Re: 파킨슨 증후군 5. corticobasal degeneration 피질기저 증후군

[문형철]

Clin Park Relat Disord. 2019; 1: 66–71.

Published online 2019 Aug 30. doi: 10.1016/j.prdoa.2019.08.005

PMCID: PMC8288513

PMID: 34316603

Corticobasal degeneration and corticobasal syndrome: A review

Vasilios C. Constantinides,a,⁎ George P. Paraskevas,a Panagiotis G. Paraskevas,b Leonidas Stefanis,a and Elisabeth Kapakia

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Abstract

Corticobasal degeneration (CBD) is a rare neurodegenerative disorder. The most common presentation of CBD is the corticobasal syndrome (CBS), which is a constellation of cortical and extrapyramidal symptoms and signs. Clinical-pathological studies have illustrated that CBD can present with diverse clinical phenotypes, including a non-fluent, agrammatic primary progressive aphasia syndrome, a behavioral, dysexecutive and visuospatial syndrome, as well as a progressive supranuclear palsy-like syndrome. Conversely, multiple pathologies, such as CBD, Alzheimer's disease and progressive supranuclear palsy may underlie a patient with CBS. This clinical-pathological overlap emphasizes the need for biomarkers that will assist in the accurate diagnosis of patients with CBS. This review presents an overview of the pathological, genetic, clinical and therapeutic characteristics of CBD, with an emphasis on the imaging (structural and functional) and biochemical (cerebrospinal fluid) biomarkers of CBD.

파킨슨병(PD)과 피질 기저 증후군(CBS)의 감별 진단은

두 질환의 비대칭적 발병으로 인해

초기 단계에서 어려울 수 있습니다.

임상적으로 겹치는 부분이 있지만,

이 두 질환에 관여하는

해부학적 회로는 서로 다릅니다.

저희는

이러한 질환의 기저에 있는 병리 생리학적 메커니즘을 규명하기 위해

약물 무경험 PD 및

CBS 환자의 R2 눈 깜박임 반사 회복 주기(R2BRRC)와

대뇌피질 두께(CTh)를 평가했습니다.

임상적으로 PD 및 CBS 가능성이 있는 환자를 모집했습니다. R2BRRC는 100-150-200-300-400-500-750 ms의 자극 간 간격(ISI)에서 양측으로 평가되었습니다. 각 ISI에 대한 R2BRRC의 비대칭 지수(AI)를 계산했습니다. 환자들은 구조적 뇌 MRI와 반구 CTh를 촬영하고 MRI의 AI를 계산했습니다. 약물 경험이 없는 PD 환자 14명과 조기 CBS 진단을 받은 환자 10명이 등록되었습니다.

PD 환자의 R2BRRC는 100 및 150 ms의 ISI에서 영향을 덜 받은 쪽(LAS) 자극에 대해 뇌간 흥분성이 증가한 것으로 나타났으며(p<0.001), 대부분의 영향을 받은 쪽(MAS)에 비해 증가된 반면, CBS에서는 LAS와 MAS 간의 차이가 발견되지 않았습니다. ISI-100 ms에서 R2BRRC의 AI는 PD에서 더 높게 나타나 유의미한 차이를 보였습니다. CTh 분석에서는 MAS 반대편 반구 피질 용적에서 그룹 간 유의미한 차이를 보였으며, 반대로 MRI의 AI는 CBS에서 유의미하게 높았습니다. PD 환자는 CBS에 비해 비대칭적인 뇌간 흥분성 패턴을 보였습니다. 반대로 CBS 환자는 대뇌피질 위축의 비대칭 패턴을 보였습니다. 피질과 피질하 뇌 구조와 관련된 이러한 상반된 신경 생리학적 및 구조적 이상 패턴은 이러한 장애의 기저에 있는 다양한 병태생리학적 메커니즘을 강조할 수 있습니다.

Keywords: Corticobasal syndrome, Corticobasal degeneration, Biomarkers, MRI, PET, Spect, Cerebrospinal fluid

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1. Introduction

Rebeiz et al. first described in 1967 three patients with slowly progressive “clumsiness” and a variety of asymmetrical extrapyramidal signs, including rigidity, dystonia and myoclonus, with relatively intact cognitive functions [1]. They introduced the term “corticonigral degeneration with neuronal achromasia” to describe this entity. This disorder was largely forgotten until 1989, when Marsden et al. introduced the term “corticobasal degeneration” [2].

Over the following years, the terms corticobasal degeneration (CBD), which refers to the pathological entity of a specific 4-repeat (4R) tauopathy, and corticobasal syndrome (CBS), which refers to the phenotype, have been used interchangeably. This has greatly added to the confusion surrounding the subject, implying that all CBD patients present with a CBS phenotype and vice versa. Pathological criteria were established in 2002 [3], and clinical diagnostic criteria in 2013 [4], further adding to the uncertainty.

Clinical-pathological studies have greatly enhanced our knowledge of the biochemistry, genetics, pathology and clinical manifestations of this rare neurodegenerative disorder. These studies have illustrated the clinical diversity of CBD, which can present with the classical CBS phenotype, but also as primary progressive aphasia, a frontal-dysexecutive-spatial syndrome and a Richardson-like syndrome [4]. Conversely, the pathological heterogeneity of CBS also has been emphasized, with diverse diseases such as CBD, Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal degeneration with TDP-43 (FTD-TDP43) manifesting as CBS [5].

피질 기저 증후군(CBS)과 같은

비정형 파킨슨 증후군(AP)은

파킨슨병(PD)에 비해

더 빠르게 진행되고 레보도파 반응성이 떨어지는 것이 특징인

희귀 신경 퇴행성 질환입니다(Jabbari 등. 2020).

