HIV status [J]. Clin infect Dis, 2012,55 (12):1615-1622.
[5]柯吴坚,车雅敏,刘原君等。性病门诊性传播疾病病原体感染情况调查[J]。天津医科大学学报,2010,4：655-658.
[6]Wang QQ, Chen XS, Yin YP, et al. HIV/STD pattern and its associated risk factors among male STD clinic attendees in China:a foci for HIV intervention[J]. BMC Public Health,2011,11:955.
[7]龚向东,叶顺章,张君炎等.1999-2001年我国性病流行病学分析[J].中华皮肤科杂志,2002,35(3)：178-182.
[8]Hook EW. A syphilis wish list-better data, better tests[J]. Clin infect Dis,2012, 55(12):1623-1624.
[9]Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines:2010[J]. MMWR,2010,59(RR-12):1-110.
[10]World Health Organization. Sexually transmitted infections management guidelines 2012. Geneva:WHO,2012[http://www.who.int/HIV_AIDS
[11]Hayes R, Watson-Jones D, Celum C, et al. Treatment of sexually transmitted infections for HIV prevention:End of the road or new beginning[J]? AIDS 2010,24(s4):15-26.
[12]Lukehart SA, Hook EW, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum:implications for diagnosis and treatment[J]. Ann Intern Med,1988,109(11):855-862.
[13]Ducas J, Robson HG. Cerebrospinal fluid penicillin levels during therapy for latent syphilis[J]. JAMA,1981,246(22):2583-2584.
[14]Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis:association with clinical and laboratory features[J]. J Infect Dis,2004,189(3):369-376.
[15]龙振华.实用梅毒病学[M].北京：北京科学技术出版社,2009,56-57.
[16]Holman KM, Wolff M, Sena AC, et al. Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy[J]. Sex Transm Dis,2012,39 (8):645-647.
[17]Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals [J]. Clin Infect Dis,2000,30(3): 540-544.
[18]Bai ZG, Yang KH, Liu YL,et al. Azithromycin vs. benzathine penicillin G for early syphilis:a meta- analysis of randomized clinical trials[J]. Int J STD AIDS,2008,19(4):217-221.
[19]Sena AC, Wolff M, Martin DH, et al. Predictors of Serological Cure and Serofast StateAfter Treatment in HIV-Negative Persons With Early Syphilis[J]. Clin Infect Dis,2011,53(11):1092-1099.
[20]Gonzalez-Lopez JJ, Fernandez Guerre ML, Lujan R,et al. Factors determining serologic response to treatment in patients with syphili[J]. Clin Infect Dis,2009, 49(10):1505-1511.
[21]Marra CM, Longstreth WT Jr, Maxwell CL,et al. Resolution of serum and cerebro-spinal fluid abnormalities after treatment of neurosyphilis:influence of concomitant human immunodeficiency virus infection[J]. Sex Transm Dis, 1996,23(3):184-189.
[1]Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines:2010[J].MMWR,2010,59(RR-12):1-110.
[2]Stoner, BP. Current controversies in the management of adult syphilis[J].Clin Infect Dis,2007,44(S3):S130-146.
[3]Stamm LV. Global challenge of antibiotic-resistant treponema pallidum[J]. Antimicrob Agents Chemother,2010,54(2):583-589.
[4]Bai ZG, Yang KH, Liu YL,et al. Azithromycin vs. benzathine penicillin G for early syphilis:a meta- analysis of randomized clinical trials[J]. Int J STD AIDS,2008,19(4):217-221.
[5]Ison CA. Antimicrobial resistance in sexually transmitted infections in the developed world:implications for rational treatment[J]. Curr Opin Infect Dis, 2012,25(1):73-78.
[6]Ghanem KG, Erbelding EJ, Cheng WW,et al. Doxycycline compared with benzathine penicillin for treatment of early syphilis[J]. Clin Infect Dis,2006, 42 (6):e45-49.
[7]Wong T, Singh AE, De P. Primary syphilis:serological treatment response to doxycycline/tetracycline versus benzathine penicillin[J]. Am J Med,2008,121 (10):903-908.
[8]Mitchell SJ, Engelman J, Kent CK,et al. Azithromycin-resistant syphilis infection:San Francisco, California,2000-2004[J]. Clin Infect Dis,2006,42 (3):337-345.
[9]Rekart M L, Patrick DM, Chakraborty B,et al. Targeted mass treatment for syphilis with oral azithromycin[J]. Lancet,2003,361(9354):313-314.
[10]Rolfs RT, Joesoef MR, Hendershot EF, et al. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. The Syphilis and HIV Study Group[J]. N Engl J Med,1997,337 (5):307-314.
