脑白质微结构改变与帕金森病认知功能损害的关系
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摘要
第一章背景和目的
认知功能损害是帕金森病(Parkinson's disease, PD)常见的非运动症状之一,近年来日渐受到重视。它可以表现为轻度认知功能障碍(mild cognitive impairment, MCI)或痴呆。MCI在PD早期即可出现,被称为“帕金森病合并轻度认知功能障碍(Parkinson's Disease with Mild Cognitive Impairment, PD-MCI)",即使在新诊断的PD患者中,也有约20%-30%合并MCI。它预示着将来的认知功能下降,包括进展为帕金森病痴呆(Parkinson's disease with dementia, PDD)。 MCI是PDD的独立危险因素,二者病理基础可能类似。PDD除了导致患者残疾,还会加倍PD的死亡风险并增加护理负担。对PD患者的认知功能进行早期筛查,将有助于早期发现PDD的高风险人群,可能为早期诊断和早期干预MCI创造机会,包括应用改善认知功能的药物等,从而减慢其发展为PDD的进程,改善PD预后。
临床医生需要简便快速且敏感的认知功能筛查工具。仅有少数几个量表被用于评估PD的认知功能,但是具有一定局限性。例如简易智能精神状态量表(mini mental state examination, MMSE),虽然在筛查PD患者认知功能损害仍然常用,但由于其缺少评估执行功能和复杂注意力的评估,故在该人群中的应用受到质疑。蒙特利尔认知评估量表(Montreal Cognitive Assessment, MoCA)是根据临床经验并参考MMSE的认知项目设置和评分标准而制订,是一种高效快速的MCI筛查工具。在MCI和早期阿尔兹海默病的筛查中,MoCA的敏感性高于MMSE。在早期PD患者中,执行和视空间等认知域常被累及。由于MoCA纳入了评估复杂视空间、执行和注意功能的项目,提示该量表可能较MMSE更适合筛查PD患者的认知功能损害。目前,仅有四项研究比较了MoCA和MMSE在PD人群中的应用,均提示MoCA可能更适合PD患者认知功能损害的筛查。但是,这些研究具有一些局限性。这四项结果均没有设置非PD的对照组,所以,其结果不能够证实在非PD的正常MMSE,总分的老年个体中,是否会在MoCA评估中显示同样水平的认知损害。在本研究中,我们假设MoCA在PD患者认知功能损害的筛查中较MMSE更敏感,并克服了上述研究的局限性,设置了性别、年龄和受教育程度与PD组相匹配的正常对照组来比较两个量表在筛查PD认知功能损害中的敏感性和特异性。
即便是那些病程较长的PD患者,其常规磁共振通常是正常的。核医学技术,如单光子发射计算机断层成像术(Single Poton Emission Computed Tomography, SPECT)和正电子发射计算机断层显像(Positron Emission computed Tomography, PET)使用特殊示踪技术提供了最好的诊断的敏感性及特异性,但是由于装置价格昂贵、实用性低而限制了其临床应用。弥散张量成像(Diffusion Tensor Imaging, DTI)是一种新的磁共振(Magnetic Resonance Imaging, MRI)技术,能够在三维空间内定量分析活体组织内水分子自由扩散速率和方向以间接评估白质纤维的完整性。由于DTI在脑白质体积丢失明显前就能检测到微结构改变,并且在显示白质病理学的敏感性逐渐增加,越来越多地被应用于多种神经系统疾病(如多系统萎缩、路易体痴呆、多发性硬化和肌萎缩侧索硬化)等疾病来测量活体的白质组织的微结构改变。但是关于PD患者白质改变的DTI研究却非常少。最近的DTI研究显示,PD患者的额叶、前运动区、扣带、苍白球、上纵束以及黑质-纹状体环路投射纤维等区域的部分各向异性(fractional anisotropy, FA)值下降,这提示在PD患者疾病早期即出现广泛的脑白质微结构损害。
PD患者认知功能损害的机制尚不清楚。PD的认知功能损害不同于阿尔兹海默病(Alzheimer disease, AD)。 PD认知损害所累及的认知域包括视空间、注意、记忆和执行功能等,特别是注意、视空间和执行功能损害较突出,而记忆、语言损害则不如AD明显,所以PDD以“皮质下”认知损害为主,而AD则以“皮质性”认知损害为主。这提示,白质病变可能在PD认知功能损害的发生过程发挥了重要作用。脑白质由许多纤维束组成,它将皮层和皮层下灰质连接起来,联系着脑的各个部分,在脑的高级功能中发挥着重要作用。白质的完整是保证轴突传导功能的基础。当白质发生病变,可能使得通过该部位的与智能活动有关的环路纤维联系中断,从而表现为认知功能障碍。脑白质纤维改变已经被发现与AD的发病有关。但是目前尚没有关于脑白质损害与PD认知状态的神经病理学研究。定量研究PD患者的脑白质微结构的改变对阐明PD认知功能损害的病理过程可能有重要意义。DTI能够对脑白质微结构进行定量测量,在活体评估白质的完整性。当白质的病理改变破坏了轴突的方向同一性,FA值将会下降。有几篇文章报道,在帕金森病患者的一些脑白质区域(如额叶、上纵束)出现FA值上升和平均弥散系数(mean diffusivity, MD)下降,这提示帕金森病患者脑白质微结构的改变。一些磁共振研究探讨了白质改变和PD认知状态的关系,如,有学者发现PDD患者白质改变的水平要显著高于非痴呆的PD患者,提示白质改变可能在PDD中发挥了重要作用。但是,脑白质改变对PD认知功能损害的影响仍然不清楚。
目前,国内尚没有关于脑白质微结构改变与PD认知功能状态的磁共振DTI研究,国外的相关研究也很少,其中仅有一篇文章的研究对象包括了帕金森病合并轻度认知功能障碍(PD-MCI)的患者。但这项发表于2011年的研究存在一些局限性：(1)该研究没有详细评估PD患者的认知功能状态,例如执行、记忆、视空间、注意和语言等认知域的功能损害情况,所以他们没有把PD-MCI的诊断建立在低于正常人群神经心理测试值1.5个标准差的基础上；(2)该研究使用的为1.5T磁共振,而3.0T磁共振会提供相对更为清晰的图像和更为准确的数据。在我们的研究中,根据神经心理测试组来更科学地诊断PD-MCI,并使用3.0T磁共振获得更准确图像数据。此外,我们的研究对象中同时包括了帕金森病认知正常组(PD-CogNL)、帕金森病合并轻度认知功能障碍(PD-MCI)和帕金森病痴呆(PDD)三种不同认知功能状态的帕金森病患者,更全面、更准确地探讨了脑白质改变与帕金森病认知状态的关系。在本研究中,我们假设这些脑白质微结构异常与PD患者的认知功能损害有关,白质微结构改变可能是认知障碍的病理基础,并使用磁共振DTI技术在活体中无创地比较不同认知功能状态的PD患者脑白质微结构改变的差异,分析认知功能状态与脑白质微结构改变的关系,探讨PD认知功能损害的可能病理过程。
第二章材料与方法
2.1研究对象：
2.1.1PD组：A.共纳入PD患者64例,年龄64.4l±10.433岁；符合中华医学会神经病学分会运动障碍及帕金森病学组的诊断标准。B.排除标准：各种继发性帕金森综合征及帕金森叠加综合征；曾经接受脑深部刺激等手术或伽马刀治疗的原发性PD；合并精神分裂症或其他重症精神病；严重心、肝、肾等脏器器质性损害；明显的双侧基底节钙化、明显的纹状体腔隙性梗死、脑积水和脑白质异常；无法完成MRI检查(如幽闭恐惧症等)；依从性差：汉密尔顿抑郁量表评分>20分。C.分组：根据帕金森病患者的认知功能状态分为三组。①帕金森病认知功能正常(Parkinson's Disease-Cognitively Normal, PD-CogNL)组：认知功能正常的帕金森病患者,不符合轻度认知功能障碍或帕金森病痴呆的诊断标准。②帕金森病合并轻度认知功能障碍(PD-MCI)组：参照Petersen等的诊断标准,患者有认知功能下降的主诉,在神经心理测试组所包括的四个认知域中(注意、视空间、执行和记忆),至少有一项低于正常人群的1.5个标准差。根据PD-MCI患者所累及认知域的范围,再细分为以下三种类型：遗忘型轻度认知损害(Amnesticmild cognitive impairment, aMCI);单个认知域非记忆轻度认知损害(Single non-memorymild cognitive impairment, snmMCI);多个认知域轻度认知损害(Multiple domainsmild cognitive impairment, md-MCI)。③帕金森病痴呆(PDD)组：参照国际运动障碍协会作业队(the task force of the Movement Disorder Society, MDS-TF)的PDD诊断标准。
2.1.2对照组：健康对照21例,性别、年龄和受教育程度与病例组相匹配,均无神经疾病和精神疾病病史,在磁共振成像中无结构异常,无可能影响认知功能状态的情况,简明智能精神状态量表(MMSE)评分≥26分。
2.2观察指标：
2.2.1一般资料：设计患者一般资料调查表,在患者知情的情况下收集患者一般资料,如：年龄、性别、受教育程度、职业、现病史、既往史、用药史、起病时间、症状体征等信息。
2.2.2量表评估：评定由专科的临床医师执行。①统一帕金森病评定量表(Unified Parkinson's Disease Rating Scale, UPDRS):采用UPDRS Ⅲ评价帕金森病患者运动障碍的程度。②改良的Hoehn-Yahr帕金森病分期量表：对有“开关”现象的患者评分在“开”期进行。③简易智能精神状态量表(MMSE):评估认知功能水平。④中国版韦氏成人智力量表(the Chinese revision of the Wechsler Adult Intelligence Scale, WAIS-RC)和中国版韦氏记忆量表(the Chinese revision of the Wechsler Memory Scale, WMS):评估由两名受过专门训练的医务人员严格按手册规定的方法操作。采用WAIS-RC(?)行量表中的数字广度测试、木块图、相似性项目分别评估注意、视空间和执行等功能；采用WMS的再生、理解记忆等项目评估记忆功能。⑤画钟试验(Clock Drawing Test, CDT):让被检者画一个钟表的表盘,标出所有的数字,指针指向11点10分。采用国内常用的3分计分法来计分,分为轮廓、数字和指针3个项目,每项标画正确记1分,总分3分,少于3分视为异常。⑥汉密尔顿抑郁量表(the Hamilton Depression Scale, HAMD):评价患者是否合并抑郁情绪。⑦蒙特利尔认知评估量表(Montreal Cognitive Assessment, MoCA):满分为30分。如果受试者受教育年限≤12年,则在测试结果上加1分以校正文化程度的偏倚。<26分,提示有认知功能损害。⑧MMSE和MoCA两个量表在筛查PD认知功能中的比较分析：将各个条目归结至广泛应用的认知域(如视空间、记忆、语言和定向力)。其中,视空间认知域包括两个量表的复制图形和MoCA中的画钟试验；记忆认知域包括回忆3个(MMSE)或5个(MoCA)词组；语言认知域包括两个量表中的词语重复、命名部分和MMSE中的词语阅读理解项目。此外,MoCA量表还包括了5个执行和注意认知域的项目,如：词语流畅性、数字广度、连线试验、词语抽象和听到“1”时拍手等五项。由于连续数字减法在两个量表中的权重不同,我们去除了该条目以便于更直接地比较两个量表。