그럼에도 불구하고

일반적인 임상 특징과 질환의 비대칭적 발병으로 인해

CBS와 PD의 임상 감별 진단은 특히 발병 초기에 어려울 수 있습니다.

R2 깜박임 반사 회복 주기(R2BRRC)는

뇌간 흥분성을 평가하는 데 사용되는 신경생리학적 도구로,

일반적으로 PD에 걸린 환자에서 증가합니다(Kimura 1973).

특히

R2BRRC의 비대칭 지수(AI)는

100%의 특이도로

초기 PD 환자를

다계통 위축(MSA) 및 진행성 핵상마비(PSP)의 영향을 받는 환자와

구별합니다(Sciacca 외. 2020a).

반면, 최적의 R2BRRC 컷오프 점수를 사용하면

일상적인 임상 진료에서 CBS와 MSA 및 PSP의 감별 진단에 사용할 수 있으며,

CBS 환자는 정상적인 뇌간 흥분성을 보입니다(Sciacca 등. 2018, 2020b).

구조적 자기공명영상(MRI)을 포함한 신경영상 연구를 고려할 때,

CBS 환자는 일반적으로 임상적으로 가장 영향을 많이 받는 쪽(MAS)의 반대편인

후전두엽과 두정엽을 포함하는 비대칭적인 피질 위축을 나타냅니다(Constantinides 외. 2019).

또한

CBS는 PSP 환자와 같은 다른 AP에 비해 뇌실 내 침범 및 대칭 패턴을 갖는

더 두드러진 뇌실 상부 위축 패턴을 보였습니다 (Whitwell et al. 2014).

그러나

질병의 초기 단계에서는 MRI의 질적 평가가

PD와 CBS의 감별 진단에 결정적일 수 없었습니다.

따라서

뇌간 흥분성을 탐구하는 신경 생리 학적 데이터와 함께

피질 구조의 정량적 분석과 함께

고급 MRI 신경 영상 방법을 사용하면 감별 진단에 유용 할 수 있습니다.

이 탐색적 연구의 목적은 약물을 사용하지 않는 PD 및 CBS 환자에서 MRI의 인공지능으로 뇌간 흥분성과 반구 피질 두께 부피를 계산하여 질병의 초기 단계에서 감별 진단에 도움이 되는 뇌간 흥분성을 평가하는 것입니다.

2. Epidemiology

Robust epidemiological data on CBD are lacking because of the rarity of the disease, the great clinical pathological heterogeneity of the disorder and the lack of established criteria until recently. It is estimated that it is ten times rarer than progressive supranuclear palsy (PSP) [6]. Its' incidence is estimated at 0.6–0.9/100,000/year and it represents 4–6% of patients with Parkinsonism. A single study projected a preval‎ence of 4.9–7.3 per 100.000, based on incidence and mean survival data. However, in a cohort of 120,000, no case of CBD was described [7,8].

Mean age at disease onset is about 64 years [4], whereas the youngest pathologically confirmed case was 43 years old [9]. There could be a slight female predominance [10,11]. Mean survival is estimated at 6.5 years [4].

2. 역학

CBD에 대한 강력한 역학 데이터는

질병의 희귀성,

장애의 큰 임상 병리학적 이질성 및

최근까지 확립 된 기준의 부족으로 인해 부족합니다.

진행성 핵상 마비(PSP)보다

10배 더 드문 것으로 추정됩니다[6].

발병률은

연간 0.6~0.9/10만 명으로 추정되며

파킨슨병 환자의 4~6%를 차지합니다.

한 연구에서는 발병률과 평균 생존 데이터를 기반으로 10만 명당 4.9~7.3명의 유병률을 예측했습니다. 그러나 120,000 명의 코호트에서 CBD 사례는 설명되지 않았습니다 [7,8].

평균 발병 연령은 약 64세[4]이며,

병리학적으로 확인된 최연소 사례는 43세[9]였습니다.

여성이 약간 우세할 수 있습니다 [10,11].

평균 생존 기간은

6.5년으로 추정됩니다[4].

3. Pathology

Dickson et al. established pathological criteria for CBD in 2002 [3]. CBD is characterized by neuronal and glial pathological lesions, which contain abnormally hyper-phosphorylated microtubule associated tau protein. For this reason, CBD is considered a tauopathy, alongside PSP, frontotemporal degeneration (FTD) and Alzheimer's disease.

Tau protein can present in six isoforms. This depends on the presence of three (3R) or four (4R) microtubule binding regions, due to alternate splicing of exon 10 of the microtubule associated protein tau (MAPT) gene, as well as the presence of no, one or two oligonucleotides (N1, N2), coded by exons 2 and 3 respectively in the N-terminal segment of tau protein.

CBD and PSP are 4R-tauopathies, FTD (Pick's disease) is a 3R-tauopathy and AD harbors both 3R- and 4R-tau isoforms. Differential diagnosis on a pathological basis of CBD from other tauopathies relies on specific pathological lesions as well as diverse distribution of these lesions among different diseases.

Ballooned or achromatic neurons were considered pathognomonic of CBD by Rebeiz et al., particularly when located in the cortical gray matter or less commonly in basal ganglia [1]. However, it is now evident that tau pathology in astrocytes is more important in discriminating PSP from CBD. Thus, astrocytic plaques are pathognomonic of CBD, whereas PSP is characterized by tufted astrocytes. Other, less specific tau-lesions of CBD are neuronal inclusions, threads and coiled bodies [12,13]. Coiled bodies, which are oligodendroglial tau depositions also differ between PSP and CBD, but on an ultra-structural level [14,15]. Moreover, CBD has more widespread cortical pathology, whereas PSP has more hindbrain pathology [16]. It is worth mentioning that even pathological examination cannot safely differentiate PSP from CBD (90% specificity) [3].