[11]Myint M, Bashiri H,Harrington RD,et al. Relapse of secondary syphilis after benzathine penicillin G. Molecular analysis[J]. Sex Transm Dis,2004,31(3): 196-199.
[12]Marra CM, Maxwell CL,Tantalo LC,et al. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis[J]. Clin Infect Dis,2008,47(7): 893-899.
[13]Sena AC, Wolff M, Martin DH, et al. Predictors of serological cure and serofast State after treatment in HIV-negative persons with early syphilis[J]. Clin Infect Dis,2011,53(11):1092-1099.
[14]Gordon S, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high- dose intravenous penicillin G in patients with human immunodeficiency virus infection[J]. N Engl J Med,1994,331(22):1469-1473.
[15]Walter T, Lebouche B, Miailhes P,et al. Symptomatic relapse of neurologic syphilis after benzathine penicillin G therapy for primary or secondary syphilis in HIV-infected patients[J]. Clin Infect Dis,2006,43(6):787-790.
[16]Zhou P, Gu X, Lu H,et al.Re-evaluation of serological criteria for early syphilis treatment efficacy:progression to neurosyphilis despite therapy [J]. Sex Transm Infect,2012,88(5):342-345.
[17]Lukehart SA, Hook EW, Baker-Zander SA, et al. Invasion of the central nervous system by Treponema pallidum:implications for diagnosis and treatment[J]. Ann Intern Med,1988,109(11):855-862.
[18]Ghanem KG, Erbelding EJ, Wiener ZS.Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases[J].Sex Transm Infect,2007,83(2):97-101.
[19]Spornraft-Ragaller P, Abraham S, Lueck C,et al. Response of HIV-infected patients with syphilis to therapy with penicillin or intravenous ceftriaxone[J]. Eur J Med Res,2011,16(2):47-51.
[20]Douglas JM Jr. Penicillin treatment of syphilis-clearing away the shadow on the land[J]. JAMA,2009,301(7):769-771.
[21]Fowler VG Jr, Maxwell GL,Myers SA,et al. Failure of benzathine penicillin in a case of seronegative secondary syphilis in a patient with acquired immunodeficiency syndrome:case report and review of the literature[J]. Arch Dermatol,2001,137 (10):1374-1376.
[22]Gonzalez-Lopez JJ, Fernandez Guerre ML, Lujan R,et al. Factors determining serologic response to treatment in patients with syphili[J]. Clin Infect Dis,2009, 49(10):1505-1511.
[23]Holman KM, Mark Wolff M, Sena AC, et al.Rapid plasma reagin titer variation in the 2 weeks after syphilis therapy[J]. Sex Transm Dis,2012,39(8): 645-647.
[24]Dowell ME, Ross PG, Musher DM, et al. Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus[J]. Am J Med,1992,93(5):481-488.
[25]Marra CM, Longstreth WT Jr, Maxwell CL,et al. Resolution of serum and cerebro- spinal fluid abnormalities after treatment of neurosyphilis:influence of concomitant human immunodeficiency virus infection[J]. Sex Transm Dis, 1996,23(3):184-189.
[26]Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents for neurosyphilis in human immunodeficiency virus-infected individuals[J]. Clin Infect Dis,2000,30(3): 540-544.
[27]Horberg MA, Ranatunga DK, Quesenberry C, et al.Syphilis epidemiology and clinical outcomes in HIV-infected and HIVuninfected patients in Kaiser Permanente Northern California[J]. SexTransm Dis,2010,37(1):53-58.
[28]Marra CM, Tantalo LC, Maxwell CL, et al. The rapid plasma regain test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis. Sex Transm Dis,2012,39(6):453-457.
[29]Samoff E, Koumans EH, Gibson JJ,et al. Pre-treatment syphilis titers: distribution and evaluation of their use to distinguish early from late latent syphilis and to prioritize contact investigations[J]. Sex Transm Dis,2009, 36(12):789-793.
[30]Muller I, Brade V, Hagedorn HJ,et al. Is serological testing a reliable tool in laboratory diagnosis of syphilis? meta-analysis of eight external quality control surveys performed by the German infection serology proficiency testing program[J]. J Clin Microbiol,2006,44(4):1335-1341.
[31]Creegan L, Bauer HM, Samuel MC,et al. An evaluation of the relative sensitivities of the venereal disease research laboratory test and the Treponema pallidum particle agglutination test among patients diagnosed with primary syphili[J]. Sex Transm Dis,2007,34(12):1016-1018.
[32]Janier M, Chastang C, Spindler E, et al. A prospective study of the influence of HIV status on the seroreversion of serological tests for syphilis [J]. Dermatology,1999,198(4):362-369.