2.2.3磁共振弥散张量成像(Diffusion Tensor Imaging, DTI):
(1)MR检查：使用GE Signa HDxt America3.0T MR仪进行头部扫描,使用头部正交发射、接收线圈,对所有检查对象均行颅脑MR常规平扫检查和弥散张量成像(DTI)。扫描参数如下：(1)快速梯度回波(fast-spin echo sequence, FSPE)序列T1WI,空间分辨率1.0mm×1.0mm×1.0mm, TR1794ms, TE27.3ms, TI1100ms,矩阵288×224,FOV240mm,层厚1.0mm,间距0.5mm。(2)磁共振弥散张量成像(DTI),DTI序列为16个方向,共采集704层；单次激发自旋回波EPI序列,TR12s, TE87.9ms,,矩阵130×128, FOV240mm,体素3.4×3.4×3mm3,b值1000s/mm2。轴面扫描层面平行于前-后联合线(AC-PC线)。
(2)DTI数据后处理：在AW4.4workstation工作站上运用the Functool image analysis软件包进行图像后处理,在T2WEPI(b=0)及彩色编码DTI技术(ccDTI)上,采用圆形感兴趣区(rigion-of-interest, ROI)(大小约20-50mm2)对不同脑区白质纤维进行FA值测量。于T2WEPI (b=0)图像上选取层面,分别在额叶白质、顶叶白质、颞叶白质、枕叶白质、胼胝体膝部及压部、锥体束、前扣带束、后扣带束、上纵束等区域左右对称部位选取ROI。其中额叶白质(50mm2)、胼胝体膝部(20mm2)、胼胝体压部(20mm2)、前扣带束(20mm2)、后扣带束(20mm2)和上纵束(50mm2)选择在侧脑室体部最大层面；顶叶白质(50mm2)选择在中央沟的最高层面；颞叶白质(50mm2)选择在外侧裂的最低层面；枕叶白质(50mm2)选择在侧脑室枕角的最低层面；锥体束分别选在红核层面的大脑脚(20mm2)和内囊后肢前部(20mm2)(如图2-1所示)。以扫描层面完全匹配的常规T1WI和T2WI序列作为解剖参考图像。
2.2.4统计学处理：
采用SPSS13.0统计软件包对所有数据进行统计分析。一般资料采用描述性分析；计量资料以均数±标准差(x±s)表示；计数资料采用例数(n)及百分率(%)表示。均数间多重比较,先进行Levene方差齐性检验,方差齐者采用方差分析,方差不齐者采用秩和检验；计数资料之间比较采用Pearson χ2检验。采用ROC曲线图来比较MoCA和MMSE的总分和各认知域在区分帕金森病(PD)患者和健康对照的敏感性和特异性。首先采用单因素方差分析(one-way ANOVA)比较不同认知功能状态PD患者及对照组相应脑白质区域的FA值的差异。当初步筛选出FA值有四组间显著性差异的脑白质区域后,再采用LSD ANOVA行组间两两比较。采用Logistic多元回归分析(Forward Wald)以进一步对有差异的影响因素进行校正提取。采用Spearman相关分析观察认知功能状态与FA值之间的关系。检验水准取p=0.05,p<0.05认为差异具有统计学意义。
第三章结果
3.1患者的一般资料：
帕金森病认知功能正常(PD-CogNL)组、帕金森病合并轻度认知功能障碍(PD-MCI)组、帕金森病痴呆(PDD)组和对照组在年龄、性别和受教育年限的差异无显著性意义(p>0.05)；三组不同认知功能状态的PD患者在病程年限的差异无显著性意义(p>0.05)；三组PD患者的UPDRS运动评分和Hoehn-Yahr分级的差异有统计学意义(p<0.01),其中PDD组、PD-MCI组高于PD-CogNL组。
3.2MoCA和MMSE在筛查帕金森病认知功能损害中的比较：
PD组的MoCA和MMSE,总分均低于对照组,差异有统计学意义(p<0.001)。此外,组内比较显示,不论是PD组还是对照组的MoCA,总分均低于MMSE,总分(p<0.001)。当以MMSE作为评估所有PD患者的总体认知功能标准时,64例患者中19例异常,占PD总例数的29.7%；而当以MoCA作为评估标准时,49例异常,占总数的76.6%。在45例MMSE,总分正常的PD患者中,有30例的MoCA,总分异常,占MMSE,总分正常PD患者的66.7%。我们比较了PD患者和对照组在MoCA和MMSE,总分和五个认知域的得分。曲线下面积(Area Under the Curve, AUC)分析显示,MoCA和MMSE两个量表在总分方面均能显著区分PD患者和对照组(p<0.01)；但是,MoCA,总分在保持相当水平特异性时,显示了更高的敏感性。在视空间、记忆和语言等认知域方面,只有MoCA显示了具有统计学意义的曲线下面积(AUC)；而且与MMSE相应的认知域相比,MoCA显示了更高的敏感性和特异性。两个量表在定向认知域方面的AUC均能够较好地区分PD组和对照组(p<0.01)。此外,仅有MoCA包括的执行和注意认知域在组间辨别上也显示出显著性曲线下面积(AUC)(p<0.01)。
3.3非痴呆早期PD患者脑白质微结构的改变：
根据PD患者的Hoehn-yahr分级,将其分成两组,早期PD组和中晚期PD组。前者是指Hoehn-yahr分级1-2级的PD患者,共33例,其中1例为PDD患者,故本组64例病例中,共有非痴呆早期PD患者32例。我们比较了两组相应脑白质区域的FA值。我们发现,非痴呆早期PD患者的一些脑白质区域(如双侧颞叶、左侧前扣带束和胼胝体压部)的FA值较对照组降低,两组差异有统计学意义(p<0.05)。
3.4PD患者认知功能状态与脑白质改变的关系：
与对照组相比,帕金森病痴呆(PDD)组和帕金森病合并轻度认知功能障碍(PD-MCI)组的左侧额叶、右侧颞叶白质和双侧前扣带束的FA值下降；PD-MCI组的左侧颞叶白质和胼胝体膝部的FA值下降；帕金森病认知功能正常(PD-CogNL)组的左侧枕叶白质和左侧前扣带束的FA值下降,差异有显著性意义(p<0.05). PDD左侧扣带前束和胼胝体压部的FA值低于其他三组,差异有统计学意义(p<0.05)。采用Logistic回归校正了UPDRS运动评分和Hoehn-yahr分级的影响后,左侧扣带前束和胼胝体膝部的FA值的下降仍有统计学意义(p<0.05)。但是,四组在其他脑白质部位的FA值无显著性差异。我们按照PD患者的三种认知功能状态,即认知正常、轻度认知功能障碍和痴呆进行等级划分；并将FA值有组间显著性差异的脑白质部位筛选出来后,采用Spearman相关分析了这些部位FA值与PD患者认知功能状态的关系。Spearman相关分析显示,左侧额叶、右侧颞叶、左侧枕叶、左侧扣带前束、右侧扣带前束、胼胝体压部的FA值与PD患者的认知功能状态呈负相关(p<0.05)。提示帕金森病患者认知状态越差,部分脑白质区域的FA值下降越明显。
第四章结论
4.1认知功能损害是帕金森病(PD)患者常见的非运动症状之一,即使在PD的早期,其发生率也较高。其中单认知域损害较多认知域损害更为常见,以记忆、执行及视空间等认知域损害相对较多,对PD患者进行认知功能筛查有重要意义。
4.2蒙特利尔认知评估量表(MoCA)在筛查帕金森病患者认知功能损害方面优于简明智能精神状态量表(MMSE)。MoCA量表在相当水平特异性时,在总分和多个认知域(如视空间、记忆和语言)的敏感性均高于MMSE。
4.3非痴呆早期PD患者部分脑白质区域的各项异性值(FA)下降,提示在PD患者在疾病早期即出现较广泛的脑白质微结构的改变,也提示PD患者的脑损害延伸至基底节之外,这可能是PD患者一些非运动症状的基础。使用磁共振弥散张量成像(DTI)评估PD患者脑白质微结构的损害可能有助于早期诊断及病情的监测。
4.4PD患者部分脑白质区域的微结构改变与其认知功能状态相关。左侧前扣带束、胼胝体膝部可能在PD认知功能损害的发生过程中发挥重要作用。脑白质微结构改变可能是PD患者认知功能损害的病理基础之一。
Chapter I:Background and Objective
Cognitive impairment, an important non-motor feature of Parkinson's disease(PD), has recently gained increasing recognition. It can range from mild cognitive impairment (MCI) to dementia. It is estimated that MCI occur in20%to30%of the patients with PD, even among those newly diagnosed, and predict future cognitive decline, including progression to PD with dementia (PDD). MCI is one of key risk factors for PDD. Beside the disability it creates, PDD doubles the mortality risk of PD and increased caregiver burden. Early diagnosis of MCI will create a potential new target for therapeutic intervention, which may be more effective at slowing progression for PDD.