CBD appears to be a neural network specific disorder, as is the case with many other neurodegenerative diseases. It initially affects the dorsolateral prefrontal cortex and basal ganglia circuits, with more posterior regions affected as the disease progresses. Importantly, the initial pathological disorder is the astrocytic plaque, with neurons and oligodendroglia being affected in more advanced disease stages. Phenotypical variation in CBD depends on the topography and burden of the pathological lesions [17].

Interestingly, despite being 4-R tauopathies, PSP and CBD have some biochemical differences. As indicated by immunoblotting of brain extracts, diverse tau fragments are present in PSP and CBD, implying different tau proteolytic pathways. These differences may contribute to the phenotypical variation of the two disorders [18].

3. 병리학

Dickson 등은 2002 년에

CBD에 대한 병리학 적 기준을 설정했습니다 [3].

CBD는

비정상적으로 과인산화된 미세소관 관련 타우 단백질을 포함하는

경세포 및 신경교 병리학적 병변이 특징입니다.

이러한 이유로

CBD는 PSP, 전두측두엽 변성(FTD), 알츠하이머병과 함께

타우 병증으로 간주됩니다.

타우 단백질은 6가지 이소형으로 존재할 수 있습니다. 이는 미세소관 관련 단백질 타우(MAPT) 유전자의 엑손 10의 교대 스플라이싱으로 인한 3개(3R) 또는 4개(4R) 미세소관 결합 영역의 존재 여부와 타우 단백질의 N-말단 세그먼트에 각각 엑손 2와 3으로 코드화된 올리고뉴클레오티드(N1, N2)가 하나 또는 둘인지 여부에 따라 달라집니다.

CBD와 PSP는 4R-타우 병증, FTD(픽병)는 3R-타우 병증, AD는 3R 및 4R-타우 이소폼을 모두 보유합니다. 다른 타우 병증과의 병리학적인 감별 진단은 특정 병리학적인 병변과 다른 질병들 사이에서 이러한 병변의 다양한 분포에 의존합니다.

풍선형 또는 무색 뉴런은 특히 피질 회백질에 위치하거나 덜 일반적으로 기저핵에 위치할 때 Rebeiz 등에 의해 CBD의 병리학적 병변으로 간주되었습니다 [1]. 그러나 이제 성상교세포의 타우 병리가 PSP와 CBD를 구별하는 데 더 중요하다는 것이 분명해졌습니다. 따라서 성상교세포 플라크는 CBD의 병리학적 특징인 반면, PSP는 술 모양의 성상교세포가 특징입니다. CBD의 다른 덜 구체적인 타우 병변은 신경 내포물, 실 및 코일 바디입니다 [12,13]. 희소돌기아교 타우 침착물인 코일 바디도 PSP와 CBD 간에 차이가 있지만, 매우 구조적인 수준에서 차이가 있습니다 [14,15]. 또한 CBD는 더 광범위한 피질 병리를 가지고 있는 반면, PSP는 더 많은 후뇌 병리를 가지고 있습니다 [16]. 병리학 적 검사조차도 PSP와 CBD를 안전하게 구별 할 수 없다는 점을 언급 할 가치가 있습니다 (특이도 90 %) [3].

CBD는 다른 많은 신경 퇴행성 질환의 경우와 마찬가지로 신경 네트워크 특정 장애로 보입니다. 처음에는 배측 전전두엽 피질과 기저핵 회로에 영향을 미치며, 질병이 진행됨에 따라 더 많은 후부 영역이 영향을 받습니다. 중요한 것은 초기 병리학적 장애는 성상세포 플라크이며, 더 진행된 질병 단계에서는 뉴런과 희돌기아교세포가 영향을 받는다는 점입니다. CBD의 표현형 변화는 병리학적 병변의 지형과 부담에 따라 달라집니다 [17].

흥미롭게도, 4-R 타우 병증임에도 불구하고 PSP와 CBD는 생화학적 차이가 있습니다. 뇌 추출물의 면역 블 롯팅에서 알 수 있듯이, 다양한 타우 조각이 PSP와 CBD에 존재하며, 이는 서로 다른 타우 단백질 분해 경로를 암시합니다. 이러한 차이는 두 질환의 표현형적 변이에 기여할 수 있습니다 [18].

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4. Diagnostic criteria

Various sets of diagnostic criteria have been proposed over the years, focusing exclusively on the CBS presentation of CBD [[19], [20], [21], [22], [23], [24], [25]]. The most recent established clinical diagnostic criteria, which were introduced in 2013, aimed to expand the phenotypical spectrum of CBD, by incorporating diverse clinical phenotypes [4]. These criteria were based on clinical-pathological studies of CBD and attempted to illustrate the great clinical–pathological diversity of CBS and CBD.

Based on these criteria, five clinical syndromes are accepted for CBD. These include the probable and possible CBS; a frontal-behavioral and spatial syndrome (FBS); a non-fluent agrammatic primary progressive aphasia syndrome (nfa-PPA); and a progressive supranuclear palsy-like syndrome (PSPS).

A probable CBD diagnosis requires an age of onset greater than 50 years, whereas a family history or a known genetic mutation affecting tau protein is not permitted. Of the five phenotypes, only the probable CBS and the FBS and nfa-PPA (with the addition of a CBS feature) are eligible for a probable CBD diagnosis.

