국내 근위축측삭경화증 환자의 인지기능 장애에 대한 연구

Abstract

Background: Cognitive impairment is associated with a negative prognosis in amyotrophic lateral sclerosis (ALS), as well as with clinical specificity. We investigate neuropsychological function in ALS patients without known genetic mutations in a Korean tertiary clinic.

Methods: Three hundred and eighteen patients were enrolled in a prospective longitudinal cohort from September 2008 to February 2012. At the time of diagnosis of sporadic ALS, we carried out genetic and comprehensive neuropsychological tests on all patients, and collected demographic and clinical characteristics. Six cognitive domains, namely executive function, attention, language, calculation, visuospatial function and memory were evaluated. ANOVA and t-tests were used to assess differences in clinical characteristics and neuropsychological parameters between sporadic ALS patients. The Kaplan-Meier method and Cox proportional hazard model were used for survival analysis.

Results: One hundred and sixty-six patients were categorized into five subtypes: normal cognition (ALS pure), cognitive impairment (ALSci), behavioral impairment (ALSbi), frontotemporal dementia (ALS-FTD), and other types of dementia. Seventy patients (70/166, 42.2%) were cognitively or behaviorally impaired. Among the impaired patients, eight (8/166, 4.8%) had FTD-type dementia and one (1/166, 0.6%) was Alzheimer’s disease-type. The ALS patients with cognitive impairment (ALSci) and with FTD (ALS-FTD) were more severely impaired in executive function, attention, language and memory than the cognitively intact ALS patients (ALS pure). In a survival analysis, ALSci (β=1.925, p=0.025) and ALS-FTD groups (β=4.150, p=0.019) tended to have shorter survival than the ALS pure group.

Conclusions: About half of ALS patients without known genetic variation have cognitive or behavioral impairment. ALS patients with cognitive abnormalities, especially FTD, have a poorer prognosis than those without cognitive impairment. In neuropsychological profiling, executive tasks were effective in identifying cognitive impairment in the ALS patients. It would be useful for clinicians to classify ALS according to neuropsychological profiles, and screen for subtle cognitive impairment. |근위축측삭경화증은 주로 운동신경 손상에 의한 근 위약 및 근 위축이 주증상인 질환이지만, 최근 연구에 의해 인지기능 저하, 자율신경계 이상, 감각증상 등이 동반되는 다계통질환으로 받아들여지고 있다. 이 중에서 인지기능 장애는 근위축측삭경화증의 임상적 특이성과 관련이 있을 뿐만 아니라 예후 예측에서 음의 상관관계를 가지는 것으로 알려져 있다. 본 연구는 국내 3차 의뢰병원의 근위축측삭경화증 환자군을 대상으로 신경심리검사를 통해 신경심리학적 기능을 확인하고, 신경심리학적 기능 저하에 따른 임상적 특징과 생존기간과의 연관성을 확인하고자 한다. 근위축측삭경화증 환자는 한양대학교병원 신경과 루게릭병클리닉에서 진행 중인 전향적 코호트 내에서 2008년 9월부터 2012년 2월까지 모집하였다. 모든 환자들은 개정된 El Escorial criteria에 따라 근위축측삭경화증으로 진단하였고, 유전자 검사를 통해 SOD1, C9ORF72, FUS, TARDBP, ANG, OPTN 유전자가 음성이며 가족력이 없는 산발성 근위축측삭경화증으로 진단된 환자를 등록하였다. 전체 318명의 환자가 등록되었으며 근위축측상경화증 이외의 인지기능 저하를 유발할 수 있는 신경학적 질환을 가지고 있는 환자들은 제외하였다. 인구통계학적 조사와 근위축측삭경화증와 관련된 임상지표에 대한 조사를 실시하였고, 신경심리검사를 실시하여 전두엽/실행기능, 주의력, 언어능력, 계산능력, 시공간능력, 그리고 기억력의 세부 기능에 대한 검사를 실시하였다. 신경심리학적 결과에 따른 분류를 통해 임상적 특징을 비교하고 Kaplan-Meier 생존방법과 Cox 회귀분석을 적용하여 생존분석을 실시하였다. 최종적으로 166명의 환자가 등록되었으며 인지기능과 행동심리기능을 확인한 신경심리학적 결과에 따라 총 다섯 군으로 분류하였다.각 군은 96명(57.8%)의 인지 및 행동심리기능이 정상인 군(ALS pure), 38명(22.9%)의 인지기능이 손상된 군(ALSci), 23명(13.9%)의 행동심리기능이 손상된 군(ALSbi), 인지기능과 행동심리기능이 심하게 손상되어 치매 단계에 도달한 환자로 8명(4.8%)에서 전두측두엽치매가 동반된 군(ALS-FTD), 그리고 1명(0.6%)의 다른 형태의 치매가 동반된 군(ALS-other dementia)으로 분류된다. ALSci군과 ALS-FTD군에서 ALS pure군에 비해 실행기능, 주의력, 언어능력 및 기억력에서 심한 장애를 나타났다. 생존분석에서 ALSci군(β=1.925, p=0.025)과 ALS-FTD군(β=4.150, p=0.019)에서 ALS pure군에 비해 짧은 생존기간을 나타내며 좋지 않은 예후를 보이고 있었다. 이번 연구를 통해 근위축측삭경화증의 후보유전자가 없는 산발성 근위축측삭경화증 환자 중 42%의 환자에서 인지기능 또는 행동심리기능이 손상된 것을 확인할 수 있었다. 신경심리검사의 세부항목 중, 실행기능 검사가 효율적으로 인지기능 장애를 확인할 수 있는 항목이다. 또한 생존분석을 통해 인지기능 장애를 동반하거나 전두측두엽치매가 동반하게 될 경우 나쁜 예후를 나타내는 것을 확인할 수 있었다. 이러한 신경심리검사를 통해 근위축측삭경화증을 분류하는 것은 임상적 접근 및 예후 예측을 위해 임상의들에게 유용할 것이며, 추후 연구에서는 초기의 미약한 인지기능 장애에 대한 선별검사 방법에 대한 연구를 필요로 할 것이다.; Background: Cognitive impairment is associated with a negative prognosis in amyotrophic lateral sclerosis (ALS), as well as with clinical specificity. We investigate neuropsychological function in ALS patients without known genetic mutations in a Korean tertiary clinic.