A rapid and easily applied screening test sensitive to cognitive impairment in PD is a more practical approach for clinicians. Only few screening measures have been developed to assess global cognitive functioning in PD, but each has its own limitations. The Mini-Mental State Examination (MMSE) remains the most commonly used screening instrument for PD, but its use in this population has been questioned, both because the MMSE relies heavily on intact verbal rather than visuospatial skills, and because it lacks items to assess executive functions and complex attention. Recently, a new cognitive screening instrument, the Montreal Cognitive Assessment (MoCA), was designed to address some of the limitations of the MMSE. It assesses a broader range of cognitive domains than the MMSE and is more challenging from a cognitive standpoint overall. The MoCA has been shown to be more sensitive than the MMSE for the detection of MCI and mild AD in the general population. The domains of executive and visuospatial function are known to be affected in early PD. Owing to inclusion of complex visuospatial, executive function and attention items into the MoCA, it is implied that MoCA maybe more sensitive than MMSE in evaluating cognitive deficits in PD. There were four studies that used the MoCA in PD populations, and all suggest that the MoCA may be a more appreciate screening instrument for cognitive impairment seen in PD, which is according to our findings. However, these studies have some limitations. However, all of them did not have matched non-PD control group, so it cannot be confirmed whether the non-PD elderly individuals having normal MMSE scores would have demonstrated similar levels of deficits on the MoCA scores. In our study, we hypothesized that the MoCA would be more sensitive than the more widely used MMSE to cognitive impairment in the individuals with PD, and included matched health controls to compare the specificity and sensitivity of two instuments in detecting cognitive impairment of PD.
Structural MR imaging results are usually normal in PD patients, even in those undergoing a long disease duration. Single-photon emission CT and Positron-emission tomography, nuclear medicine techniques, provide the best diagnostic sensitivity and specificity, however high cost and low availability of equipment limited their vability. Diffusion tensor imaging (DTI), an MRI technique, can indirectly evaluate the integrity of white-matter tracts by measuring water diffusion and its directionality in three dimensions. Due to its capability of detecting the microstructural alteration of the white matter before volume loss becomes evident, DTI is increasingly being used to measure white-matter tissue microstructure in vivo in various neurological diseases such as multiple system atrophy, diffuse Lewy body disease, multiple sclerosis and amyotrophic lateral sclerosis. However, there are few studies characterizing white matter diffusion changes in patients with PD. Some recent DTI studies showed the evidence that reduced FA in patients with PD in front lobes, premotor areas, the cingulum, in the corpus callosum and the superior longitudinal fasciculus, in the region of interest along a line between the substantia nigra and the lower part of the putamen/caudate complex, suggesting widespread microstructural damage to white matter occurs in early stages of PD.
The pathological process of cognitive impairment in PD patients is still unclear. The impaired cognitive domains of PDD are different from that of Alzheimer disease (AD). A wide variety of cognitive deficits in the patients with PD have been reported, even early in the course of the disease, including visuospatial, attention, memory and executive function. Specifically, deficits in attention, visuospatial and executive functions tend to predominate in PDD, however memory and language impairments play a less significant role than they do in AD, so that a "subcortical"cognitive impairment pattern dominates in PDD. White matter comprises many tracts interconnecting parts of the brain, and it play important roles in higher brain functions. White matter alterations are described to contribute to dementia in Alzheimer disease. To our knowledge, there still have no neuropathological studies detecting the relationship between white matter damage and cognitive status in Parkinson's disease. Quantitative studies of white matter in vivo may be helpful to elucidate the pathological process of cognitive deficits in PD. Diffusion tensor imaging (DTI) can provide quantitative measures of the microstructural integrity of white matter and can ewaluates the microstructural alterations of the white matter via water diffusion in vivo. When white-matter pathology disrupts the coherent orientation of axons, FA of tissue will decrease. Several DTI studies in PD patients have reported decreased fractional anisotropy (FA) and increased mean diffusivity (MD) of white matter, including the frontal lobe, and superior cerebellar peduncle, which implied degradation of the microstructure. Some MRI studies investigated the relationship between white matter and cognitive status in PD. For example, some previous studies found that PDD had significantly higher levels of white matter alterations than the PD without dementia. These findings suggest that white matter alterations may contribute to dementia in PD. However, the effect of white matter alterations on cognitive impairment of the patients with PD is still unclear.
As far as we know, only a few studies investigated the relationship between white matter alteration and cognitive status in PD by using diffusion tensor imaging, and only one of them studied the relationship between white matter alteration and cognitive status in PD including PD-MCI, and PDD at the same time. However, there were some limitations in this study published in2011:for example, they did not assess detailed neuropsychological status of patients such as executive, amnestic, visuospatial, attention, and language deficits, so they did not define patients with PD-MCI based on1.5standard deviation below mean score in neuropsychological tests; all MRI scans of this study were acquired on the same1.5Tesla clinical scanner, which probably provide less accruable data compared to3.0Tesla clinical scanner. In our study, we defined PD-MCI based on Neuropsychoclogical test battery, acquired all data from3.0T MR, and drawing the ROIs, a simple and practical measure which could easily be implemented in any clinical radiological setting, aimed to investigate the relationship between white matter alteration and cognitive status including both PD-MCI and PDD. We hypothesized that abnormalities of white matter microstructure is related to the cognitive impairment in PD. In this study, we compared the white-matter alteration among the PD patients with different cognitive status by DTI to elucidate the probably pathological process of conginite impairment in PD.
Chapter Ⅱ:Materials and Methods
2.1Subjects
Sixty-four patients with idiopathic PD (34men and30women; mean age,64.41±10.433years) were enrolled. The diagnosis of possible or probable PD was confirmed by a movement disorders specialist according to established criteria. Basic demographic and clinical information, including the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr stage were obtained from all PD subjects. Exclusion Criteria include:(1) Patients who had undergone deep brain stimulation (DBS) were excluded.(2) Subjects whose MR imaging finding suggests a diagnosis of atypical parkinsonism were excluded.(3) Subjects who had other brain disorders, or underlying diseases that could affect the brain such as uncontrolled hypertension and chronic kidney diseases, were excluded.(4) Subjects who scored above20on the Hamilton Depression Scale (HAMD) were excluded, because of the concern that depression can affect scores on neuropsychologic testing.(5) The patients who could not have MRI performed were excluded.
All patients underwent a neuropsychological test battery, and then were divided into three groups according to their cognitive status:(1) Parkinson's Disease-Cognitively Normal (PD-CogNL). Subjects were found to be cognitively intact and reported no functional deficit due to cognitive problems. They did not meet criteria for MCI or dementia as outlined below.(2) Parkinson's Disease-Mild Cognitive Impairment (PD-MCI). Criteria for PD-MCI were along the lines of Petersen et al. Individuals had subjective cognitive complaint(s), demonstrated a deficit of at least1.5standard deviation (SD) below the normative data mean score in at least one of four cognitive domains assessed in the battery, but cognitive deficits did not result in significant functional decline. Table1shows the neuropsychological test battery with the associated cognitive domains.(3) PD with dementia (PDD). PDD was diagnosed by the criteria of the task force of the Movement Disorder Society (MDS-TF). Based on the aforementioned above criteria, were enrolled24PD-CogNL,30PD-MCI and10PDD cases.
