대한치매학회지 : 제 1 권제 2 호 2002 Journal of the Korean Dementia Association. 2002; 1: 파킨슨증상을동반한치매 : 진행성핵상마비 이재홍 울산대학교의과대학신경과학교실 Dementia with Parkinson

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1 대한치매학회지 : 제 1 권제 2 호 2002 Journal of the Korean Dementia Association. 2002; 1: 파킨슨증상을동반한치매 : 진행성핵상마비 이재홍 울산대학교의과대학신경과학교실 Dementia with Parkinsonism: Progressive Supranuclear Palsy Jae-Hong Lee, M.D. Department of Neurology, University of Ulsan College of Medicine, Seoul, Korea Address for correspondence Jae-Hong Lee, M.D. Department of Neurology, Asan Medical Center, Pungnap-2dong, Songpa-gu, Seoul , Korea Tel: Fax: jhlee@amc.seoul.kr This article reviews recent advances in the study of progressive supranuclear palsy (PSP) including the new insights into the pathogenesis. PSP is a tauopathy affecting the specific areas of the basal ganglia and the brain stem. Supranuclear gaze palsy, postural instability and falls, and subcortical dementia are unique for the diagnosis. In early stages when supranuclear opthalmoplegia is not apparent, however, it is often challenging to differentiate PSP from the other degenerative disorders presenting parkinsonism with dementia. Several clinical features that distinguish PSP from non-psp cases were suggested. On neuropsychological test, patients with PSP typically shows slow mental operation, retrieval type of amnesia, personality change with apathy or depression, and executive dysfunction. This prominent frontal dysfunction is mainly due to frontostriatal circuit disruption caused by basal ganglionic pathology. The cortical form of progressive supranuclear palsy simulating cortical dementia has been reported in which neocortical neurofibrillary tangles and/or neuropil threads are predominant. Key Words: Progressive supranuclear palsy, Tauopathy, Parkinsonism, Subcortical dementia 진행성핵상마비 (progressive supranuclear palsy) 는처음이병을기술한이들의이름을따서일명 Steele-Richardson-Olszewski syndrome이라고도한다. Steele 등이 1964년도에진행성핵상마비 series를보고 [1] 한이래로이병에대해많은것이알려지긴했어도여전히그원인이나발병기전은모르는상태이고특별한치료도없는실정이다. 1. 역학대다수의퇴행성신경계질환이그러하듯이진행성핵상마비도적절한 population-based survey가없어정확한유병률이나발병률을알기가어렵다. 대체적인유병률은 100,000명당 5-6명으로파킨슨병의 10분의 1정도의빈도인것으로보고되고있다 [2]. 인종에따른차이는없으나 2:1 정도로남자에서더흔한경향이있고발병연령은대개 50대후반이나 60대중반이다. 진행성핵상마비의진행은빠른편이어서증상발생후 median survival이 5-10년인것으로알려져있다. 2. 원인원인은아직밝혀져있지않다. Steele 등은이병이원발성 중추신경계퇴행성질환아니면바이러스감염후에생기는퇴행성질환일것이라고주장한바있으나 [1] viral origin은아닐것으로생각된다. McCrank 등은진행성핵상마비환자에서 organic solvents에노출된사례가많음을들어이것과의연관성을제시하기도했으나 [3] 후속연구에서는이를뒷받침하는소견이나오지않았다. 가족성진행성핵상마비의보고가있는것으로보아 hereditary progressvie supranuclear palsy가있을것으로여겨진다. 한가계의연구에의하면상염색체우성으로 5대에걸쳐진행성핵상마비가관찰되었으나한환자에서만병리학적으로확진되었다 [4]. 대다수의진행성핵상마비는산발성 (sporadic) 으로발생하는것으로여겨진다. 진행성핵상마비는기본적으로타우단백질환 (tauopathy) 으로서타우단백 (tau protein) 은세포내미세관 (microtubule) 을안정시키는 microtubule-associated protein이다. 진행성핵상마비환자의부검뇌에서는 4개의 microtubule binding domain을갖는 tau isoform (4-repeat tau) 이선택적으로증가되어있다고한다 [5]. 염색체 17q21에있는 tau locus의다형성 (polymorphism) 이진행성핵상마비의위험발병인자라는최근보고가있다 [6]. 형질전환쥐 (transgenic mice for human 4-repeat tau) 가개발돼앞으로이병의연구에큰진전이있을것으로 77