[33]Knaute DF,Graf N, Lautenschlager S, et al. Serological response to treatment of syphilis according to disease stage and HIV Status[J].Clin Infect Dis, 2012,55 (12):1615-1622.
[34]Castro R, Prieto ES, da Luz Martins Pereira F. Nontreponemal tests in the diagnosis of neurosyphilis:an evaluation of the Venereal Disease Research Laboratory (VDRL) and the Rapid Plasma Reagin (RPR) tests[J]. J Clin Lab Anal 2008,22(4):257-261.
[35]Jiang Y, Chen X, Ma X, et al. The usefulness of toluidine red unheated serum test in the diagnosis of HIV-negative neurosyphilis [J]. Sex Transm Dis,2011, 38 (3):244-245.
[36]Hart G. Syphilis tests in diagnostic and therapeutic decisionmaking[J].Ann Intern Med,1986,104(3):368-376.
[37]Jaffe HW, Larsen SA, Peters M, et al. Tests for treponemal antibody in CSF[J]. Arch Intern Med,1978,138(2):252-255.
[38]Harding AS, Ghanem KG. The Performance of cerebrospinal fluid treponemal-pecific antibody tests in neurosyphilis:a systematic review[J].Sex Transm Dis, 2012,39(4):291-297.
[39]Izzat NN, Bartruff JK, Glicksman JM, et al. Validity of the VDRL test on cerebrospinal fluid contaminated by blood[J]. Br J Vener Dis,1971,47(3): 162-164.
[40]Lee JW, Wilck M, Venna N. Dementia due to neurosyphilis with persistently negative CSF-VDRL[J]. Neurology,2005,65(10):1838-1840.
[41]Castro R'Prieto ES, da Luz Martins Pereim E. Nontreponemat tests in the diagnosis of neurosyphilis:all evaluation of the Venereal Disease Research Laboratory(VDRL) and the Rapid Plasma Reagin(RPR) tests[J]. J Clin Lab Anal,2008,22(4):257-261.
[42]Dunlop EM. Survival of treponemes after treatment, comments, clinical conclusions and recommendations [J]. Genitourin Med,1985,61(5):293-301.
[43]Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosis and interpretationof tests for syphilis[J]. Clin Microbiol Rev,1995,8(1):1-21.
[44]Romanowski B, Sutherland R, Fick GH, et al. Serologic response to treatment of infectious syphilis[J]. Ann Intern Med.1991,114(12):1005-1009.
[45]Lukehart SA. Serologica testing after therapy for syphilis:is there a test for cure[J]? Ann Intern Med,1991,114(12):1057-1058.
[46]Haas JS,Bolan QLarsen SA,et al. Sensitivity of treponemal tests for detecting prior treated syphilis during human immunodeficiency virus infection[J].J Infect Dis,1990,162(4):862-866.
[47]French P, Gomberg M, Janier M,et al. IUSTI:2008 European guidelines on the management of syphilis[J]. Int J STD AIDS,2009,20(5):300-309.
[48]Ghanem KG, Moore RD, Rompalo AM,et al. Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-Infected patients[J]. Clin Infect Dis,2008,47(2):258-265.
[49]Moore JE. The modern treatment of syphilis [M].2nd ed. Baltimore, MD: Charles C Thomas Books,1941.
[50]龙振华.实用梅毒病学[M].北京：北京科学技术出版社,2009,56-57.
[51]Guinan ME.Treatment of primary and secondary syphilis:defining failure at three- and six-month follow-up[J]. JAMA,1987,257(3):359-360.
[52]Manavi K, McMillan A.The outcome of treatment of early latent syphilis and syphilis with undetermined duration in HIV-infected and HIV-uninfected patients[J]. Int J STD AIDS,2007,18(12):814-818.
[53]Smith NH, Musher DM, Huang DB, et al. Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin[J]. Int J STD AIDS,2004,15(5):328-332.
[54]Brown ST, Zaidi A, Larsen SA, et al. Serological response to syphilis treatment:a new analysis of old data[J]. JAMA,1985,253(9):1296-1299.
[55]Knaute DF, Graf N, Lautenschlager S,et al. Serological response to treatment of syphilis according to disease stage and HIVstatus[J]. Clin infect Dis,2012, 55 (12):1615-1622.
[56]Fiumara NJ. Treatment of seropositive primary syphilis:an evaluation of 196 patients[J]. Sex Transm Dis,1977,4(3):92-95.
[57]Fiumara NJ. Treatment of secondary syphilis:an evaluation of 204 patients. Sex Transm Dis,1977,4(3):96-99.
[58]Hook EW, Behets F, van Damm K, et al. A phase III equivalence trial of azithromycin vs benzathine penicillin for treatment of early syphilis [J]. J Infect Dis,2010,201(11):1729-1735.