21age-and sex-matched healthy control persons were recruited. All of them had negative anamnesis for neurologic and psychiatric disorders, no relative with a diagnosis of parkinsonism, no abnormalities on structural MR imaging, and no condition that might impair cognition (i.e., head injury, and substance abuse). Controls were assessed with the Mini-Mental State Examination and had a total score greater than26.
2.2Neuropsychoclogical test
Subjects were administered some Neuropsychoclogical tests following standard procedures by trained research staff. The tests included the Mini-Mental State Examination (MMSE); the Beijing Montreal Cognitive Assessment(MoCA); the Chinese revision of the Wechsler Adult Intelligence Scale(WAIS-RC); the Chinese revision of the Wechsler Memory Scale(WMS); the Diagnostic and Statistical Manual IV(DSM-IV) and the Hamilton Depression Scale. Patients were encouraged to take their regularly scheduled PD medications during the study visit so that they would be evaluated in their "on" state. The MMSE and the Beijing MoCA assess a range of cognitive skills on a scale of0to30points with higher scores indicating better performance and a suggested impairment cutoff of a score less than26on either test. One point was added to an individual's score of MoCA if she/he had twelve years or fewer of formal education, for a total maximum of30points. Seeing that the items included in two instruments vary by type and level of difficulty, and identical items receive differential weighting, an item-by-item comparison is unsuitable for this study. As an alternative, we divided individual items into four widely used cognitive domains (visuospatial, memory, language, and orientation) based on previous researches. The visuospatial items included design copy(both tests) and figure drawing to command (MoCA only). The memory items included recall of either three (MMSE) or five (MoCA) previously presented words. The language items included phrase/sentence repetition, naming (both tests), verbal commands, and reading comprehension (MMSE only). The MoCA also includes a fifth executive function/attention domain comprised of items for phonemic fluency, visuospatial sequencing/alternation based on auditory span,verbal abstraction, and target detection using auditory attention for the number "1". Because of differential weighting of the serial subtraction items in two tests, we leaved out this item to permit more direct comparisons between instruments.
2.3MRI Acquisition Protocol
All MRI scans were acquired on the same3.0Tesla clinical scanner (GE Signa HDxt America) with8Channel head coil. Head motion was minimised with restraining foam pads provided by the manufacturer. High-resolution T1-weighted MRI was acquired axially using fast-spin echo sequence with the parameters of288×224acquisition,240mm field of view, TE27.3ms and TR1794ms. Diffusion tensor images were then obtained using single-shot echo-planar acquisition from16gradient directions with the following parameters:130×128acquisition matrix with704slices,240mm field of view,3.4×3.4×3mm3voxels, TE87.9ms, TR12s, b-factor of1000s/mm2, without cardiac gating.
2.4ROIs Analysis of FA
All images were post-processed on a AW4.4workstation using a program of the Functool image analysis software (GE Healthcare). FA values were obtained from various white matter regions on the DTI scan using regions of interest (ROIs), positioned as shown in Fig1. ROIs setting and measurement of FA values were performed by an experienced neuroradiologist blinded to the profiles of patients. The FA values of ROIs were compared between the four groups. Temporal white matter ROIs (50mm2) was sampled posterolaterally to the lateral fissure on the most caudal slice where the lateral fissure was present. Frontal white matter (50mm2), anterior/posterior cingulate bundle (20mm2), genu and splenium of the corpus callosum (20mm2), and superior longitudinal fasciculus (50mm2) were sampled on the slice that included a fully volumed lateral ventricule. ROIs of parietal white matter (50mm2) were positioned in the white matter posterior to the central sulcus on the most caudal slice where it was visible. The occipital white matter (50mm2) was placed within the optic radiations on the most caudal slice where the occipital horn of the lateral ventricle was imaged. An ROI positioned on the corticospinal tract (20mm2) at the level of the red nucleus, an ROI positioned on the corticospinal tract at the level of the internal capsule (20mm2).
2.5Statistical Analysis
Statistical analyses were carried out using SPSS software. Statistical analysis of demographic and clinical data was performed using analysis of variance with post-hoc Turkey's HSD test for continuous variables, Kruskal-Wallis test with post-hoc Mann-Whitney U-tests for noncontinuous variables, and v2test for categorical data. The receiver operating characteristic (ROC) analyses were used to examine the ability of the two tests to differentiate between PD and control subjects by the total scores and cognitive domains. FA values were compared among the four groups using one-way ANOVA. Fisher's PLSD was used for post-hoc analysis. The Unified Parkinoson's Disease Rating Scale (UPDRS) motor score, Hoehn-yahr stage and each FA value that showed significant differences in the first analysis were then used as variables for Logistic regression analysis, and corrected the influence of UPDRS motor score and Hoehn-yahr stage. We also examined correlation analysis between FA values that showed a significant difference and the different status of PD patients. A two-sided significance level of P<0.05was considered to be statistical significant.
Chapter III:Result
There were no significant differences on age, gender, disease duration, or education years among PD-CogNL, PD-MCI, PDD and controls. Both the UPDRS motor score and Hoehn-Yahr stage were significantly higher in PDD (P<0.01), and PD-MCI (P<0.05) compared to patients with PD-CogNL.
3.1A comparison of MoCA and MMSE for screening cognitive deficits in the patients with Parkinson's disease
Compared with controls, the PD group had significantly lower total scores on both the MoCA and the MMSE. The scores'ranges of the MoCA in both PD group and controls were broader than that of the MMSE. In addition, within-group comparisons indicated that both the PD (Wilcoxon z=-6.707; P<0.01) and controls (Wilcoxon z=-3.147; P<0.05) scores lower on the MoCA compared to the MMSE. When we evaluated the congntive function of the patients with PD by MoCA,76.6%of them were abnormal, however when evaluated by MMSE, only29.7%were abnormal. Among45PD patients having normal MMSE scores,66.7%of them met predefined criteria for cognitive impairment based on their MoCA score. We examined performance of the two groups on total scores and five cognitive domains by ROC analysis. The area under the curve (AUC) values showed that both instruments could significantly differentiate PD from controls on total scores; however, the MoCA score yielded higher sensitivity than the MMSE while maintaining a comparable level of specificity. Both tests accomplished group discrimination on orientation domain successfully. On the contrary, only the MoCA yielded significant AUC values for visuospatial, memory, and language scores, with higher sensitivity and specificity relative to the comparable MMSE domains. Moreover, executive function/attention score of the MoCA yielded a significant AUC for group discrimination.
3.2The white matter alterations in the patients with PD without dementia
In the patients with PD without dementia (Hoehn and Yahr stages I and II), the FA were decresed in some white matter regions, such as bilateral temporal, left anterior cingulate bundle and splenium of the corpus callosum.
3.3FA values comparison among PD patients with different cognitive status:
Median FA values for each of the white matter regions in four groups are showed in table3-6. Compared to controls, PDD and PD-MCI showed a significant FA reduction in left frontal, right temporal white matter and bilateral anterior cingulated bundles; PD-MCI showed a significant FA reduction in temporal white matter and genu of the corpus callosum; PD-CogNL showed significant FA reduction in left occipital white matter and left anterior cingulated bundle. PDD showed a significant FA reduction in left anterior cingulated bundle, splenium of the corpus callosum compared to other three groups. Even after considering the influence of UPDRS motor score and Hoehn-yahr stage, the FA reduction in left anterior cingulated bundle and genu of the corpus callosum remained significant. However, no significant FA difference was demonstrated for other areas between the four groups. There were significant negative correlations between cognitive status of PD and FA values of some white matter, such as:left frontal, right temporal, left occipital white matter, bilateral anterior cingulated bundles and splenium of the corpus callosum.
Chapter IV:Conclusion
4.1Cognitive impairment is a common non-motor feature of Parkinson's disease (PD), even among those in the early stages of disease, and single domainmild cognitive impairment is more common than multiple domainsmild cognitive impairment. It is important to recognize cognitive impairment in the patients with PD.
4.2The Montreal Cognitive Assessment (MoCA) achieved higher sensitivity to screening cognitive impairment in the patients with PD without sacrificing specificity in tototal score and many domains relative to the Mini-Mental State Examination (MMSE). MoCA appears to be the preferable measure for screening cognitive impairment in the patients with PD.
4.3In the patients with PD without dementia, the FA were decresed in some white matter regions, which implied widespread microstrutural damage occurs already in the early stages of PD. DTI is helpful to evaluate the white matter damage in PD.
4.4The patients with PD had significant micro structural alteration in the some white matter, and correlated with the cognitive status of patients. White matter damage especially in the left anterior cingulate bundle and genu of the corpus callosum probably underlies the cognitive impairments of PD to some extent.