For a possible CBS diagnosis, the criteria are more lenient. No age of disease onset is required, and a positive family history or a known tau-protein mutation is allowed. A possible CBD diagnosis can be established with a possible CBS phenotype, an FBS or nfa-PPA syndrome (without additional CBS features), or in cases of a PSP-S with an additional CBS feature.

Two studies examined the sensitivity and specificity of these clinical criteria, based on small cohorts of pathologically confirmed CBD patients [26,27]. Both studies concluded that the current diagnostic criteria lack specificity and that no clinical feature can confidently differentiate between CBD and a non-CBD pathology (more commonly AD or PSP) in a CBS patient. This emphasizes the need for biomarkers to determine the underlying pathology in a CBS patient.

5. Clinical features

Corticobasal syndrome is characterized by cortical and extrapyramidal signs. Apraxia, cortical sensory deficits and alien limb phenomena are the most common cortical signs, whereas asymmetrical Parkinsonism, dystonia and myoclonus comprise the extrapyramidal signs.

Parkinsonism in corticobasal syndrome is characteristically highly asymmetrical or unilateral. There have been rare reports of symmetric corticobasal degeneration [28]. In a minority of patients there can be moderate but transient levodopa response. Tremor, when present, is phenotypically atypical. It usually is a positional or action tremor, can be irregular and often has a myoclonic quality [4]. Typical levodopa-induced dyskinesias, resembling PD, have also been described [29].

Dystonia is present in 40% of CBD patients [30]. About 80% of patients have upper limb dystonia, whereas cervical, lower limb dystonia and blepharospasm are rare. Usually dystonia presents within the first two years of the disease course and is highly related to myoclonus.

Myoclonus seems to be of the cortical reflex type, based on giant somatosensory potentials and the latency between EEG and EMG [31]. Myoclonus in CBD has been hypothesized to result from abnormal hyper-excitability of the primary motor cortex, due to lack of inhibitory input from the sensory cortex [32]. The lack of a giant somatosensory potential in cases of CBD has been attributed to the profound parietal atrophy in the later stages of CBD [33].

Apraxia is the clinical hallmark of CBS. Although considered relatively specific for CBD, some apraxia studies have argued that apraxia is present in as many as 75% of PSP patients [34,35] and 30% of PD patients [36]. Quantitative analyses, however, have demonstrated that there are differences in the severity of apraxia (particularly in intransitive movements) [34,37]. Moreover, qualitative analyses, including error-type profiling, could also differentiate between the two disorders [35]. CBD patients have more severe distal than proximal apraxia, which supports the notion of limb-kinetic apraxia [38].

The alien-limb syndrome was initially described as a subjective difficulty recognizing one's limb as his own, particularly in the absence of visual input [39]. It can be divided in a posterior or sensory variant, which relates to sensory hemi-neglect. Hand or arm elevation may be present, which is usually position-dependent and can be induced by sensory stimuli. The patient has a sense that the arm does not belong to him [40]. The anterior or motor variant is characterized by extreme utilization and grasping behavior, more often of the dominant hand, which can result in inter-manual conflict (i.e. one hand unintentionally interfering with or even obstructing purposeful movements of the other hand) [41]. A bilateral, asymmetric alien limb syndrome has been reported [42].

Clinical-pathological studies have proven that many CBD patients can present with other syndromes. These include prominent language disturbances, which more commonly manifest as the non-fluent agrammatic variant of primary progressive aphasia. Some CBD patients exhibit a frontal – behavioral phenotype, which cannot readily be distinguished from the behavioral variant of frontotemporal dementia. However, these patients commonly have additional visuospatial and visuoconstructive deficits, which are rarely encountered in behavioral variant FTD (bv-FTD). Another common phenotype is a Richardson-like syndrome, with prominent supranuclear palsy and early falls, as well as frontal-dysexecutive and pseudobulbar syndrome [4].

Apart from these established clinical phenotypes of CBD, there are rarer manifestations of this disease. These include dementia with an amnestic phenotype (AD-like) [43,44], progressive orofacial apraxia [45], conduction-type aphasia with prominent difficulty in repetition [46], posterior cortical atrophy, with optic ataxia, oculomotor apraxia and simultagnosia [47], frontal-type gait disorder [48] and a prominent pseudobulbar syndrome with dysarthria and emotional lability [49].

5. 임상적 특징

피질 기저 증후군은

피질 및 추체외로 징후가 특징입니다.

운동 실조증,

피질 감각 결핍 및 외계인 사지 현상이

가장 흔한 피질 징후인 반면

비대칭 파킨슨증, 근긴장 이상증 및 근간대증은 추체외로 징후를 구성합니다.

피질 기저부 증후군의 파킨슨병은

특징적으로 매우 비대칭적이거나 일측성입니다.

드물게 대칭 피질 기저부 변성에 대한 보고가 있었습니다 [28].

소수의 환자에서 중등도이지만

일시적인 레보도파 반응이 있을 수 있습니다.

떨림이 있는 경우

표현형적으로 비정형적입니다.

일반적으로

위치성 또는 행동성 진전이며,

불규칙할 수 있고

종종 근간대성 진전[4]을 동반합니다.

PD와 유사한

전형적인 레보도파 유발 운동 이상증도 설명되었습니다 [29].

근긴장 이상증은

CBD 환자의 40%에서 나타납니다 [30].

