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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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Progress in cognitive dysfunction of Huntington's Disease

  • LI Bin , 1 ,
  • HE Qin 2 ,
  • LUO Yongjie , 3
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  • 1 Department of Geriatrics, Sixth People's Hospital of Chengdu, Chengdu 610000, China
  • 2 The fourth ward of Chengdu Eighth People's Hospital, Chengdu 610000
  • 3 Department of Neurology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu 610072

Received date: 2020-08-20

  Revised date: 2020-09-10

  Online published: 2020-12-25

Abstract

Huntington's disease is an autosomal dominant neurodegenerative disease characterized by progressive exacerbation of dance-like symptoms, cognitive dysfunction and mental disorders. Although the disease is determined by the motor symptoms clinical onset, but before the emergence of motor symptoms, non-motor symptoms have been increasingly recognized and valued. As one of the non-motor symptoms, cognitive dysfunction can appear in all stages of the disease, and the therapeutic effect is not ideal, which brings a huge burden to the patients and their caregivers. This paper reviews the neuropsychological features, imaging features and related research progress of cognitive dysfunction in Huntington's disease.

Cite this article

LI Bin , HE Qin , LUO Yongjie . Progress in cognitive dysfunction of Huntington's Disease[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2020 , 3(4) : 320 -324 . DOI: 10.3969/j.issn.2096-5516.2020.04.013

亨廷顿病,既往曾被称为亨廷顿舞蹈病(Huntington's chore),是一种常染色体显性遗传的神经变性疾病。致病基因IT15位于染色体4p16.3中,其外显子1上的CAG三核苷酸重复次数与发病密切相关[1],当CAG重复次数大于40次时必然患病。流行病学显示亚洲人群HD患病率为0.40/10万,而欧洲/北美以及大洋洲患病率为5.7/10万[2]。通常发病年龄30~50岁,病程15~25年,少数在青少年期起病。病理方面,该病主要累及尾状核、壳核及大脑皮层。临床症状主要表现为进行性加重的舞蹈样症状、认知功能障碍和精神障碍,另外还可出现睡眠障碍、体重减轻、自主神经功能障碍、癫痫等少见非运动症状。认知功能障碍可出现在尚无运动症状的前驱期HD(prodromal Huntington Disease, prHD)患者中。Paulsen等[3]的研究发现随着时间的推移,疾病进展不同的prHD均可出现认知能力的下降。Verny等[4]的研究发现与对照组相比,HD阳性基因携带者在心理运行速度、注意力和执行功能等方面均存在显著差异。Duff等[5]将轻度认知功能障碍(Mild cognitive impairment, MCI)的概念运用于prHD中,发现近40%的prHD符合MCI的诊断标准,且越接近运动诊断的个体其MCI发生率越高,其中非遗忘型MCI比遗忘型MCI更常见,单域MCI比多域MCI更常见。
近年来,越来越多研究发现HD认知功能障碍可早于运动症状出现。本文就HD的认知功能障碍的执行功能、注意力、记忆力、嗅觉、情感识别、感知力、处理速度、时间感知等神经心理学特征,相关影像学表现及最新治疗进展情况作一综述。

1 神经心理学特征

1.1 执行功能

执行功能是指确立目标、制定和修正计划、实施计划,从而进行有目的活动的能力,与额叶-皮质下环路受损有关。HD的所有认知功能障碍中执行功能障碍所占比例最高[6]。在一项对prHD个体的日常认知功能评估的纵向研究中,发现其中执行功能障碍是最常见,且进行性加重[7]。执行功能的降低可表现为工作能力、金钱管理能力、驾驶技能等的下降[8]。HD患者在连线试验(Trail Making Test, TMT)[9]的执行功能测试中得分出现明显下降。Papp等[10]使用Towers Task来评估HD基因阳性人群的执行功能,发现prHD患者中执行功能也可出现下降,而且发现病情较重、疾病进展较快的HD患者表现更慢、更欠准确。O'Rourke等[9]分析了767例prHD患者的连线试验结果,发现视知觉加工主要影响TMT的A部分,执行功能主要影响TMT的B部分;与对照组相比,距离临床诊断前9~15年的prHD个体中,其TMT分数确实是有下降的。上述研究均表明不论是未发病的prHD,还是已发病的HD患者,其执行功能均不同程度受损,且执行功能障碍程度与疾病进展相关。