认知功能损害是帕金森病(Parkinson's disease, PD)常见的非运动症状之一,近年来日渐受到重视。它可以表现为轻度认知功能障碍(mild cognitive impairment, MCI)或痴呆。MCI在PD早期即可出现,被称为“帕金森病合并轻度认知功能障碍(Parkinson's Disease with Mild Cognitive Impairment, PD-MCI)",即使在新诊断的PD患者中,也有约20%-30%合并MCI。它预示着将来的认知功能下降,包括进展为帕金森病痴呆(Parkinson's disease with dementia, PDD)。 MCI是PDD的独立危险因素,二者病理基础可能类似。PDD除了导致患者残疾,还会加倍PD的死亡风险并增加护理负担。对PD患者的认知功能进行早期筛查,将有助于早期发现PDD的高风险人群,可能为早期诊断和早期干预MCI创造机会,包括应用改善认知功能的药物等,从而减慢其发展为PDD的进程,改善PD预后。
临床医生需要简便快速且敏感的认知功能筛查工具。仅有少数几个量表被用于评估PD的认知功能,但是具有一定局限性。例如简易智能精神状态量表(mini mental state examination, MMSE),虽然在筛查PD患者认知功能损害仍然常用,但由于其缺少评估执行功能和复杂注意力的评估,故在该人群中的应用受到质疑。蒙特利尔认知评估量表(Montreal Cognitive Assessment, MoCA)是根据临床经验并参考MMSE的认知项目设置和评分标准而制订,是一种高效快速的MCI筛查工具。在MCI和早期阿尔兹海默病的筛查中,MoCA的敏感性高于MMSE。在早期PD患者中,执行和视空间等认知域常被累及。由于MoCA纳入了评估复杂视空间、执行和注意功能的项目,提示该量表可能较MMSE更适合筛查PD患者的认知功能损害。目前,仅有四项研究比较了MoCA和MMSE在PD人群中的应用,均提示MoCA可能更适合PD患者认知功能损害的筛查。但是,这些研究具有一些局限性。这四项结果均没有设置非PD的对照组,所以,其结果不能够证实在非PD的正常MMSE,总分的老年个体中,是否会在MoCA评估中显示同样水平的认知损害。在本研究中,我们假设MoCA在PD患者认知功能损害的筛查中较MMSE更敏感,并克服了上述研究的局限性,设置了性别、年龄和受教育程度与PD组相匹配的正常对照组来比较两个量表在筛查PD认知功能损害中的敏感性和特异性。
即便是那些病程较长的PD患者,其常规磁共振通常是正常的。核医学技术,如单光子发射计算机断层成像术(Single Poton Emission Computed Tomography, SPECT)和正电子发射计算机断层显像(Positron Emission computed Tomography, PET)使用特殊示踪技术提供了最好的诊断的敏感性及特异性,但是由于装置价格昂贵、实用性低而限制了其临床应用。弥散张量成像(Diffusion Tensor Imaging, DTI)是一种新的磁共振(Magnetic Resonance Imaging, MRI)技术,能够在三维空间内定量分析活体组织内水分子自由扩散速率和方向以间接评估白质纤维的完整性。由于DTI在脑白质体积丢失明显前就能检测到微结构改变,并且在显示白质病理学的敏感性逐渐增加,越来越多地被应用于多种神经系统疾病(如多系统萎缩、路易体痴呆、多发性硬化和肌萎缩侧索硬化)等疾病来测量活体的白质组织的微结构改变。但是关于PD患者白质改变的DTI研究却非常少。最近的DTI研究显示,PD患者的额叶、前运动区、扣带、苍白球、上纵束以及黑质-纹状体环路投射纤维等区域的部分各向异性(fractional anisotropy, FA)值下降,这提示在PD患者疾病早期即出现广泛的脑白质微结构损害。
PD患者认知功能损害的机制尚不清楚。PD的认知功能损害不同于阿尔兹海默病(Alzheimer disease, AD)。 PD认知损害所累及的认知域包括视空间、注意、记忆和执行功能等,特别是注意、视空间和执行功能损害较突出,而记忆、语言损害则不如AD明显,所以PDD以“皮质下”认知损害为主,而AD则以“皮质性”认知损害为主。这提示,白质病变可能在PD认知功能损害的发生过程发挥了重要作用。脑白质由许多纤维束组成,它将皮层和皮层下灰质连接起来,联系着脑的各个部分,在脑的高级功能中发挥着重要作用。白质的完整是保证轴突传导功能的基础。当白质发生病变,可能使得通过该部位的与智能活动有关的环路纤维联系中断,从而表现为认知功能障碍。脑白质纤维改变已经被发现与AD的发病有关。但是目前尚没有关于脑白质损害与PD认知状态的神经病理学研究。定量研究PD患者的脑白质微结构的改变对阐明PD认知功能损害的病理过程可能有重要意义。DTI能够对脑白质微结构进行定量测量,在活体评估白质的完整性。当白质的病理改变破坏了轴突的方向同一性,FA值将会下降。有几篇文章报道,在帕金森病患者的一些脑白质区域(如额叶、上纵束)出现FA值上升和平均弥散系数(mean diffusivity, MD)下降,这提示帕金森病患者脑白质微结构的改变。一些磁共振研究探讨了白质改变和PD认知状态的关系,如,有学者发现PDD患者白质改变的水平要显著高于非痴呆的PD患者,提示白质改变可能在PDD中发挥了重要作用。但是,脑白质改变对PD认知功能损害的影响仍然不清楚。
目前,国内尚没有关于脑白质微结构改变与PD认知功能状态的磁共振DTI研究,国外的相关研究也很少,其中仅有一篇文章的研究对象包括了帕金森病合并轻度认知功能障碍(PD-MCI)的患者。但这项发表于2011年的研究存在一些局限性：(1)该研究没有详细评估PD患者的认知功能状态,例如执行、记忆、视空间、注意和语言等认知域的功能损害情况,所以他们没有把PD-MCI的诊断建立在低于正常人群神经心理测试值1.5个标准差的基础上；(2)该研究使用的为1.5T磁共振,而3.0T磁共振会提供相对更为清晰的图像和更为准确的数据。在我们的研究中,根据神经心理测试组来更科学地诊断PD-MCI,并使用3.0T磁共振获得更准确图像数据。此外,我们的研究对象中同时包括了帕金森病认知正常组(PD-CogNL)、帕金森病合并轻度认知功能障碍(PD-MCI)和帕金森病痴呆(PDD)三种不同认知功能状态的帕金森病患者,更全面、更准确地探讨了脑白质改变与帕金森病认知状态的关系。在本研究中,我们假设这些脑白质微结构异常与PD患者的认知功能损害有关,白质微结构改变可能是认知障碍的病理基础,并使用磁共振DTI技术在活体中无创地比较不同认知功能状态的PD患者脑白质微结构改变的差异,分析认知功能状态与脑白质微结构改变的关系,探讨PD认知功能损害的可能病理过程。
第二章材料与方法
2.1研究对象：
2.1.1PD组：A.共纳入PD患者64例,年龄64.4l±10.433岁；符合中华医学会神经病学分会运动障碍及帕金森病学组的诊断标准。B.排除标准：各种继发性帕金森综合征及帕金森叠加综合征；曾经接受脑深部刺激等手术或伽马刀治疗的原发性PD；合并精神分裂症或其他重症精神病；严重心、肝、肾等脏器器质性损害；明显的双侧基底节钙化、明显的纹状体腔隙性梗死、脑积水和脑白质异常；无法完成MRI检查(如幽闭恐惧症等)；依从性差：汉密尔顿抑郁量表评分>20分。C.分组：根据帕金森病患者的认知功能状态分为三组。①帕金森病认知功能正常(Parkinson's Disease-Cognitively Normal, PD-CogNL)组：认知功能正常的帕金森病患者,不符合轻度认知功能障碍或帕金森病痴呆的诊断标准。②帕金森病合并轻度认知功能障碍(PD-MCI)组：参照Petersen等的诊断标准,患者有认知功能下降的主诉,在神经心理测试组所包括的四个认知域中(注意、视空间、执行和记忆),至少有一项低于正常人群的1.5个标准差。根据PD-MCI患者所累及认知域的范围,再细分为以下三种类型：遗忘型轻度认知损害(Amnesticmild cognitive impairment, aMCI);单个认知域非记忆轻度认知损害(Single non-memorymild cognitive impairment, snmMCI);多个认知域轻度认知损害(Multiple domainsmild cognitive impairment, md-MCI)。③帕金森病痴呆(PDD)组：参照国际运动障碍协会作业队(the task force of the Movement Disorder Society, MDS-TF)的PDD诊断标准。
2.1.2对照组：健康对照21例,性别、年龄和受教育程度与病例组相匹配,均无神经疾病和精神疾病病史,在磁共振成像中无结构异常,无可能影响认知功能状态的情况,简明智能精神状态量表(MMSE)评分≥26分。
2.2观察指标：
2.2.1一般资料：设计患者一般资料调查表,在患者知情的情况下收集患者一般资料,如：年龄、性别、受教育程度、职业、现病史、既往史、用药史、起病时间、症状体征等信息。
2.2.2量表评估：评定由专科的临床医师执行。①统一帕金森病评定量表(Unified Parkinson's Disease Rating Scale, UPDRS):采用UPDRS Ⅲ评价帕金森病患者运动障碍的程度。②改良的Hoehn-Yahr帕金森病分期量表：对有“开关”现象的患者评分在“开”期进行。③简易智能精神状态量表(MMSE):评估认知功能水平。④中国版韦氏成人智力量表(the Chinese revision of the Wechsler Adult Intelligence Scale, WAIS-RC)和中国版韦氏记忆量表(the Chinese revision of the Wechsler Memory Scale, WMS):评估由两名受过专门训练的医务人员严格按手册规定的方法操作。采用WAIS-RC(?)行量表中的数字广度测试、木块图、相似性项目分别评估注意、视空间和执行等功能；采用WMS的再生、理解记忆等项目评估记忆功能。⑤画钟试验(Clock Drawing Test, CDT):让被检者画一个钟表的表盘,标出所有的数字,指针指向11点10分。采用国内常用的3分计分法来计分,分为轮廓、数字和指针3个项目,每项标画正确记1分,总分3分,少于3分视为异常。⑥汉密尔顿抑郁量表(the Hamilton Depression Scale, HAMD):评价患者是否合并抑郁情绪。⑦蒙特利尔认知评估量表(Montreal Cognitive Assessment, MoCA):满分为30分。如果受试者受教育年限≤12年,则在测试结果上加1分以校正文化程度的偏倚。<26分,提示有认知功能损害。⑧MMSE和MoCA两个量表在筛查PD认知功能中的比较分析：将各个条目归结至广泛应用的认知域(如视空间、记忆、语言和定向力)。其中,视空间认知域包括两个量表的复制图形和MoCA中的画钟试验；记忆认知域包括回忆3个(MMSE)或5个(MoCA)词组；语言认知域包括两个量表中的词语重复、命名部分和MMSE中的词语阅读理解项目。此外,MoCA量表还包括了5个执行和注意认知域的项目,如：词语流畅性、数字广度、连线试验、词语抽象和听到“1”时拍手等五项。由于连续数字减法在两个量表中的权重不同,我们去除了该条目以便于更直接地比较两个量表。