[59]Hook EW 3rd, Martin DH, Stephens J,et al. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis[J]. Sex Transm Dis,2002,29(8):486-490.
[60]Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy:does HIV status matter[J]? Clin Infect Dis,2004,38(7):1001-1006.
[61]Rose MS, Fick GH, Romanowski B, et al.First year serologic response to treatment for syphilis:a model for predictiom of seroreversion[J]. Stat Med, 1997,16(18):2103-2115.
[62]Kim JH, Psevdos G, Suh J,et al. Factors influencing syphilis treatment failure and/or re-infection in HIV co-infected patients:immunosuppression or behaviors[J]. Chin Med J(Engl),2011,124(14):2123-2126.
[63]Baker-Zander SA, Shaffer JM, Lukehart SA. VDRL antibodies enhance phagocytosis of treponema pallidum by macrophages[J]. J Infect Dis,1993, 167(5):1100-1105.
[64]Kovaiou RD, Grubeck-Loebenstein B. Age-associated changes within CD4+T cells[J]. Immunol Lett,2006,107(1):8-14.
[65]Engelhart DA, Jenkins AJ. Comparison of drug concentrations in postmortem cerebrospinal fluid and blood specimens[J]. J Anal Toxicol,2007,31(9): 581-587.
[66]Mealey KL, Greene S, Bagley R, et al.P-glycoprotein contributes to the blood-brain, but not blood-CSF, barrier in a spontaneous canine P-glycoprotein knockout model [J]. Drug Metab Dispos,2008,36(6):1073-1079.
[67]Mori S, Takanaga H, Ohtsuki S, et al. Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells[J]. J Cereb Blood Flow Metab, 2003;23(4):432-440.
[68]Rousselle C, Clair P, Temsamani J, Scherrmann JM. Proved brain delivery of benzylpenicillin with a peptide-vector-mediated strategy [J]. J Drug Target, 2002,10(4):309-315.
[69]Serragui S, Yahyaoui M, Hassar M,et al. A comparison study of two therapeutic protocols for neurosyphilis[J]. Therapie,1999,54(5):613-621.
[70]Azimi PH, Janner D, Berne P, et al.Concentrations of procaine and aqueous penicillin in the cerebrospinal fluid of infants treated for congenital syphilis [J]. J Pediatr,1994,124(4):649-653.
[1]Lynn WA, Lightman S. Syphilis and HIV:a dangerous combination[J]. Lancet Infect Dis,2004,4(7):456-466.
[2]de Almeida SM, Bhatt A, Riggs PK, et al. Cerebrospinal fluid human immunodeficiency virus viral load in patients with neuro syphilis [J]. J Neurovirol,2010,16(1):6-12.
[3]Chen XS, Gong XD, Liang GJ, et al. Epidemiologic trends of sexually transmitted diseases in China[J]. Sex Transm Dis,2000,27(3):138-142.
[4]杨文林,杨健,黄新宇。近10年梅毒血清固定患者临床分析[J].临床皮肤科杂志,2005,34(11)：719-721.
[5]吴志华,现代皮肤性病学[M].广州：广东人民出版社,1999,350.
[6]杨文林,杨健,许教雄等。梅毒血清固定的系统受累状况[J].临床皮肤科杂志,2012,41(7)：406-408.
[7]Wohrl S, Geusau A. Neurosyphilis is unlikely in patients with late latent syphilis and anegative blood VDRL test[J]. Acta Derm Venereol,2006,86(4): 335-339.
[8]陈玲玲,季孙平,施辛等。梅毒血清固定患者的抑郁情绪调查和生活质量评估[J]。苏州医学,2011,34(1)：33-35.
[9]Chan DJ. Syphilis and HIV co-infection:when is lumbar puncture indicated[J]? Curr HIV Res,2005,3(1):95-98.
[10]Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus[J]. N Engl J Med,1987,316(25):1569-1572.
[11]Thomaidis L, Bertou G, Critselis E, et al. Cognitive and psychosocial development of HIV pediatric patients receiving highly active anti-retroviral therapy:a case-control study[J]. BMC Pediatr,2010,10:99.
[12]Al-Khindi T, Zakzanis KK, van Gorp WG. Does Antiretroviral Therapy Improve HIV-Associated Cognitive Impairment? A Quantitative Review of the Literature[J]. J Int. Neuropsychol. Soc,2011,17(6):956-969.
[13]Burgess PW, Gonen-Yaacovi G, Volle E. Functional neuroimaging studies of prospective memory:What have we learnt so far[J]? Neuropsychologia,2011, 49 (8):2246-2257.
[14]Woods SP, Iudicello JE, Moran LM, et al. HIV-associated prospective memory impairment increases risk of dependence in everyday functioning [J]. Neuropsychology,2008,22(1):110-117.