2 78 이재홍 Oxidative stress -Oxidative damage to DNA, RNA, protein and lipids -Increased transition metal ions -Increased inos levels Fig. 1. The possible interactions between oxidative stress, mitochondrial dysfunction and tau in the formation of neurofibrillar tangles (NFTs) in progressive supranuclear palsy (PSP). 예상된다. 진행성핵상마비의발병이 multi-infarct state와원인적으로관련성이있다는보고도있다. Dubinski와 Jankovic은 small vessle disease에의한 multi-infarct state를보이는진행성핵상마비증례들을기술한바있다 [7]. Ghika와 Bogousslavsky 는진행성핵상마비로임상진단을받은환자의 81% 에서고혈압병력이있음을보고하였다 [8]. 그러나현재로서다발성뇌경색이나고혈압이얼마나진행성핵상마비의발병에관여하는지는알수없다. 최근에는 increased oxidative damage와 mitochondrial dysfunction이발병기전에중요한것으로여겨지고있다 [9]. 사립체 (mitochondria) 는세포내유리기 (intracellular free radicals) 의주된공급원으로사립체기능저하가있으면유리기의발생이크게늘고그결과추가적인산화성손상이사립체단백질, 지질, 또는 DNA에작용하고이것은다시사립체기능저하를가중시키는악순환을초래한다. 진행성핵상마비는이러한 oxidative damage와 mitochondrial dysfunction의상호작용에여러가지유전적, 환경적요인이덧붙여짐으로써미세관의해중합 (polymerization of microtubules) 과 4-repeat tau의과인산화가초래되고그결과신경원섬유농축체 (NFTs) 와뇌세포소실이발생한다는것이다 (Fig. 1). 3. 임상소견 Mitochondrial dysfunction -Decreased complex l activity -Increased free aocnitase, KGDHC activities radical production -Decreased ATP levels -Impaired Ca 2+ buffering -Increased [Ca 2+ ] NFTs -MMP activation -Hyper phosphorylation of fau -Depolymerization of miaciubules -Increased transglulaminase activity Tau -Overexpression of 4-repeat tau TRENDS in Neurosaiencas 진행성핵상마비의핵심적인임상소견은 1) supranuclear gaze palsy, 2) pseudobulbar palsy, 3) neck dystonia, 4) parkinsonism, 5) poor equilibrium with falls, 6) subcortical dementia로요약할수있다. 고도로진행된진행성핵상마비는이러한특징적인소견을대부분다보이므로진단에어려움이없으나초기에, supranuclear gaze palsy가나타나기전에는진 행성핵상마비진단이쉽지않다. 파킨슨증상을보이는다른많은신경계질환들과의감별이어렵기때문이다. 초기증상은대개 postural instability와 falls로시작한다 [10]. 구음장애, 서동 (bradykinesia), 시각장애, 인지기능장애나행동장애로시작하는경우도있다. Supranuclear ophthalmoplegia는진행성핵상마비진단에가장중요한임상소견이다. 진행성핵상마비의 supranuclear gaze palsy로인정되려면 downward gaze palsy가있어야한다. Upward gaze palsy는진행성핵상마비외에도파킨슨병이나정상노인에서도관찰할수있기때문이다. 또한 saccade movement가느려져있고 oculocephalic movement 는보존돼있다. Eyelid 이상도흔히관찰되는데, eyelid retraction, blepharospasm, ptosis, apraxia of eyelid opening and closing, decreased blink rate 등의소견을보인다. 진행성핵상마비환자에서파킨슨병에서와같이서동, 수지진전, 경직등이나타나지만부검환자증례분석에의하면, 서동은증상시작후 1년내에보이는경우가불과 22% 에불과하였다 [11]. 또다른연구에의하면진전 (tremor) 은진행성핵상마비환자의 12-16% 에서만관찰되었다 [12]. Axial dystonia는이보다훨씬흔하게나타나부검으로확인된진행성핵상마비환자의 50% 에서관찰된다고한다 [13]. Limb dystonia, blepharospasm, oromandibular dystonia도종종보인다. 보행장애는진행성핵상마비환자에서항상관찰되는데대개발병초기부터나타난다. stiff, broad-based gait를보이며몸을돌릴때뒤로잘넘어진다. 파킨슨병처럼 slow, short stride, shuffling, festinating, freezing, postural instability를보이나파킨슨병과달리보행시 arm swing은보존돼있다. 구음장애, 연하장애가흔히동반된다. 발음은 spastic dysarthria 로 slow, strained quality를보이며병이진행하면서점차나빠져나중에는거의알아들을수없는소리를낸다. 인지기능장애가흔하게관찰된다. 보고에의하면환자의약 50% 가치매를보이는것으로알려져있다 [1, 14, 15]. 병의경과중비교적일찍부터나타난다. 치매는피질하성치매 (subcortical dementia) 양상으로 bradyphrenia (slow mental activity), forgetfulness, personality or behavioral change, executive dysfunction을특징으로한다 [14]. cognitive slowing을보이는데, 검사자의질문에대답하거나간단한과제를해결하는데시간이아주오래걸린다. 행동이상으로는 self-guided behavior가잘안돼탈억제 (disinhibition) 현상을보인다. 검사중손뼉을세번만치라고하면중단없이계속치고검사자의동작을그대로흉내내는것을자주관찰할수있다. 우울증을보이는경우가흔하고대식증 (bulimia) 같은강박적행동을보이기도한다. 가장뚜렷한이상은집행기능에서찾아볼수있다. 집행기능은새로운상황에적절히적응하는데중요하게관여함으로써문제해결, 계획수립, 새로운개념의창출, 주위환경변화에맞춘사고와행동의도출을가능케한다. 집행기능장애 (dysexecutive