2.2.3磁共振弥散张量成像(Diffusion Tensor Imaging, DTI):
(1)MR检查：使用GE Signa HDxt America3.0T MR仪进行头部扫描,使用头部正交发射、接收线圈,对所有检查对象均行颅脑MR常规平扫检查和弥散张量成像(DTI)。扫描参数如下：(1)快速梯度回波(fast-spin echo sequence, FSPE)序列T1WI,空间分辨率1.0mm×1.0mm×1.0mm, TR1794ms, TE27.3ms, TI1100ms,矩阵288×224,FOV240mm,层厚1.0mm,间距0.5mm。(2)磁共振弥散张量成像(DTI),DTI序列为16个方向,共采集704层；单次激发自旋回波EPI序列,TR12s, TE87.9ms,,矩阵130×128, FOV240mm,体素3.4×3.4×3mm3,b值1000s/mm2。轴面扫描层面平行于前-后联合线(AC-PC线)。
(2)DTI数据后处理：在AW4.4workstation工作站上运用the Functool image analysis软件包进行图像后处理,在T2WEPI(b=0)及彩色编码DTI技术(ccDTI)上,采用圆形感兴趣区(rigion-of-interest, ROI)(大小约20-50mm2)对不同脑区白质纤维进行FA值测量。于T2WEPI (b=0)图像上选取层面,分别在额叶白质、顶叶白质、颞叶白质、枕叶白质、胼胝体膝部及压部、锥体束、前扣带束、后扣带束、上纵束等区域左右对称部位选取ROI。其中额叶白质(50mm2)、胼胝体膝部(20mm2)、胼胝体压部(20mm2)、前扣带束(20mm2)、后扣带束(20mm2)和上纵束(50mm2)选择在侧脑室体部最大层面；顶叶白质(50mm2)选择在中央沟的最高层面；颞叶白质(50mm2)选择在外侧裂的最低层面；枕叶白质(50mm2)选择在侧脑室枕角的最低层面；锥体束分别选在红核层面的大脑脚(20mm2)和内囊后肢前部(20mm2)(如图2-1所示)。以扫描层面完全匹配的常规T1WI和T2WI序列作为解剖参考图像。
2.2.4统计学处理：
采用SPSS13.0统计软件包对所有数据进行统计分析。一般资料采用描述性分析；计量资料以均数±标准差(x±s)表示；计数资料采用例数(n)及百分率(%)表示。均数间多重比较,先进行Levene方差齐性检验,方差齐者采用方差分析,方差不齐者采用秩和检验；计数资料之间比较采用Pearson χ2检验。采用ROC曲线图来比较MoCA和MMSE的总分和各认知域在区分帕金森病(PD)患者和健康对照的敏感性和特异性。首先采用单因素方差分析(one-way ANOVA)比较不同认知功能状态PD患者及对照组相应脑白质区域的FA值的差异。当初步筛选出FA值有四组间显著性差异的脑白质区域后,再采用LSD ANOVA行组间两两比较。采用Logistic多元回归分析(Forward Wald)以进一步对有差异的影响因素进行校正提取。采用Spearman相关分析观察认知功能状态与FA值之间的关系。检验水准取p=0.05,p<0.05认为差异具有统计学意义。
第三章结果
3.1患者的一般资料：
帕金森病认知功能正常(PD-CogNL)组、帕金森病合并轻度认知功能障碍(PD-MCI)组、帕金森病痴呆(PDD)组和对照组在年龄、性别和受教育年限的差异无显著性意义(p>0.05)；三组不同认知功能状态的PD患者在病程年限的差异无显著性意义(p>0.05)；三组PD患者的UPDRS运动评分和Hoehn-Yahr分级的差异有统计学意义(p<0.01),其中PDD组、PD-MCI组高于PD-CogNL组。
3.2MoCA和MMSE在筛查帕金森病认知功能损害中的比较：
PD组的MoCA和MMSE,总分均低于对照组,差异有统计学意义(p<0.001)。此外,组内比较显示,不论是PD组还是对照组的MoCA,总分均低于MMSE,总分(p<0.001)。当以MMSE作为评估所有PD患者的总体认知功能标准时,64例患者中19例异常,占PD总例数的29.7%；而当以MoCA作为评估标准时,49例异常,占总数的76.6%。在45例MMSE,总分正常的PD患者中,有30例的MoCA,总分异常,占MMSE,总分正常PD患者的66.7%。我们比较了PD患者和对照组在MoCA和MMSE,总分和五个认知域的得分。曲线下面积(Area Under the Curve, AUC)分析显示,MoCA和MMSE两个量表在总分方面均能显著区分PD患者和对照组(p<0.01)；但是,MoCA,总分在保持相当水平特异性时,显示了更高的敏感性。在视空间、记忆和语言等认知域方面,只有MoCA显示了具有统计学意义的曲线下面积(AUC)；而且与MMSE相应的认知域相比,MoCA显示了更高的敏感性和特异性。两个量表在定向认知域方面的AUC均能够较好地区分PD组和对照组(p<0.01)。此外,仅有MoCA包括的执行和注意认知域在组间辨别上也显示出显著性曲线下面积(AUC)(p<0.01)。
3.3非痴呆早期PD患者脑白质微结构的改变：
根据PD患者的Hoehn-yahr分级,将其分成两组,早期PD组和中晚期PD组。前者是指Hoehn-yahr分级1-2级的PD患者,共33例,其中1例为PDD患者,故本组64例病例中,共有非痴呆早期PD患者32例。我们比较了两组相应脑白质区域的FA值。我们发现,非痴呆早期PD患者的一些脑白质区域(如双侧颞叶、左侧前扣带束和胼胝体压部)的FA值较对照组降低,两组差异有统计学意义(p<0.05)。
3.4PD患者认知功能状态与脑白质改变的关系：
与对照组相比,帕金森病痴呆(PDD)组和帕金森病合并轻度认知功能障碍(PD-MCI)组的左侧额叶、右侧颞叶白质和双侧前扣带束的FA值下降；PD-MCI组的左侧颞叶白质和胼胝体膝部的FA值下降；帕金森病认知功能正常(PD-CogNL)组的左侧枕叶白质和左侧前扣带束的FA值下降,差异有显著性意义(p<0.05). PDD左侧扣带前束和胼胝体压部的FA值低于其他三组,差异有统计学意义(p<0.05)。采用Logistic回归校正了UPDRS运动评分和Hoehn-yahr分级的影响后,左侧扣带前束和胼胝体膝部的FA值的下降仍有统计学意义(p<0.05)。但是,四组在其他脑白质部位的FA值无显著性差异。我们按照PD患者的三种认知功能状态,即认知正常、轻度认知功能障碍和痴呆进行等级划分；并将FA值有组间显著性差异的脑白质部位筛选出来后,采用Spearman相关分析了这些部位FA值与PD患者认知功能状态的关系。Spearman相关分析显示,左侧额叶、右侧颞叶、左侧枕叶、左侧扣带前束、右侧扣带前束、胼胝体压部的FA值与PD患者的认知功能状态呈负相关(p<0.05)。提示帕金森病患者认知状态越差,部分脑白质区域的FA值下降越明显。
第四章结论
4.1认知功能损害是帕金森病(PD)患者常见的非运动症状之一,即使在PD的早期,其发生率也较高。其中单认知域损害较多认知域损害更为常见,以记忆、执行及视空间等认知域损害相对较多,对PD患者进行认知功能筛查有重要意义。
4.2蒙特利尔认知评估量表(MoCA)在筛查帕金森病患者认知功能损害方面优于简明智能精神状态量表(MMSE)。MoCA量表在相当水平特异性时,在总分和多个认知域(如视空间、记忆和语言)的敏感性均高于MMSE。
4.3非痴呆早期PD患者部分脑白质区域的各项异性值(FA)下降,提示在PD患者在疾病早期即出现较广泛的脑白质微结构的改变,也提示PD患者的脑损害延伸至基底节之外,这可能是PD患者一些非运动症状的基础。使用磁共振弥散张量成像(DTI)评估PD患者脑白质微结构的损害可能有助于早期诊断及病情的监测。
4.4PD患者部分脑白质区域的微结构改变与其认知功能状态相关。左侧前扣带束、胼胝体膝部可能在PD认知功能损害的发生过程中发挥重要作用。脑白质微结构改变可能是PD患者认知功能损害的病理基础之一。
Chapter I:Background and Objective
Cognitive impairment, an important non-motor feature of Parkinson's disease(PD), has recently gained increasing recognition. It can range from mild cognitive impairment (MCI) to dementia. It is estimated that MCI occur in20%to30%of the patients with PD, even among those newly diagnosed, and predict future cognitive decline, including progression to PD with dementia (PDD). MCI is one of key risk factors for PDD. Beside the disability it creates, PDD doubles the mortality risk of PD and increased caregiver burden. Early diagnosis of MCI will create a potential new target for therapeutic intervention, which may be more effective at slowing progression for PDD.