환자의 약 80%가 상지 근긴장 이상증을 보이는 반면, 경추, 하지 근긴장 이상증 및 안검 경련은 드뭅니다. 일반적으로 근긴장 이상은 질병 경과 후 첫 2년 이내에 나타나며 근간대성과 밀접한 관련이 있습니다.

근간대성은 거대한 체성 감각 전위와 뇌파와 심전도 사이의 지연 시간을 기반으로 한 피질 반사 유형 인 것으로 보입니다 [31]. CBD의 근간대성은 감각 피질의 억제 입력 부족으로 인해 일차 운동 피질의 비정상적인 과흥분성으로 인해 발생하는 것으로 가설이 제기되었습니다 [32]. CBD의 경우 거대한 체성 감각 잠재력의 부족은 CBD의 후기 단계에서 심각한 두정엽 위축에 기인합니다 [33].

아프락시아는 CBS의 임상적 특징입니다. CBD에 비교적 특이적인 것으로 간주되지만, 일부 아프락시아 연구에 따르면 PSP 환자의 75% [34,35] 및 PD 환자의 30% [36]에서 아프락시아가 존재한다고 주장했습니다. 그러나 정량적 분석에 따르면 운동 실조증의 심각도(특히 전이 운동에서)에 차이가 있는 것으로 나타났습니다[34,37]. 또한 오류 유형 프로파일링을 포함한 정성적 분석도 두 장애를 구분할 수 있습니다 [35]. CBD 환자는 근위부 운동 실조증보다 원위부 운동 실조증이 더 심하며, 이는 사지 운동 실조증의 개념을 뒷받침합니다 [38].

외계인 사지 증후군은 처음에는 특히 시각적 입력이 없을 때 자신의 사지를 자신의 것으로 인식하는 데 주관적인 어려움을 겪는 것으로 설명되었습니다 [39]. 외계인 증후군은 후방 또는 감각 변종으로 나눌 수 있으며, 이는 감각 반사와 관련이 있습니다. 손이나 팔이 올라가는 증상이 나타날 수 있으며, 이는 일반적으로 위치에 따라 달라지며 감각 자극에 의해 유발될 수 있습니다. 환자는 팔이 자신의 것이 아니라는 느낌을 받습니다 [40]. 전방 또는 운동 변형은 우세한 손의 극단적인 사용 및 잡기 행동이 특징이며, 이는 종종 수동 간 충돌(즉, 한 손이 의도하지 않게 다른 손의 의도적인 움직임을 방해하거나 심지어 방해할 수 있음)을 초래할 수 있습니다[41]. 양측성 비대칭 외계인 사지 증후군이 보고되었습니다 [42].

임상 병리학 연구에 따르면 많은 CBD 환자에게 다른 증후군이 나타날 수 있음이 입증되었습니다. 여기에는 두드러진 언어 장애가 포함되며, 이는 원발성 진행성 실어증의 비 유창성 어법 변형으로 더 일반적으로 나타납니다. 일부 CBD 환자는 전두측두엽 치매의 행동 변형과 쉽게 구별할 수 없는 전두엽 행동 표현형을 보입니다. 그러나 이러한 환자들은 일반적으로 추가적인 시각 공간 및 시각 구조적 결함이 있으며, 이는 행동 변이형 FTD(bv-FTD)에서는 거의 발생하지 않습니다. 또 다른 일반적인 표현형은 리처드슨 유사 증후군으로, 두드러진 핵상 마비와 조기 낙상, 전두-이성 및 가성 구근 증후군이 있습니다[4].

이러한 확립된 CBD의 임상 표현형 외에도 이 질환의 드문 증상이 있습니다. 여기에는 기억상실 표현형(AD 유사)을 가진 치매[43,44], 진행성 구안면 실어증[45], 반복에 현저한 어려움을 겪는 전도형 실어증[46], 시 운동 실조증, 안구 운동 실어증 및 동시 실어증을 동반하는 후피질 위축증[47], 전두엽 보행 장애[48], 구음 장애와 정서적 불안정성을 동반하는 현저한 가성 전구 증후군[49] 등이 있습니다.

6. Genetics

CBD is a predominantly sporadic disease. Familial cases due to a microtubule associated tau protein (MAPT) mutation (Ν296Ν) have been reported [50]. The family in this case harbored neuropathological characteristics of CBD but had a clinical phenotype of early-onset dementia with prominent behavioral symptoms. Moreover, the G389R, p.N410H and P301S MAPT mutations have been described in cases of sporadic CBS [[51], [52], [53]].

LRKK2 mutations, classically underlying familial case of Parkinson's disease, can also rarely present as CBS [54,55]. Progranulin (PGRN) mutations can present with variable phenotypes, including CBS [[56], [57], [58], [59]]. In a northern Italian cohort, PGRN mutations were present in 30% of sporadic CBS patients and in 75% of familial CBS patients [60]. Interestingly, this region has an extremely high percentage of familial CBS [61]. The hexanucleotide (GGGGCC) repeat expansion in intron 1 of C9orf72 gene, which is usually associated with FTD-MND spectrum disorders and relates to TDP-43 pathology, has also been reported to present as CBS [62].

A single report of familial 4R-tauopathy has also been reported, with pathologic confirmation of CBD and PSP in two siblings. No mutation was recorded [63].

Analysis of tau polymorphisms in 57 pathologically confirmed CBD patients, revealed a higher frequency of the HQ and H1/H1 haplotype in this cohort, as is the case in PSP patients. No pathogenic mutation in MAPT was evident in any of the patients [64].VEGF haplotypes have also been reported to confer an increased risk for CBS [65]. A large genome-wide association study found significant genetic overlap between CBD and PSP in the MAPT H1 region, as well as SNPs in or near MOBP, CXCR4, EGFR, and GLDC. Interestingly, there was genetic overlap only in the MAPT haplotype between CBD and FTD [66]. A family with a presenilin 1 mutation, AD pathology and CBS phenotype has also been described [67].