Methods: Three hundred and eighteen patients were enrolled in a prospective longitudinal cohort from September 2008 to February 2012. At the time of diagnosis of sporadic ALS, we carried out genetic and comprehensive neuropsychological tests on all patients, and collected demographic and clinical characteristics. Six cognitive domains, namely executive function, attention, language, calculation, visuospatial function and memory were evaluated. ANOVA and t-tests were used to assess differences in clinical characteristics and neuropsychological parameters between sporadic ALS patients. The Kaplan-Meier method and Cox proportional hazard model were used for survival analysis.

Results: One hundred and sixty-six patients were categorized into five subtypes: normal cognition (ALS pure), cognitive impairment (ALSci), behavioral impairment (ALSbi), frontotemporal dementia (ALS-FTD), and other types of dementia. Seventy patients (70/166, 42.2%) were cognitively or behaviorally impaired. Among the impaired patients, eight (8/166, 4.8%) had FTD-type dementia and one (1/166, 0.6%) was Alzheimer’s disease-type. The ALS patients with cognitive impairment (ALSci) and with FTD (ALS-FTD) were more severely impaired in executive function, attention, language and memory than the cognitively intact ALS patients (ALS pure). In a survival analysis, ALSci (β=1.925, p=0.025) and ALS-FTD groups (β=4.150, p=0.019) tended to have shorter survival than the ALS pure group.

Conclusions: About half of ALS patients without known genetic variation have cognitive or behavioral impairment. ALS patients with cognitive abnormalities, especially FTD, have a poorer prognosis than those without cognitive impairment. In neuropsychological profiling, executive tasks were effective in identifying cognitive impairment in the ALS patients. It would be useful for clinicians to classify ALS according to neuropsychological profiles, and screen for subtle cognitive impairment.