3 파킨슨증상을동반한치매 : 진행성핵상마비 79 syndrome) 는 trail making test, Stroop test, word fluency, Wisconsin card sorting test 등을통해확인할수있다. 기억력검사를해보면수행이저조하나힌트를주거나재인 (recognition) 을시키면훨씬잘하게되는데이는정보의등록 (registration) 이나저장 (retention) 은큰문제없으나인출 (retrieval) 이잘안됨으로써 recall deficit가발생하는것이다. 작업기억 (working memory) 이떨어져새로이획득한정보를충분한기간동안유지하지못하고간섭자극을억제해야하는작업수행시단기기억이잘이루어지지못하는현상을보인다. 치매가진행되어도약간의관념운동성실행증 (ideomotor apraxia) 을제외하고는 instrumental function이대부분보존된다. 결국전두엽장애로진행성핵상마비의인지장애를요약할수있다. 4. 진행성핵상마비와치매진행성핵상마비때보이는파킨슨증상과안구운동이상은기능해부학적으로비교적잘설명될수있지만인지기능장애에대해서는그발생기전이나뒷받침하는해부학적구조가불분명한상태이다. 신경심리검사나 PET 촬영을해보면진행성핵상마비는다른피질하성치매 (subcortical dementia) 에비해훨씬심한전두엽기능장애를나타낸다 [16-18]. 여기에대해서는몇가지의설명이가능하다. 우선은일차적인선조체이상으로그원인을돌릴수있다. 즉, frontostriatal cognitive" circuit의정상적인정보처리가안됨으로써결과적으로 frontal deafferentation이초래되는것이다 [16]. 선조체손상은또한 anterior cingulate attention" circuit와 lateral-orbitofrontal social affect" circuit에도지장을초래해전두엽기능장애를가져온다. 둘째는, Parkinson's disease dementia 때와같이진행성핵상마비의병변침범부위에의해 mesocorticolimbic dopaminergic alteration이초래되는것으로설명할수있다. 셋째는, 진행성핵상마비의병변이직접대뇌피질을침범하는상황이다. 10예의진행성핵상마비환자를분석한한병리보고에의하면모든예에서대뇌피질 (neocortex) 에 tangles와 neuropil threads가관찰되었고 neocortical tangles가가장많이발견된곳은 Brodmann's area 4였고주로 layers V-VI인것으로나타났다 [19]. 드물게진행성핵상마비환자에서실어증, 실행증, 편측무시등의피질성기능장애 (cortical dysfunction) 를보이는경우가있고심지어는분명한 perceptual-motor 증상을보여 corticobasal degeneration으로오인되는예도보고돼있다 [20]. 또 entorhinal cortex가침범돼 hippocampal-isocortex disconnection이초래됨으로써알쯔하이머병과유사한임상양상을보이기도한다. 이러한경우들은병변의해부학적분포가다른것으로밝혀져있다. 즉, 대뇌피질에 tau pathology인 neocortical tangles 와 neuropil threads가집중적으로많이발견된다는것이다. 결국, 진행성핵상마비가전형적인피질하성치매를보이는경우는주로기저핵병변에의한 frontostriatal circuit dysfunction이 작용하고일부전두엽대뇌피질자체의병리가관여해기저핵을침범하는다른퇴행성질환에비해전두엽기능장애가더심하게나타난다고할수있다. 그러나피질성치매 (cortical dementia) 를보이는비전형적인경우는진행성핵상마비의병리학적변화가대뇌피질에주로발생하는데기인한다. 5. 감별진단 비전형적파킨슨증과치매를동시에보이는질환들이감별진단의대상이된다. 진행성핵상마비는대개안구운동이상과 L- dopa 무반응으로다른질환들과임상적으로구분이가능하다. 감별진단의대상이되는질환은크게 neurodegenerative disease와 nondegenerative disease로나누어생각할수있다. 1) neurodegenerative diseases -Parkinson's disease -corticobasal degeneration -multiple system atrophy -dementia with Lewy bodies -Creutzfeldt-Jakob disease -Pick's diesease -primary pallidal atrophy 2) nondegenerative diseases -multi-infarct state -Whipple's disease -Wilson's disease Livitan 등은통계학적분석을통해진행성핵상마비를다른퇴행성질환과구분해줄수있는임상적속성을찾아내고자하였다 [21]. 그들의연구에의하면, 파킨슨병과의감별점은 unstable gait, absence of tremor-dominant disease, absence of a response to levodopa가통계학적으로의미가있었다고하였다. 루이체치매 (dementia with Lewy bodies) 와는 supranuclear vertical gaze palsy, gait instability, absence of delusions로구분할수있었고 multiple system atrophy (MSA) 와는 supranuclear vertical gaze palsy, increased age at symptom onset로, corticobasal degeneration (CBD) 과는 gait abnormality, severe upward gaze palsy, bilateral bradykinesia, absence of alien limb syndrome으로구분이가능하였다. 또픽병 (Pick's disease) 과의감별은 postural instability가가장유의하였다. 6. 진단 과거여러임상진단기준이제시된바있으나진단의민감도와특이도를높이고세계적으로널리사용하기위한목적으로 1996 년도에 the National Institute of Neurological Disorders and