7. Imaging

7.1. Spect – PET studies

Functional imaging modalities have been applied to assist in the differential diagnosis of atypical Parkinsonism, as well as in an attempt to characterize the underlying pathology in a patient with CBS. Perfusion studies using [123I]iodoamphetamine-SPECT indicated that there is decreased perfusion in the inferior prefrontal, sensorimotor, and posterior parietal cortices of CBS patients compared to PSP. Basal ganglia perfusion did not discriminate between the two diseases. CBD patients had more extensive and asymmetric rCBF reductions than in PSP, with the two diseases sharing medial frontal involvement [68]. Likewise, by use of 99mTc HmPaO SPECT, CBD patients could be discriminated from PD patients, since CBD patients exhibited decreased perfusion in the temporoinsular, temporoparietal, and frontal medial regions [69].

A recent FDG-PET study has implied that there are differences in brain perfusion in patients with AD, PSP and CBD who present as CBS. CBS-AD patients presented with posterior, asymmetric hypometabolism, including the lateral parietal and temporal lobes and the posterior cingulate. PSP-CBS had a more anterior hypometabolic pattern, including the medial frontal regions and the anterior cingulate. CBS-CBD showed a similar pattern to CBS-AD, with a more marked, bilateral involvement of the basal ganglia [70].

Another approach is the use of radioligands, which bind to specific pathological proteins, thus providing in vivo information on the disease underlying a patient with CBS. [(11)C]Pittsburgh compound B is strongly indicative of Alzheimer's disease, as it binds to amyloid pathology. By use of this ligand, CBS-AD patients were found to have greater visuospatial and sentence repetition deficits, as well as different cortical atrophy patterns compared to CBS patients with a non-AD pathology [71]. More interestingly, over the past 3 years radioligands have emerged, that bind to tau protein. (18)F-AV-1451 PET provided different binding profiles among CBD, AD and PSP patients, indicating a role in their differential diagnosis. Interestingly, binding of this radioligand correlated with tau pathology burden, but did not correspond to cortical atrophy or hypometabolism in CBD patients [72].

Methodological issues however have arisen, since a mismatch between ante- and postmortem binding to 4R tau lesions was evident. Furthermore, it seems this ligand only binds to a small fraction of 4R pathology [73]. Interestingly, (18)F-AV-1451 binding depended on the presence of amyloid pathology and on the clinical presentation in another study [74]. General issues that have to be resolved relate to non-specific radioligand binding and the specificity of binding to tau isotypes (i.e., 3R vs. 4R vs mixed pathology). Other radiotracers, such as 18F-THK5351 PET have also been tested with the same goal [75].

7.2. MRI studies

The imaging hallmark of CBD is the asymmetrical cortical atrophy, which is more pronounced in the peri-rolandic region (anterior and posterior central gyrus), posterior frontal and parietal lobes, contralaterally to the clinically more severely affected side. Cortical atrophy asymmetry becomes more pronounced as the disease progresses.

An abnormally increased signal on proton density MRI sequences in the region of maximal atrophy has also been described in as many as 80% of patients [76]. This could represent demyelination secondary to axonal damage rather than gliosis. Basal ganglia atrophy can also be present, with abnormally increased signal in T2 weighted images, particularly in the posterior lateral border of the putamen [[77], [78], [79]].

Midbrain atrophy, as well as corpus callosum atrophy, more prominent posteriorly can also be evident [80,81]. The “eye of the tiger” sign, considered pathognomonic for pantothenate kinase-associated neurodegeneration, has also been described in a CBD patient [82].

In volumetry studies, CBS patients present cortical atrophy which is more prominent in the posterior frontal lobes (supplementary motor cortex, dorsal premotor and prefrontal cortex, anterior central gyrus) as well as in the anterior parietal lobe (upper parietal lobule). Less severe atrophy is found in the superior temporal and parahippocampal gyri, the caudate, thalamus and cerebellum [83]. Rate of atrophy is greater in the premotor cortex, the primary motor cortex, the somatosensory region 3a, the superior parietal region and the corticospinal tracts. Subcortically, maximum atrophy rate was recorded in the head of the caudate, the putamen, the globus pallidus, the motor region of the thalamus (anterior ventral and lateral ventral nuclei) and substantia nigra [84].

Differences in atrophy patterns in CBS depend on the underlying pathology. Premotor cortex, supplemental motor area and insula are affected irrespective of the pathology and are characteristic of CBS-CBD and CBS-PSP. However TDP-43 patients exhibit more pronounced frontotemporal atrophy (particularly in the prefrontal cortex) and AD patients frontoparietally (particularly parietally) [85]. CBS patients with underlying AD had more prominent posterior temporal and inferior parietal atrophy compared to non-AD pathology, based on volumetry [86].