1.2 注意力

注意力包括集中、准确、及时进行心理资源的分配与转移主体之间的能力。注意力缺陷在HD及prHD患者中是常见的。HD患者注意力下降的原因可能是对一些自动化任务的能力下降,从而导致对任务的注意力的分散,而上述部分在健康人群中通常是能够自动完成的[11]。HD患者注意力受损以后可能会导致处理速度减慢[12],注意力资源分配减少[13],以及对需要保持注意力的任务的执行障碍[9]

1.3 记忆力

记忆力问题在HD中也较常见。虽然HD中存在学习和外显记忆问题,但很可能其内隐记忆系统更容易被累及。内隐记忆主要包括参与协调的动作和技能,它们使个体完成骑自行车、演奏乐器和开车等任务。在prHD阶段,对于视觉记忆的研究目前尚无统一结论[6]。在视觉空间学习测验上,有研究发现prHD中特定空间位置视觉设计的回忆受损[14]。根据现有的研究,prHD中学习和记忆的缺陷可能只出现在复杂的学习任务中,而且必须要仔细识别才能被检测出来[15]。上述研究结果表明在prHD和HD患者中,需要进一步的研究来论证基底节的直接和间接途径以及海马引起的学习记忆障碍问题[16-17]

1.4 嗅觉

Hamilton等[18]的研究表明HD患者在确诊时可能已有15年以上的嗅觉受损,但没有帕金森病患者的嗅觉障碍突出,且传统嗅觉测试方法可能无法检测出来。最新HD基因大鼠模型中,研究发现早期嗅觉障碍与嗅球及梨状皮层的结构、梨状神经元数量减少、神经元核和酪氨酸羟化酶的表达水平改变有关[19]。在prHD人群中嗅觉识别程度从正常到受损均可存在[20-21],这表明嗅觉系统在疾病的早期就可能受到损害。最近有研究使用宾夕法尼亚大学嗅觉鉴定试验来检测及追踪HD的疾病进展,印证了嗅觉测试的敏感性[20,22]

1.5 情感识别

情感识别障碍,即交流过程中对面部表情或语调传达出的情感的识别障碍,可出现在疾病的早期阶段。据推测,这种早期且普遍的损害可能与日益增加的社会关系中的困难有关。随着脑部灰质和白质萎缩的增加,特别是枕叶的楔叶和舌回,这种能力进一步下降[23]。Eddy等[24]的研究发现在prHD和HD患者中,存在对复杂心境的理解障碍,洞察力降低等问题,也存在社交能力上的不足[25]

1.6 感知力

部分HD患者中出现对自己的行为和感觉的感知力下降。Duff等[26]研究发现离运动诊断越远的prHD参与者,对自我执行功能障碍的评估报告越准确,但随着运动诊断的接近,自我感知力逐渐降低,对自身执行功能障碍的评估越欠准确。Sitek等[27]发现HD患者也明显低估了自己的记忆功能障碍,而且与病程和病情严重程度有关。McCusker等[28]的综述总结了HD患者在运动、认知行为及功能等方面的感知能力,发现在整个病程中均有下降。随着HD症状的进展,HD患者报告结果(patient-reported outcomes, PROS)的心理测量可靠性可能受到影响,临床医生应综合其他类型的评估[29]。HD的感知力下降被认为可能是由额叶和基底神经节之间的通路中断引起的。

1.7 处理速度

HD早期变化最早、最敏感的指标之一就是思维速度的变化。HD患病高风险的人在普通脑力劳动时开始出现困难,即完成同样一件事情时需要花费更多的时间,这是因为大脑只能通过加速运转来处理那些曾经能够自动完成的任务来代偿,并唤起大脑的备用区域,上述任何过程均会减慢处理速度[30]。处理速度被认为是影响prHD中最常见的认知障碍[30-31],Maroof等[31]的研究将prHD患者根据离运动诊断的远近分成三个不同的亚组,将HD患者根据疾病进展分成三个阶段,在上述所有三个prHD亚组中以及已诊断HD的三个阶段中,其处理速度均表现出线性下降趋势。

1.8 时间感知

定时任务常用来检测神经系统疾病中的认知功能障碍,因为它涉及了许多重要的心理功能。许多研究表明prHD及HD患者在对时间的感知和定时任务时均出现损害。Rowe等[32]用Self-paced Timing来检测prHD个体的时间感知能力,发现他们的自我节奏敲击时间的精确度明显下降,而且越接近运动诊断时越严重。大型观察性研究(TRACK-HD和PREDICT-HD)也发现在prHD患者和HD患者中定时任务均表现出受损[33]