4 80 이재홍 Table 1. Mandatory Exclusion and Supportive Criteria for Progressive Supranuclear Palsy Mandatory Exclusion Criteria Recent history of encephalitis Alien limb syndrome, cortical sensory loss, focal frontal or temporoparietal atrophy Hallucinations or delusions unrelated to dopaminergic therapy Cortical dementia of Alzheimer s type Prominent, early cerebellar symptoms or prominent, early unexplained dysautonomia Severe, asymmetric parkinsonian signs Neuroradiologic evidence of relevant structural abnormality Whipple s disease confirmed by polymerase chain reaction Supportive Criteria Symmetric akinesia or rigidity, proximal greater than distal Abnormal neck posture, especially torticollis Poor or absent response of parkinsonism to L-dopa therapy Early dysphagia or dysarthria Early onset of cognitive impairment including at least two of the following: apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior, or frontal release signs Stroke and the Society for Progressive Supranuclear Palsy (NINDS-SPSP) 에서후원한 International Workshop에서새로운진단기준을제정한바있다. 진단의확실도 (diagnostic certainty) 에따라다음의 3가지로구분하였다 [22]. 1) Possible PSP: presence of a gradually progressive neurologic disorder with onset at age of 40 years or older, either vertical supranuclear gaze palsy or both slowing of the vertical saccades and prominent postural instability with falls in the first year of onset and no evidence of other diseases that could explain these features. These criteria are substantially sensitive but less specific. 2) Probable PSP: vertical supranuclear palsy, prominent postural instability, and falls in the first year of onset and other features of possible PSP 3) Definite PSP: history of probable or possible PSP and histopathologic evidence of typical PSP mandatory exclusion과 supportive criteria를 Table 1에소개하였다. 7. 신경영상검사대부분의경우 CT나 MRI소견은비특이적 (nonspecific) 이다. 병이상당히진행된시점에서는다음과같은소견들이관찰될수있다. -thinning of the AP diameter of the midbrain tectum and tegmentum -atrophy of the colliculi -disproportionate enlargement of the sylvian fissures and posterior third ventricle -high signal in the periaqueductal gray matter 18 F-fluorodopa PET 영상촬영을했을때파킨슨병에서는 putamen에국한해 tracer uptake가떨어지는데반해진행성핵상마비에서는 putamen과 caudate 모두에서 uptake가떨어진 다. 또한 FDG-PET에서는전두엽에포도당대사가현저하게저하돼있는것을관찰할수있다 [23]. 8. 신경병리소견진행성핵상마비는 tau pathology를가지는 tauopathy로서, 특징적으로기저핵과뇌간에다량의 neurofibrillary tangle (NFT) 이나 neuropil threads를보인다. neuronal degeneration과 gliosis가피질하또는뇌간의특정신경핵에집중되는특징적인병변분포를보인다. 진행성핵상마비의 histopathological hallmark는 fibrillary gliosis, demyelination, intracytoplasmic vacuoles, straight NFT로요약할수있다. NFT는 Alzheimer's disease때와달리 flame shape가아니라 globose shape를이룬다. NFT를구성하는 filament는지경 nm의 unpaired filaments로밝혀져있다. 