Diffusion studies indicate that CBD patients exhibit increased mean diffusivity values in the anterior and posterior central gyrus, the middle frontal gyrus bilaterally and the superior and inferior frontal gyrus contralateral to the most affected side [87]. Likewise, by means of diffusion indices, CBS patients exhibited lower fractional anisotropy and greater apparent diffusion coefficient (ADC) values in the corticospinal tract and posterior corpus callosum compared to controls [88]. Diffusion indices may also assist in the differential diagnosis of CBS from PD patients, because CBS patients exhibit abnormal diffusion, particularly in the posterior segments of the corpus callosum [89]. Diffusion tensor imaging may assist in differentiating PSP from CBS patients. CBS showed a more asymmetric, posterior and supratentorial pattern of degeneration, whereas PSP exhibited more infratentorial (particularly midbrain) and symmetric pattern [90]. Furthermore, putaminal ADC values discriminated PD patients from PSP and CBD patients in a separate study. Superior cerebellar peduncle diffusion was more affected on PSP patients compared to CBD [91]. Diverse thalamic involvement in atypical Parkinsonism via diffusion measurements can also assist in differentiating PSP from CBD. PSP patients have more affected anterior and medial thalamic nuclei, whereas in CBD the motor thalamus is more affected [92].

Resting state MRI has also been applied to look into functional connectivity, particularly of thalamic and cerebellar dentate nucleus networks. It was stated that dentate nucleus connectivity differed between PSP and CBS [93].

Another approach applied recently is a multimodal analysis of gray and white matter alterations, by use of volumetry, cortical thickness and diffusion measures. This approach yielded a significant decrease in cortical thickness in the prefrontal cortex, precentral gyrus, supplementary motor area, insula, and temporal pole bilaterally in CBS when compared to controls. Volume loss was evident in the putamen, hippocampus, and accumbens bilaterally as well as the corpus callosum in CBS [94]. When applied in a cohort of CBS and PSP patients, cortical thickness of the peri-rolandic region best discriminated CBS patients from PSP, whereas volumetry was not useful to this end [95].

The same methodology was applied to differentiate CBS-AD from CBS-non AD patients. Diffusion tensor abnormalities were more severe in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus in CBS-non AD, whereas gray matter abnormalities were prominent in the precuneus and posterior cingulate in CBS-AD [96].

8. CSF biomarkers

Most studies have reported elevated total CSF tau protein compared to healthy controls [[97], [98], [99], [100], [101], [102]], although this difference did not always reach statistical significance [[103], [104], [105], [106]]. Few studies have reported increased total tau in CBS patients compared to PD [102,105], PSP [98,99,102], PDD [105] and DLB [105]. This has been proposed to represent an inherent biochemical element of CBD. A single study, however, has argued that this tau elevation may in fact represent the inclusion of CBS-AD patients in the CBS cohort. When analyzing the CBS cohort after excluding patients with a typical AD profile (elevated t-tau, ph-tau and decreased Ab42), tau protein did not differ between CBS patients and other patient groups. This emphasizes the need for CSF profiling, with exclusion of patients with typical AD-CSF profile, before examining for between-group differences in CSF biomarkers [107].

Ab42 concentration in CSF does not seem to assist in the differentiation of CBD from patients with atypical Parkinsonism or PD. A single study reported decreased Ab42 levels in CBD [103]. The same goes for τp181, with the exception of few studies which have reported elevation in CBS compared to PD and healthy controls [102] and to MSA [105]. Other studies in the field do not report a difference [101,105,106].

Neurofilament heavy chain was elevated in PSP and MSA patients compared to PD and CBS patients in a single study [108]. Neurofilament light protein also seems to be elevated in atypical Parkinsonism compared to PD, whereas glial fibrillary acidic protein (GFAF) does not seem to differentiate between PD and atypical Parkinsonism. Moreover these proteins' concentrations do not seem to alter over time [109]. This was further supported by a meta-analysis on the subject of NFL in the discrimination of PD from atypical Parkinsonism [110].

Application of an immune-PCR assay for measuring 4R- and 3R-tau isoforms in CSF did not reveal differences between 4R-tauopathies (PSP and CBD) and other causes of atypical Parkinsonism [111].

A novel approach is proteomics analysis through liquid chromatography – mass spectrometry analysis. A single study using this methodology produced several proteins (including acute phase/inflammatory and neuronal/synaptic markers), which could potentially serve as biomarkers in atypical Parkinsonism [112].

8. CSF 바이오마커

대부분의 연구에서 건강한 대조군 [[97], [ 98], [99 ], [100], [101], [102]]에 비해 총 CSF 타우 단백질이 증가했다고 보고했지만, 이러한 차이가 항상 통계적 유의성에 도달하지는 않았습니다 [[103], [ 104], [105], [106]]. PD [102,105], PSP [98,99,102], PDD [105] 및 DLB [105]에 비해 CBS 환자에서 총 타우가 증가했다고 보고한 연구는 거의 없습니다. 이는 CBD의 고유한 생화학적 요소를 나타내는 것으로 제안되었습니다. 그러나 한 연구에서는 이러한 타우 상승이 실제로 CBS-AD 환자가 CBS 코호트에 포함되었음을 나타낼 수 있다고 주장했습니다. 전형적인 AD 프로파일(t-tau, ph-tau 상승 및 Ab42 감소)을 가진 환자를 제외한 후 CBS 코호트를 분석했을 때 타우 단백질은 CBS 환자와 다른 환자 그룹 간에 차이가 없었습니다. 이는 CSF 바이오마커의 그룹 간 차이를 조사하기 전에 전형적인 AD-CSF 프로파일을 가진 환자를 제외하여 CSF 프로파일링의 필요성을 강조합니다[107].

CSF의 Ab42 농도는 비정형 파킨슨병 또는 PD 환자와 CBD를 구별하는 데 도움이 되지 않는 것으로 보입니다. 한 연구에서는 CBD에서 Ab42 수치가 감소했다고 보고했습니다 [103]. PD 및 건강한 대조군 [102] 및 MSA [105]에 비해 CBS의 상승을보고 한 몇 가지 연구를 제외하고는 τp181도 마찬가지입니다. 이 분야의 다른 연구에서는 차이를 보고하지 않았습니다 [101,105,106].