2 认知障碍的影像学特征

亨廷顿病主要累及基底节区和大脑皮质,以尾状核、壳核神经元大量变性、丢失最为明显,表现为尾状核、壳核及皮层的萎缩。在HD患者和prHD患者中均发现认知功能评估和结构MRI评估之间的相关性。Aylward等[34]的研究发现prHD患者中认知功能和运动功能与尾状核、壳核和苍白球体积是有关的,但与脑白质体积无关。Papp等[10]使用TOWERS TASK来检测HD基因阳性携带者的规划和解决问题能力,发现疾病进展较大的参与者表现得更慢,更欠准确,且表现准确性与纹状体体积呈负相关,准确性和工作记忆均与额叶白质体积呈负相关。Harrington等人[35]对325例不同进展程度的prHD个体和119例有HD家族史的基因阴性对照者在注意力和信息处理速度、工作记忆、言语学习记忆、负性情绪识别和时间加工等五个认知领域进行神经解剖学分析,发现prHD患者中,执行功能与壳核体积及颞叶上部皮层厚度有关;工作记忆与右侧枕叶、右侧额中回皮层、右侧颞中回皮层厚度和左侧尾状核体积有关;言语学习记忆与尾状核,右颞叶皮层有关;情绪识别缺陷与右壳核和右舌回有关;时间感知下降与左侧尾状核及额中叶皮层、双侧壳核有关。ScaHill等[23]的研究采用宾夕法尼亚大学嗅觉鉴定测验测量嗅觉,发现嗅觉受损与顶叶和颞叶的体积丢失有关。关于HD患者大脑白质的影像学研究中,发现枕上部、楔前叶、顶上小叶、枕中部、角回的白质与多种认知功能评估变量更为相关,特别是TMT的A部分与白质的相关性最高[36]

3 认知功能障碍相关治疗

与大多数神经变性疾病一样,亨廷顿病缺乏特异性的治疗方法,目前没有任何药物及治疗方法可以阻止、减缓甚至逆转疾病的进展,主要采用对症治疗。随着更敏感的神经心理测试方法的出现,轻度认知障碍的发现显得日益明显,通常早于运动症状出现,但HD中的认知功能障碍仍然没有有效的治疗方法[8]
Tommaso等[37]的研究发现治疗其他神经退行性疾病的药物(如治疗阿尔茨海默病认知障碍的利伐斯明,属胆碱酯酶抑制剂),在治疗HD患者的运动症状有一定疗效,同时也有改善功能性残疾和认知障碍的趋势。然而在一项以安慰剂对照的后续试验中,发现服用利伐斯明6个月与认知功能改善没有显著相关性[38]。Cubo等人[39]的研究发现另一种胆碱酯酶抑制剂盐酸多奈哌齐对HD患者认知功能障碍治疗无明显效果。其他曾被认为有效的促进中枢神经系统神经递质的药物,如选择性5-羟色胺再摄取抑制剂(西酞普兰)和去甲肾上腺素再摄取抑制剂(阿莫西汀),尽管在临床前研究中有很好的证据,但临床试验中未能显示出对早期HD患者的认知功能的改善[40-41]。最新两个针对HD患者认知功能障碍的药物仍在进一步研究中,其中一个为表没食子儿茶素-3-没食子酸酯[(2)-epigallocatechin-3-gallate],来自Eton-study的研究,处于第二阶段,目前已完成,但尚未发表;另一个药物伐伦克林(Varenicline)来自VCAS-HD研究,目前处于第二阶段,正在试验当中[42]
综上,认知功能障碍可发生在症状前HD患者和HD患者的各个阶段。既往的临床研究主要以运动症状的评估为主,而认知功能对于有HD遗传风险的人的早期症状评估来说,具有较好的潜力。在明确运动诊断之前的数十年里,认知功能障碍表现明显,应该重新研究HD的诊断标准,使临床实践与研究发现保持一致。同时还需进行大量HD认知功能相关的研究,开发适用于临床试验的认知评估工具。HD的治疗方面存在巨大挑战,尽管如此,目前有大量实验室正在研究许多有希望的新疗法,其中一些已经处于临床试验的不同阶段。相信随着科学的不断进步,终将会发现有效的、能够改善包括认知功能障碍在内的疾病进展的方法和手段。
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