A rapid and easily applied screening test sensitive to cognitive impairment in PD is a more practical approach for clinicians. Only few screening measures have been developed to assess global cognitive functioning in PD, but each has its own limitations. The Mini-Mental State Examination (MMSE) remains the most commonly used screening instrument for PD, but its use in this population has been questioned, both because the MMSE relies heavily on intact verbal rather than visuospatial skills, and because it lacks items to assess executive functions and complex attention. Recently, a new cognitive screening instrument, the Montreal Cognitive Assessment (MoCA), was designed to address some of the limitations of the MMSE. It assesses a broader range of cognitive domains than the MMSE and is more challenging from a cognitive standpoint overall. The MoCA has been shown to be more sensitive than the MMSE for the detection of MCI and mild AD in the general population. The domains of executive and visuospatial function are known to be affected in early PD. Owing to inclusion of complex visuospatial, executive function and attention items into the MoCA, it is implied that MoCA maybe more sensitive than MMSE in evaluating cognitive deficits in PD. There were four studies that used the MoCA in PD populations, and all suggest that the MoCA may be a more appreciate screening instrument for cognitive impairment seen in PD, which is according to our findings. However, these studies have some limitations. However, all of them did not have matched non-PD control group, so it cannot be confirmed whether the non-PD elderly individuals having normal MMSE scores would have demonstrated similar levels of deficits on the MoCA scores. In our study, we hypothesized that the MoCA would be more sensitive than the more widely used MMSE to cognitive impairment in the individuals with PD, and included matched health controls to compare the specificity and sensitivity of two instuments in detecting cognitive impairment of PD.
Structural MR imaging results are usually normal in PD patients, even in those undergoing a long disease duration. Single-photon emission CT and Positron-emission tomography, nuclear medicine techniques, provide the best diagnostic sensitivity and specificity, however high cost and low availability of equipment limited their vability. Diffusion tensor imaging (DTI), an MRI technique, can indirectly evaluate the integrity of white-matter tracts by measuring water diffusion and its directionality in three dimensions. Due to its capability of detecting the microstructural alteration of the white matter before volume loss becomes evident, DTI is increasingly being used to measure white-matter tissue microstructure in vivo in various neurological diseases such as multiple system atrophy, diffuse Lewy body disease, multiple sclerosis and amyotrophic lateral sclerosis. However, there are few studies characterizing white matter diffusion changes in patients with PD. Some recent DTI studies showed the evidence that reduced FA in patients with PD in front lobes, premotor areas, the cingulum, in the corpus callosum and the superior longitudinal fasciculus, in the region of interest along a line between the substantia nigra and the lower part of the putamen/caudate complex, suggesting widespread microstructural damage to white matter occurs in early stages of PD.
The pathological process of cognitive impairment in PD patients is still unclear. The impaired cognitive domains of PDD are different from that of Alzheimer disease (AD). A wide variety of cognitive deficits in the patients with PD have been reported, even early in the course of the disease, including visuospatial, attention, memory and executive function. Specifically, deficits in attention, visuospatial and executive functions tend to predominate in PDD, however memory and language impairments play a less significant role than they do in AD, so that a "subcortical"cognitive impairment pattern dominates in PDD. White matter comprises many tracts interconnecting parts of the brain, and it play important roles in higher brain functions. White matter alterations are described to contribute to dementia in Alzheimer disease. To our knowledge, there still have no neuropathological studies detecting the relationship between white matter damage and cognitive status in Parkinson's disease. Quantitative studies of white matter in vivo may be helpful to elucidate the pathological process of cognitive deficits in PD. Diffusion tensor imaging (DTI) can provide quantitative measures of the microstructural integrity of white matter and can ewaluates the microstructural alterations of the white matter via water diffusion in vivo. When white-matter pathology disrupts the coherent orientation of axons, FA of tissue will decrease. Several DTI studies in PD patients have reported decreased fractional anisotropy (FA) and increased mean diffusivity (MD) of white matter, including the frontal lobe, and superior cerebellar peduncle, which implied degradation of the microstructure. Some MRI studies investigated the relationship between white matter and cognitive status in PD. For example, some previous studies found that PDD had significantly higher levels of white matter alterations than the PD without dementia. These findings suggest that white matter alterations may contribute to dementia in PD. However, the effect of white matter alterations on cognitive impairment of the patients with PD is still unclear.
As far as we know, only a few studies investigated the relationship between white matter alteration and cognitive status in PD by using diffusion tensor imaging, and only one of them studied the relationship between white matter alteration and cognitive status in PD including PD-MCI, and PDD at the same time. However, there were some limitations in this study published in2011:for example, they did not assess detailed neuropsychological status of patients such as executive, amnestic, visuospatial, attention, and language deficits, so they did not define patients with PD-MCI based on1.5standard deviation below mean score in neuropsychological tests; all MRI scans of this study were acquired on the same1.5Tesla clinical scanner, which probably provide less accruable data compared to3.0Tesla clinical scanner. In our study, we defined PD-MCI based on Neuropsychoclogical test battery, acquired all data from3.0T MR, and drawing the ROIs, a simple and practical measure which could easily be implemented in any clinical radiological setting, aimed to investigate the relationship between white matter alteration and cognitive status including both PD-MCI and PDD. We hypothesized that abnormalities of white matter microstructure is related to the cognitive impairment in PD. In this study, we compared the white-matter alteration among the PD patients with different cognitive status by DTI to elucidate the probably pathological process of conginite impairment in PD.
Chapter Ⅱ:Materials and Methods
2.1Subjects
Sixty-four patients with idiopathic PD (34men and30women; mean age,64.41±10.433years) were enrolled. The diagnosis of possible or probable PD was confirmed by a movement disorders specialist according to established criteria. Basic demographic and clinical information, including the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr stage were obtained from all PD subjects. Exclusion Criteria include:(1) Patients who had undergone deep brain stimulation (DBS) were excluded.(2) Subjects whose MR imaging finding suggests a diagnosis of atypical parkinsonism were excluded.(3) Subjects who had other brain disorders, or underlying diseases that could affect the brain such as uncontrolled hypertension and chronic kidney diseases, were excluded.(4) Subjects who scored above20on the Hamilton Depression Scale (HAMD) were excluded, because of the concern that depression can affect scores on neuropsychologic testing.(5) The patients who could not have MRI performed were excluded.
All patients underwent a neuropsychological test battery, and then were divided into three groups according to their cognitive status:(1) Parkinson's Disease-Cognitively Normal (PD-CogNL). Subjects were found to be cognitively intact and reported no functional deficit due to cognitive problems. They did not meet criteria for MCI or dementia as outlined below.(2) Parkinson's Disease-Mild Cognitive Impairment (PD-MCI). Criteria for PD-MCI were along the lines of Petersen et al. Individuals had subjective cognitive complaint(s), demonstrated a deficit of at least1.5standard deviation (SD) below the normative data mean score in at least one of four cognitive domains assessed in the battery, but cognitive deficits did not result in significant functional decline. Table1shows the neuropsychological test battery with the associated cognitive domains.(3) PD with dementia (PDD). PDD was diagnosed by the criteria of the task force of the Movement Disorder Society (MDS-TF). Based on the aforementioned above criteria, were enrolled24PD-CogNL,30PD-MCI and10PDD cases.