[15]McDaniel MA, Glisky EL, Rubin SR, et al. Prospective memory:a neuropsy-chological study[J]. Neuropsychology,1999,13:103-110.
[16]Lui SS, Wang Y, Liu AC, et al. Prospective memory in patients with first-onset schizophrenia and their non-psychotic siblings [J]. Neuropsycholo-gia,2011,49(8):2217-2224.
[17]Zhuo K, Lu Y, Yang ZL, et al.Prospective memory performance in patients with drug-naive, first-episode psychosis [J]. Schizophr Res.,2013,143(2-3) 285-290.
[18]Lee E, Xiang YT, Man D, et al. Prospective memory deficits in patients with bipolar disorder:a preliminary study[J]. Arch Of Clin Neuropsych,2010,25 (7):640-647.
[19]Albinski R, Kliegel M, Sedek G,etal. Positive effects of subclinical depression in prospective memory and ongoing tasks in young and old adult[J], Neuropsychol Dev Cogn B Aging Neuropsychol Cogn,2012,19 (1-2):35-57.
[20]Foster ER, McDaniel MA, Repovs G, et al. Prospective memory in parkinson disease across laboratory and self-reported everyday performance[J]. Neuropsychology,2009,23(3):347-358.
[21]Kliegel M, Altgassen M, Hering A, et al.A process-model based approach to prospective memory impairment in Parkinson's disease[J]. Neuropsychologia, 2011,49(8):2166-2177.
[22]Shum D,Levin H, Chan RC. Prospective memory in patients with closed head injury:A review[J]. Neuropsychologia,2011,49(8):2156-2165.
[23]van den Berg E, Kant N, Postma A Remember to buy milk on the way home! A meta-analytic review of prospective memory in mild cognitive impairment and dementia[J]. J Int Neuropsychol Soc,2012,18(4):706-716.
[24]Woods SP, Moran LM, Carey CL, et al. Prospective memory in HIV infection: Is "remembering to remember" a unique predictor of self-reported medication management[J]? Arch Clin Neuropsychol,2008,23(3):257-270.
[25]Gupta S, Woods SP, Weber E,et al.Is prospective memory a dissociable cognitive function in HIV infection[J]? J Clin Exp Neuropsychol,2010,32 (8): 898-908.
[26]Einstein GO, McDaniel MA. Normal aging and prospective memory[J]. J Exp Psychol Learn Mem Cogn,1990,16(4):717-726.
[27]程怀东,汪凯,孟玉,等。老年人前瞻性记忆损害的研究[J]。中华神经科杂志,2006,39(9)：600-603.
[28]杨文林,杨健,黄新宇。近10年梅毒血清固定患者临床分析[J].临床皮肤科杂志,2005,34(11)：719-721.
[29]French P, Gomberg M, Janier M, IUSTI:2008 European guidelines on the management of syphilis[J]. Int J STD AIDS,2009,20(5):300-309.
[30]Lin LR,Tong ML,Fu ZG, et al. Evaluation of a colloidalgold immunochro mato- graphy assay in the detection of treponema pallidum specific IgM antibody in syphilis serofast reaction patients:a serologic marker for the relapse and infection of syphilis[J]. Diagn Microbiol Infect Dis,2011,70 (1):10-16.
[31]Agmon-Levin N, Elbirt D, Asher I,et al. Syphilis and hiv co-infection in an Israeli hiv clinic:incidence and outcome [J].Int J STD AIDS,2010,21(4):249-252.
[32]Wang J, Guo Q, Zhou P,et al. Cognitive impairment in mild general paresis of the insane:AD-like pattern[J]. Dement Geriatr Cogn Discord,2011,31(4):284-290.
[33]Miklossy J. Alzheimer's disease-a neurospirochetosis.analysis of the evidence following Koch's and Hill's criteria[J]. J Neuroinflammation,2011, 8:90.
[34]Miklossy J. Emerging roles of pathogens in Alzheimer disease[J]. Expert Rev Mol Med,2011,13:e30.
[35]Paraskevas GP, Kapaki E, Kararizou, et al. cerebrospinal fluid tau protein is increased in neurosyphilis:discrimination from syphilis without nervous system involvement[J]? Sex Transm Dis,2007,34(4):220-223.
[36]Maylor EA, Smith G, Della Sala S, et al. Prospective and retrospective memory in normal aging and dementia:an experimental study[J]. Mem Cognit, 2002,30(6):871-884.
[37]Barban F, Carlesimo GA, Macaluso E,et al. Functional brain activity within the medial and lateral portion of BA10 during a prospective memory task[J]. Behav Neurol,2013,26(3):207-209.