선조체내에서는 large cholinergic neruon 의선택적소실이관찰되고 tufted astrocytes (filamentous tau inclusions in astrocytes) 가많이나타난다 (Fig. 2). 특히조가비핵 (putamen) 내의과인산화타우-양성 (hyperphosphorylated tau-positive) tufted astrocytes는진행성핵상마비의특징적인소견으로되어있다 [24]. 이러한 abnormal astrocytes는신경세포소실이별로없는여러대뇌피질부위 ( 예를들면, 전두엽의 layer V) 나시상 (thalamus) 에도보이는것으로알려져있다 [19]. NINDS 신경병리학적진단기준에따르면병변의해부학적분포에따라 typical", atypical", combined" 의세가지아형으로분류한다. typical" 진행성핵상마비의병리소견으로인정받으려면다음의기준을만족해야한다 [25]. 1) 고밀도의 neurofibrillary tangle과 neurophil threads가 pallidum, subthalamus, sustantia nigra, pons 중적어도세군데이상에서관찰된다. 2) 저밀도에서고밀도의 neurofibrillary tangle이 striatum. oculomotor complex, medulla, dentate nucleus 중적어도세군데이상에서관찰된다.

Note the shrunken substantia nigra pars compacta (SNc), subthalamic nucleus (STN), and the internal segment of the globus pallidus (GPi), consistent with a marked loss of neurons.

5 파킨슨증상을동반한치매 : 진행성핵상마비 81 CN Put GPi STN SNc A B Fig. 2. Pathology of progressive supranuclear palsy within the basal ganglia. (A) Macroscopic view of a hemi-coronal slice of through the basal ganglia of a typical progressive supranuclear palsy brain. Note the shrunken substantia nigra pars compacta (SNc), subthalamic nucleus (STN), and the internal segment of the globus pallidus (GPi), consistent with a marked loss of neurons. By contrast, the caudate nucleus (CN) and putamen (Put) are relatively well preserved. (B) Example of tau-immunopositive tufted astrocytes (arrows) within the putamen of a PSP brain. 3) 뇌경색, 현저한미만성혹은국소성뇌위축, Lewy bodies, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, 또는알쯔하이머병의특징적인병리소견이보이지않아야한다. atypical" type는 NFTs가대뇌피질이나상기의부위가아닌다른뇌간부위에많이보일때를말한다. combined" type 는 NFTs가다른질환의병리소견과함께보일때로정의한다. 9. 치료많은약제들이치료제로시도된바있으나치료효과는거의발견할수없었다. 도파민성효과와항글루타메이트성효과를동시에보여경도의증상개선효과를일부보일수있는것으로보고돼있다 [27]. cholinesterase inhibitor인 physostigmine은진행성핵상마비환자의청각적기억력과시공간지각능력을약간개선시킬수있으나보행은오히려악화시킨다. 3) 기타이밖에도여러약제들이진행성핵상마비의일부증상을개선시킬목적으로시도되나뚜렷한효과를보이지못하고있다. 진행성핵상마비의 focal dystonia나 apraxia of eyelid opening을치료하기위해보톡스주사 (botulinum toxin injection) 가사용되기도한다. 1) L-dopa & dopamine agonists 초기단계때 L-dopa를많이사용하지만증상개선효과는미미하고오래가지못한다. 후향적연구에의하면약 40% 정도의환자에서 L-dopa에대한반응이있으나매우미미한수준이었다 [26]. L-dopa response에대한위약대조군을사용한이중맹검연구는아직없다. 향도파민제에대한반응도별로신통치않다. 2) cholinergics & anticholinergics anticholinergics 가증상개선에도움이될수도있으나그효과는 L-dopa 보다도못한것으로알려져있다. amantadine은 참고문헌 1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy; a heterogeneous degeneration involving the brainstem, basal ganglia and cerebellum with vertical gaze and psuedobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964; 10: Schrag A. Prevalence of progressive supranuclear palsy and multiple system atrophy: a cross-sectional study. Lancet 1999; 354: McCrank E, Rabheru K. Four cases of progressive supranuclear palsy in patients exposed to organic solvents. Can J Psychiatry 1989; 34:

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