신경섬유 중쇄는 단일 연구에서 PD 및 CBS 환자에 비해 PSP 및 MSA 환자에서 증가했습니다 [108]. 신경섬유 경단백질은 PD에 비해 비정형 파킨슨병에서도 상승하는 것으로 보이지만, 아교 섬유소 산성 단백질(GFAF)은 PD와 비정형 파킨슨병을 구별하지 못하는 것으로 보입니다. 게다가 이러한 단백질의 농도는 시간이 지나도 변하지 않는 것으로 보입니다[109]. 이는 PD와 비정형 파킨슨병을 구별하는 데 있어 NFL을 주제로 한 메타 분석에 의해 더욱 뒷받침되었습니다 [110].

CSF에서 4R 및 3R-타우 이소폼을 측정하기 위한 면역-PCR 분석법을 적용한 결과, 4R-타우 병증(PSP 및 CBD)과 비정형 파킨슨증의 다른 원인 간의 차이가 드러나지 않았습니다 [111].

새로운 접근법은 액체 크로마토그래피-질량 분석법을 통한 프로테오믹스 분석입니다. 이 방법론을 사용한 한 연구에서는 비정형 파킨슨병의 바이오마커로 사용될 수 있는 여러 단백질(급성기/염증성 및 신경세포/시냅스 마커 포함)을 생성했습니다 [112].

9. Treatment

No disease-modifying treatment has been approved for CBD. However, many symptoms of CBS can be symptomatically treated. Parkinsonism in CBS can be treated with levodopa, with poor and only transient response [113]. Dystonia in CBS can be successfully treated with botulinum toxin, which can temporarily improve the functionality of the affected limb [114]. Clonazepam is the first choice treatment for myoclonus [113].

Few studies indicate that physical therapy is important in CBS. Physical therapy aims to improve everyday functionality, prevent contractures, and improve rigidity [115]. No treatment has been approved for the cognitive deficits in CBS. However, it is reasonable to try acetylcholinesterase inhibitors in cases of CBS where biomarkers indicative of Alzheimer's disease are available (e.g. CSF biomarkers or [(11)C]Pittsburgh compound B PET-scan).

9. 치료

CBD에 대한 질병 수정 치료법은 승인되지 않았습니다. 그러나 CBS의 많은 증상은 증상 적으로 치료할 수 있습니다.

CBS의 파킨슨병은

레보도파로 치료할 수 있으며,

반응이 좋지 않고 일시적인 반응 만 있습니다 [113].

CBS의 근긴장 이상은

보툴리눔 독소로 성공적으로 치료할 수 있으며,

이는 영향을받은 사지의 기능을 일시적으로 향상시킬 수 있습니다 [114].

클로나제팜은

근간대성 근긴장이상증에 대한

첫 번째 선택 치료법입니다 [113].

CBS에서

물리 치료가 중요하다는 연구는 거의 없습니다.

물리 치료는

일상적인 기능을 개선하고

구축을 예방하며 경직을 개선하는 것을 목표로 합니다[115].

CBS의 인지 결함에 대한 치료법은 승인되지 않았습니다. 그러나 알츠하이머병을 나타내는 바이오마커(예: CSF 바이오마커 또는 [(11)C]피츠버그 화합물 B PET 스캔)를 사용할 수 있는 CBS의 경우 아세틸콜린에스테라제 억제제를 사용해 보는 것이 합리적입니다.

10. Conclusions

CBD can present with a multitude of phenotypes apart from the classical CBS, including behavioral, language or postural deficits. Conversely, CBS can harbor diverse pathologies, including CBD, AD, PSP and FTD-TDP43 among others. This clinical-pathological overlap emphasizes the need for biomarkers to assist in the ante mortem etiological diagnosis of a patient with CBS. To this extent, structural and functional imaging modalities, as well as CSF biomarkers have been applied. Further research on biomarkers is critical, in view of specific protein-targeting, disease modifying treatments tested in clinical trials.

10. 결론

CBD는 행동, 언어 또는 자세 결함을 포함하여 고전적인 CBS와는 별도로 다양한 표현형을 나타낼 수 있습니다. 반대로 CBS는 CBD, AD, PSP 및 FTD-TDP43을 포함한 다양한 병리를 나타낼 수 있습니다. 이러한 임상적-병리학적 중첩은 CBS 환자의 생전 병인 진단에 도움이 되는 바이오마커의 필요성을 강조합니다. 이를 위해 구조적 및 기능적 이미징 양식과 CSF 바이오마커가 적용되었습니다. 임상시험에서 테스트된 특정 단백질 표적, 질병 수정 치료법을 고려할 때 바이오마커에 대한 추가 연구는 매우 중요합니다.

Declaration of competing interest

The authors does not have any conflict of interest.

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References

1. Rebeiz J.J., Kolodny E.H., Richardson E.P., Jr. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans. Am. Neurol. Assoc. 1967;92:23–26. [PubMed] [Google Scholar]

2. Gibb W.R., Luthert P.J., Marsden C.D. Corticobasal degeneration. Brain. 1989;112(Pt 5):1171–1192. [PubMed] [Google Scholar]

3. Dickson D.W., Bergeron C., Chin S.S. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J. Neuropathol. Exp. Neurol. 2002;61(11):935–946. [PubMed] [Google Scholar]

4. Armstrong M.J., Litvan I., Lang A.E. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496–503. [PMC free article] [PubMed] [Google Scholar]