[38]Reynolds JR, West R, Braver T. Distinct neural circuits support transient and sustained processes in prospective memory and working memory [J]. Cereb Cortex,2009,19(5):1208-1221.
[39]Burgess N, Maguire EA, O'Keefe J. The human hippocampus and spatial and episodic memory[J]. Neuron,2002,35(4):625-641.
[40]Gordon BA,Shelton JT, Bugg JM, et al. Structural correlates of prospective memory[J]. Neuropsychologia,2011,49(14):3795-3800.
[41]Corbetta M, Shulman GL. Control of goal-directed and stimulus-driven attention in the brain[J]. Nat Rev Neurosci,2002,3(3):201-215
[42]Mattei PL, Beachkofsky TM, Gilson RT, et al. Syphilis:a reemerging infection [J]. Am Fam Physician,2012,86(5):433-440.
[43]Serragui S, Yahyaoui M, Hassar M, et al. A comparison study of two therapeutic protocols for neurosyphilis[J]. Therapie,1999,54(5):613-621.
[1]Adolphs R. Social cognition and the human brain[J]. Trends in Cognitive Sciences,1999,3(12):469-479
[2]Brand M, Labudda K,Markowitsch HJ.Neuropsychological correlates of decision-making in ambiguous and risky situations. Neural Networks,2006, 19 (8):1266-1276.
[3]Rangel A, Camerer C, Montague PR. A framework for studying the neurobiology of value-based decision making[J]. Nat RevNeurosci,2008,9(7): 545-556.
[4]Brand M, Labudda K, Markowitsch HJ. Neuropsychological correlates of decision-making in ambiguous and risky situations [J]. Neural Netw,2006,19 (8):1266-1276.
[5]Ernst M, Paulus MP. Neurobiology of decision making:A selective review from a neurocognitive and clinical perspective [J]. Biol Psychiatry,2005; 58(8): 597-604.
[6]Bechara A, Damasio H, Damasio AR. Emotion, decision making and the orbitofrontal cortex[J]. Cereb Cortex,2000,10(3):295-307.
[7]Bechara A, Damasio AR, Damasio H, et al. Insensitivity to future consequences following damage to human prefrontal cortex [J]. Cognition, 1994,50(1-3),7-15.
[8]Gleichgerrcht E, Ibanez A, Roca M,et al. Decision making cognition in neurodegenerative diseases[J]. Nature Reviews Neurology,2010,6(11):611-623.
[9]Eslinger PJ, Damasio AR. Severe disturbance of higher cognition after bilateral frontal lobe ablation:patient EVR[J]. Neurology,198,35 (12):1731-1741.
[10]席春华,汪凯,牛朝诗等。前额叶损伤患者的社会认知障碍[J].中华神经科杂志,2006,39(10)：651-654.
[11]Svaldi J, Philipsen A, Matthies S, et al. Risky decision-making in borderline personality disorder[J]. Psychiatry Re,2012,197(1-2):112-118.
[12]Schuermann B, Kathmann N, Stiglmayr C, et al.Impaired decision making and feedback evaluation in borderline personality disorder [J]. Psychol Med,2011, 41 (9):1917-1927.
[13]Matthies S, Philipsen A Svaldi J. Risky decision making in adults with ADHD[J]. J Behav Ther Exp Psychiatry,2012,43(3):938-946.
[14]Iudicello JE, Woods SP, Cattie JE, et al. Risky decision-making in HIV-associated neurocognitive disorders(HAND) [J]. Clin Neuropsychol, 2013,27(2):256-275.
[15]Dean AC, Altstein LL, Berman ME,et al. Secondary psychopathy, but not primary psychopathy, is associated with risky decision-making in noninstitutionalized young adults [J]. Pers Individ Dif,2013,54(2):272-277.
[16]Larquet M,Coricelli QOpolczynski G, et al. Impaired decision making in schizophrenia and orbitofrontal cortex lesion patients [J]. Schizophr Res,2010, 116(2-3):266-273.
[17]Pignatti R, Brioschi A, Mauro A,et al. Selective IGT decision-making impairment in a patient with juvenile Parkinson'sdisease and pathological gambling:a role for dopaminergic therapy [J]? Neurocase,2012,18(6):503-513.
[18]Oyama G, Shimo Y, Natori S,et al. Acute effects of bilateral subthalamic stimulation on decision-making in Parkinson's disease [J]. Parkinsonism Relat Disord,2011,17(3):189-193.
[19]Zamarian L, Hofler J, Kuchukhidze G.et al. Decision making in juvenile myoclonic epilepsy [J]. J Neurol,2013,260(3):839-846.