21age-and sex-matched healthy control persons were recruited. All of them had negative anamnesis for neurologic and psychiatric disorders, no relative with a diagnosis of parkinsonism, no abnormalities on structural MR imaging, and no condition that might impair cognition (i.e., head injury, and substance abuse). Controls were assessed with the Mini-Mental State Examination and had a total score greater than26.
2.2Neuropsychoclogical test
Subjects were administered some Neuropsychoclogical tests following standard procedures by trained research staff. The tests included the Mini-Mental State Examination (MMSE); the Beijing Montreal Cognitive Assessment(MoCA); the Chinese revision of the Wechsler Adult Intelligence Scale(WAIS-RC); the Chinese revision of the Wechsler Memory Scale(WMS); the Diagnostic and Statistical Manual IV(DSM-IV) and the Hamilton Depression Scale. Patients were encouraged to take their regularly scheduled PD medications during the study visit so that they would be evaluated in their "on" state. The MMSE and the Beijing MoCA assess a range of cognitive skills on a scale of0to30points with higher scores indicating better performance and a suggested impairment cutoff of a score less than26on either test. One point was added to an individual's score of MoCA if she/he had twelve years or fewer of formal education, for a total maximum of30points. Seeing that the items included in two instruments vary by type and level of difficulty, and identical items receive differential weighting, an item-by-item comparison is unsuitable for this study. As an alternative, we divided individual items into four widely used cognitive domains (visuospatial, memory, language, and orientation) based on previous researches. The visuospatial items included design copy(both tests) and figure drawing to command (MoCA only). The memory items included recall of either three (MMSE) or five (MoCA) previously presented words. The language items included phrase/sentence repetition, naming (both tests), verbal commands, and reading comprehension (MMSE only). The MoCA also includes a fifth executive function/attention domain comprised of items for phonemic fluency, visuospatial sequencing/alternation based on auditory span,verbal abstraction, and target detection using auditory attention for the number "1". Because of differential weighting of the serial subtraction items in two tests, we leaved out this item to permit more direct comparisons between instruments.
2.3MRI Acquisition Protocol
All MRI scans were acquired on the same3.0Tesla clinical scanner (GE Signa HDxt America) with8Channel head coil. Head motion was minimised with restraining foam pads provided by the manufacturer. High-resolution T1-weighted MRI was acquired axially using fast-spin echo sequence with the parameters of288×224acquisition,240mm field of view, TE27.3ms and TR1794ms. Diffusion tensor images were then obtained using single-shot echo-planar acquisition from16gradient directions with the following parameters:130×128acquisition matrix with704slices,240mm field of view,3.4×3.4×3mm3voxels, TE87.9ms, TR12s, b-factor of1000s/mm2, without cardiac gating.
2.4ROIs Analysis of FA
All images were post-processed on a AW4.4workstation using a program of the Functool image analysis software (GE Healthcare). FA values were obtained from various white matter regions on the DTI scan using regions of interest (ROIs), positioned as shown in Fig1. ROIs setting and measurement of FA values were performed by an experienced neuroradiologist blinded to the profiles of patients. The FA values of ROIs were compared between the four groups. Temporal white matter ROIs (50mm2) was sampled posterolaterally to the lateral fissure on the most caudal slice where the lateral fissure was present. Frontal white matter (50mm2), anterior/posterior cingulate bundle (20mm2), genu and splenium of the corpus callosum (20mm2), and superior longitudinal fasciculus (50mm2) were sampled on the slice that included a fully volumed lateral ventricule. ROIs of parietal white matter (50mm2) were positioned in the white matter posterior to the central sulcus on the most caudal slice where it was visible. The occipital white matter (50mm2) was placed within the optic radiations on the most caudal slice where the occipital horn of the lateral ventricle was imaged. An ROI positioned on the corticospinal tract (20mm2) at the level of the red nucleus, an ROI positioned on the corticospinal tract at the level of the internal capsule (20mm2).
2.5Statistical Analysis
Statistical analyses were carried out using SPSS software. Statistical analysis of demographic and clinical data was performed using analysis of variance with post-hoc Turkey's HSD test for continuous variables, Kruskal-Wallis test with post-hoc Mann-Whitney U-tests for noncontinuous variables, and v2test for categorical data. The receiver operating characteristic (ROC) analyses were used to examine the ability of the two tests to differentiate between PD and control subjects by the total scores and cognitive domains. FA values were compared among the four groups using one-way ANOVA. Fisher's PLSD was used for post-hoc analysis. The Unified Parkinoson's Disease Rating Scale (UPDRS) motor score, Hoehn-yahr stage and each FA value that showed significant differences in the first analysis were then used as variables for Logistic regression analysis, and corrected the influence of UPDRS motor score and Hoehn-yahr stage. We also examined correlation analysis between FA values that showed a significant difference and the different status of PD patients. A two-sided significance level of P<0.05was considered to be statistical significant.
Chapter III:Result
There were no significant differences on age, gender, disease duration, or education years among PD-CogNL, PD-MCI, PDD and controls. Both the UPDRS motor score and Hoehn-Yahr stage were significantly higher in PDD (P<0.01), and PD-MCI (P<0.05) compared to patients with PD-CogNL.
3.1A comparison of MoCA and MMSE for screening cognitive deficits in the patients with Parkinson's disease
Compared with controls, the PD group had significantly lower total scores on both the MoCA and the MMSE. The scores'ranges of the MoCA in both PD group and controls were broader than that of the MMSE. In addition, within-group comparisons indicated that both the PD (Wilcoxon z=-6.707; P<0.01) and controls (Wilcoxon z=-3.147; P<0.05) scores lower on the MoCA compared to the MMSE. When we evaluated the congntive function of the patients with PD by MoCA,76.6%of them were abnormal, however when evaluated by MMSE, only29.7%were abnormal. Among45PD patients having normal MMSE scores,66.7%of them met predefined criteria for cognitive impairment based on their MoCA score. We examined performance of the two groups on total scores and five cognitive domains by ROC analysis. The area under the curve (AUC) values showed that both instruments could significantly differentiate PD from controls on total scores; however, the MoCA score yielded higher sensitivity than the MMSE while maintaining a comparable level of specificity. Both tests accomplished group discrimination on orientation domain successfully. On the contrary, only the MoCA yielded significant AUC values for visuospatial, memory, and language scores, with higher sensitivity and specificity relative to the comparable MMSE domains. Moreover, executive function/attention score of the MoCA yielded a significant AUC for group discrimination.
3.2The white matter alterations in the patients with PD without dementia
In the patients with PD without dementia (Hoehn and Yahr stages I and II), the FA were decresed in some white matter regions, such as bilateral temporal, left anterior cingulate bundle and splenium of the corpus callosum.
3.3FA values comparison among PD patients with different cognitive status:
Median FA values for each of the white matter regions in four groups are showed in table3-6. Compared to controls, PDD and PD-MCI showed a significant FA reduction in left frontal, right temporal white matter and bilateral anterior cingulated bundles; PD-MCI showed a significant FA reduction in temporal white matter and genu of the corpus callosum; PD-CogNL showed significant FA reduction in left occipital white matter and left anterior cingulated bundle. PDD showed a significant FA reduction in left anterior cingulated bundle, splenium of the corpus callosum compared to other three groups. Even after considering the influence of UPDRS motor score and Hoehn-yahr stage, the FA reduction in left anterior cingulated bundle and genu of the corpus callosum remained significant. However, no significant FA difference was demonstrated for other areas between the four groups. There were significant negative correlations between cognitive status of PD and FA values of some white matter, such as:left frontal, right temporal, left occipital white matter, bilateral anterior cingulated bundles and splenium of the corpus callosum.
Chapter IV:Conclusion
4.1Cognitive impairment is a common non-motor feature of Parkinson's disease (PD), even among those in the early stages of disease, and single domainmild cognitive impairment is more common than multiple domainsmild cognitive impairment. It is important to recognize cognitive impairment in the patients with PD.
4.2The Montreal Cognitive Assessment (MoCA) achieved higher sensitivity to screening cognitive impairment in the patients with PD without sacrificing specificity in tototal score and many domains relative to the Mini-Mental State Examination (MMSE). MoCA appears to be the preferable measure for screening cognitive impairment in the patients with PD.
4.3In the patients with PD without dementia, the FA were decresed in some white matter regions, which implied widespread microstrutural damage occurs already in the early stages of PD. DTI is helpful to evaluate the white matter damage in PD.
4.4The patients with PD had significant micro structural alteration in the some white matter, and correlated with the cognitive status of patients. White matter damage especially in the left anterior cingulate bundle and genu of the corpus callosum probably underlies the cognitive impairments of PD to some extent.
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