[20]Delazer M, Zamarian L, Bonatti E,et al. Decision making under ambiguity in temporal lobe epilepsy:does the location of the underlying structural abnormality matter [J]? Epilepsy Behav,2011,20(1):34-37.
[21]Yamano M, Akamatsu N, Tsuji S, et al. Decision-making in temporal lobe epilepsy examined with the Iowa gambling task [J]. Epilepsy Rev,2011,93(1): 33-38.
[22]Delazer M, Sinz H, Zamarian L, et al. Decision making under risk and under ambiguity in Parkinson's disease [J]. Neuropsychologia,2009,47(8-9):1901-1908.
[23]Hardy DJ, Hinkin CH, Castellon SA, et al. Risky decision making assessed with the Gambling Task in adults with HIV [J]. Neuropsychology,2006,20 (3):355-360.
[24]Wardle MC, Gonzalez R, Bechara A,et al. Iowa Gambling Task performance and emotional distress interact to predict risky sexual behavior in individuals with dual substance and HIV diagnoses[J]. J Clin Exp Neuropsychol,2010,32 (10):1110-1121.
[25]Smith EE, Jonides J. Storage and executive processes in the frontal lobes[J]. Science,1999,283(5408):1657-1661.
[26]Mimura M, Oeda R, Kawamura M. Impaired decision-making in Parkinson's disease[J]. Parkinsonism Relat Disord,2006,12(3):169-175.
[27]Delazer M, Sinz H, Zamarian L, et al. Decision making under risk and under ambiguity in Parkinson's disease[J]. Neuropsychologia,2009,47(8-9):1901-1909.
[28]Iudicello JE, Woods SP, Cattie JE, et al. Risky-decision-making in HIV-associated neurocognitive disorders(HAND)[J]. Clin Neuropsychol,2013,27 (2):256-275.
[29]Gonzalez R, Vassileva J, Bechara A,et al. The influence of executive functions, sensation seeking, and HIV serostatus on the risky sexual practices of substance dependent individuals[J]. J Int Neuropsychol Soc,2005,11(2):121-131.
[30]Duarte NA, Woods SP, Rooney A, et al. Working memory deficits affect risky decision-making in methamphetamine users with attention-deficit /hyperactivity disorder[J]. J Psychiatric Res,2012,46(6):492-499.
[31]Smith B W, Mitchell DG, Hardin MG, et al.Neural substrates of reward magnitude, probability, and risk during a wheel of fortune decision-making task[J]. Neuroimage,2009,44(2):600-609.
[32]Volz KG, Schubotz RI, von Cramon DY. Frontomedian activation depends on both feedback validity and valence:fMRI evidence for contextual feedback evaluation[J]. Neuroimage,2005,27(3):564-571.
[33]Koechlin E, Corrado G, Pietrini P, et al.Dissociating the role of the medial and lateral anterior prefrontal cortex in human planning [J]. Proc Natl Acad Sci USA,2000,97(13):7651-7656.
[34]Christakou A,Brammer M,Giampietro V,et al. Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation [J]. J Neurosci,2009,29(35): 11020-11028.
[35]Rushworth MF, Noonan MP, Boorman ED, et al. Frontal cortex and reward-guided learning and decision-making [J].Neuron,2011,70(6):1054-106.
[1]Le Bihan D. Looking into the functional architecture of the brain with diffusion MRI[J].Nat Rev Neurosci,2003,4(6):469-480.
[2]Abe O, Aoki S,Hayashi N, et al.Normal aging in the central nervous system quantitative MR diffusion tensor analysis[J].Neurobiol Aging,2002,23(3):433-441.
[3]Filippi CG, Ulug AM, Ryan E, et al. Diffusion tensor imaging of patients with HIV and normal-appearing white matter on MR images of the brain[J]. Am J Neuroradiol,2001,22(2):277-283.
[4]Filley CM.White matter and behavioral neurology[J]. Ann N Y Acad Sci,2005, 1064,162-183.
[5]Benes FM, Turtle M, Khan Y,et al. Myelination of a key relay zone in the hippocampal formation occurs in the human brain during childhood, adolescence, and adulthood[J]. Arch Gen Psychiatry,1994,51 (6):477-484.
[6]Giedd JN. Structural magnetic resonance imaging of the adolescent brain[J]. Ann NY Acad Sci,2004,1021:77-85.
[7]Bartzokis G, Beckson M, Lu PH,et al. Age-related changes in frontal and temporal lobe volumes in men:a magnetic resonance imaging study[J]. Arch Gen Psychiatry,2001,58(5):461-465.
[8]Bengtsson SL,NagyZ, Skare S,et al. Extensive piano practicing has regionally specific effects on white matter development[J]. Nat Neurosci,2005,8(9): 1148-1150
[9]Chanraud S, Zahr N, Sullivan EV,et al. MR diffusion tensor imaging:a window into white matter integrity of the working brain[J]. Neuropsychol Rev,2010,20(2):209-225.
[10]Basser PJ,Mattiello J, LeBihan D, MR diffusion tensor spectroscopy and imaging[J]. Biophys J,1994,66(1):259-267.
[11]Nicoletetti G, Lodi R, Condino F, et al. Apparent diffusion coefficient measurements of the middle cerebellar peduncle differentiate the Parkinson variatent of MSA from PD and PSP[J].Brain,2006,129(Pt10):2674-2687。
[12]Lafond RE, Lukehart SA. Biological basis for syphilis[J]. Clin Microbiol Rev, 2006,19(1):29-49.
[13]Jantzen SU, Ferrea S, Langebner T,et al. Late-stage neurosyphilis presenting with severe neuropsychiatric deficits:diagnosis, therapy, and course of three patients[J]. J Neurol,2012,259(4):720-728.
[14]江婷陈少琼单鸿等。麻痹性痴呆的MRI表现(附32例报道)[J]。中华神经医学杂志,2011,10(7)：716-720.
[15]Guo Q, Zhao Q, Chen M, et al. A comparison study of mild cognitive impairment with 3 memory tests among Chinese individuals[J]. Alzheimer Dis Assoc Disord,2009,23(3):253-259.
[16]Hook EW. A syphilis wish list-better data, better tests[J]. Clin infect Dis,2012, 55(12):1623-1624.
[17]Vaillancourt DE, Spraker MB, Prodoehl J, et al. High resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease[J]. Neurology,2009,72(16):1378-1384.
[18]Koch K, Wagner G, Schachtzabel C, et al.Neural activation and radial diffusivity in schizophrenia:combined fMRI and diffusion tensor imaging study[J].Br J Psychiatry,2011,198(3):223-229.
[19]Kafantaris V, Kingsley P, Ardekani B et al.Lower orbital frontal white matter integrity in adolescentswith bipolar I disorder[J]. J Am Acad Child Adolesc Psychiatry,2009,48(1):79-86.
[20]Ragin AB, Wu Y, Storey P, et al.Diffusion tensor imaging of subcortical brain injury in patients infected with human immunodeficiency virus [J]. J Neurovirol,2005,11(3):292-298.
[21]Stubbe-Drger B, Deppe M, Mohammadi S, et al.Early microstructural white matter changes in patients with HIV:a diffusion tensor imaging study[J].BMC Neurol,2012,12:23.
[22]Miklossy J.Alzheimer's disease-a neurospirochetosis.Analysis of the evidence following Koch's and Hill's criteria[J]. J Neuroinflammation,2011, 8:90.
[23]Miklossy J. Emerging roles of pathogens in Alzheimer diseas[J]. Expert Rev Mol Med,2011,13:e30.
[24]Rovaris M, Iarnnucci G, Cercignani M, et al. Aged-relatede changes in conventional magnetization transfe and diffusion tensor MR imaging findings: study with whole brain tissue histogram analysis[J]. Radiolog,2003,227(30): 731-738.
[25]Mette RW, Henrik BWL, VanJW. Fiber crossing in human brain depicted with diffusion tensor MR imaging[J]. Radiology,2000,21(7):897-903.
[26]Burgess PW, Quayle A, Frith CD. Brain regions involved in prospective memory as determined by positron emission tomography[J]. Neuropsycholo-gia,2001,39 (6):545-555.
[27]Okuda J, Fujii T, Ohtake H, et al. Differential involvement of regions of rostral prefrontal cortex (Brodmann area 10) in time- and event-based prospective memory[J]. Int J Psychophysiol,2007,64(3):233-246.
[28]Martin T, McDaniel MA, Guyunn MJ, et al. Brain regions and their dynamics in prospective memory retrieval:A MEG study [J]. Int J Psychophysiol, 2007,64 (3):247-258.
[29]Gordon BA, Shelton JT, Bugg JM, et al. Structural Correlates of Prospective Memory[J]. Neuropsychologia,2011,49(14):3795-800.
[30]Burgess PW, Gonen-Yaacovi G, Volle E. Functional neuroimaging studies of prospective memory:What have we learnt so far[J]? Neuropsychologia,2011, 49(8):2246-2257.
[31]Reynolds JR, West R, Braver T. Distinct neural circuits support transient and sustained processes in prospective memory and working memory[J]. Cereb Cortex,2009,19(5):1208-1221.
[32]Barban F, Carlesimo GA, Macaluso E,et al. Functional brain activity within the medial and lateral portion of BA10 during a prospective memory task[J]. Behav Neurol,2013,26(3):207-209.