한국임상약학회지제 28 권제 4 호 Korean J Clin Pharm, Vol. 28, No. 4, 2018 Original Article Korean Journal of Clinical Pharmacy Official Journal of Korean College of Clinical Pharmacy pissn 1226-6051 eissn 2508-786X https://doi.org/10.24304/kjcp.2018.28.4.285 Korean journal of clinical pharmacy (Online) URL: http://www.ekjcp.org 레보도파요법중인파킨슨병환자의인지장애위험인자연구 김경숙 1,2 이경은 2 * 이명구 2 * 1 충북대학교병원약제부, 2 충북대학교약학대학 (2018 년 7 월 27 일접수 2018 년 10 월 12 일수정 2018 년 10 월 29 일승인 ) Risk Factors for Cognitive Impairment in Patient with Parkinson s Disease Treated with Levodopa Kyung Sook Kim 1,2, Kyung Eun Lee 2 *, and Myung Koo Lee 2 * 1 Department of Clinical Pharmacy, Chungbuk National University Hospital, Cheongju 28644, Republic of Korea 2 Department of Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea (Received July 27, 2018 Revised October 12, 2018 Accepted October 29, 2018) ABSTRACT Background: Long-term levodopa therapy relieves the motor dysfunction associated with Parkinson s disease (PD), but has various effects on non-motor symptoms, including cognitive dysfunction, hallucinations, and affective disorders, and can exacerbate certain aspects of dementia-like cognitive dysfunction. Here, we investigated the relationship between levodopa treatment and development of dementia in patients with PD. Methods: This retrospective study analyzed 76 consecutive patients with PD who had taken levodopa between 2011 and 2015. The participants were initially free of dementia and had initial daily levodopa doses of below 600 mg. Patients who did and did not develop comorbid dementia were compared in terms of potential predictor variables, including PD onset age, sex, levodopa doses, and non-dementia comorbidities. Results: Of the 76 patients, 21 (27.6%) developed dementia, which was followed by hallucinations and insomnia. The independent predictors of incident dementia were PD onset age and second-year and third-year average levodopa doses that were higher than the first-year average levodopa dose. Patients who developed dementia had significantly higher average daily levodopa doses and levodopa dose increases over the 6-year treatment period than those who did not develop dementia. In addition, patients with higher levodopa doses were more likely to experience hallucinations. Conclusion: These results suggest that increases in levodopa doses may be associated with a greater risk of cognitive impairment in patients with PD. Therefore, motor and cognitive functions and levodopa dose increases should be evaluated regularly during long-term levodopa therapy in patients with PD. KEY WORDS: Parkinson disease, levodopa, cognitive dysfunction, dementia 파킨슨병은흑질과선조체의도파민신경계손실이주원인이며, 환자는진전, 운동완서, 강직, 보행장애등의운동장애 1) 및인지기능장애, 불안장애, 우울증등과같은비운동성장애로고통을받고있다. 2) 최근, 노인인구의증가로파킨슨병환자가증가하고, 이에따른파킨슨병치매환자가증가하여전체치매환자중약 3-4% 가파킨슨병치매이며, 파킨슨병에서치매가발생할위험도는동일연령의정상노인보다 6배나높 은것으로보고되고있다. 3) 레보도파 (levodopa) 는 1960년대후반부터파킨슨병의운동장애증상을조절하기위하여사용되는가장효과적인치료약물이며, 4) 파킨슨병환자는레보도파약물요법으로상당기간양질의삶을유지할수있게되었다. 5) 그러나, 레보도파의장기간사용은파킨슨병의진행과더불어많은문제를일으키는것으로보고되고있다. 레보도파의장기투여는파킨슨병의 *Correspondence to: Myung Koo Lee, Department of Pharmacy, College of Pharmacy, Chungbuk National University, 194-21, Osongsaemyung 1-ro, Osong, Heungduk-gu, Cheongju 28160, Republic of Korea Tel: +82-43-261-2822, Fax: +82-43-268-2732 E-mail: myklee@cbnu.ac.kr *Co-correspondence to: Kyung Eun Lee, Department of Pharmacy, College of Pharmacy, Chungbuk National University, 194-21, Osongsaemyung 1-ro, Osong, Heungduk-gu, Cheongju 28160, Republic of Korea Tel: +82-43-261-3590, Fax: +82-43-268-2732 E-mail: kaylee@cbnu.ac.kr 285
286 / Korean J Clin Pharm, Vol. 28, No. 4, 2018 진행을촉진시키고있으며, 약물효과의감소뿐만아니라이상운동증, 운동동요등의약물이상반응을유발한다. 6,7) 또한, 장기간레보도파의사용은기립성저혈압, 인지기능장애, 우울증등의증상을심화시킨다. 8) 도파민신경계는사람과동물의학습과기억에관여하며, 9) 초기파킨슨병환자는레보도파의투여에의한도파민신경계의활성화로인지기능이개선되기도한다. 10) 그러나, 고농도레보도파의투여는파킨슨병동물모델에서활성산소 (reactive oxygen species) 의형성에의하여도파민신경계의세포사 (apoptosis) 를유도하며, 11,12) 파킨슨병환자에서언어학습및인지기능장애를촉진하기도한다. 13,14) 그러므로파킨슨병의주치료약물인레보도파는투여용량및투여기간에따라도파민신경계의신경독성을나타내고인지기능장애를촉진할수있다. 15) 그러나레보도파약물요법과파킨슨병환자의인지기능장애발생의상관관계에대한연구는국내에서는진행되지않고있다. 따라서본연구는레보도파약물요법을시행하는파킨슨병환자를대상으로인지기능검사를시행하여치매로진단받은환자군을치매군, 치매로진단받지않은환자를비치매군으로나누어레보도파복용량과파킨슨병치매발병에대한상관관계를후향적으로조사하였다. 연구방법 연구대상본연구는충북대학교병원신경과에내원하여 2011년 1월부터 2015년 12월까지연간레보도파처방내역이있는환자 154명중에서, 추체외로장애, 운동장애, 진행성핵상마비등파킨슨병이외의원인으로레보도파치료를받은환자및이차성파킨슨병환자는제외하고, 파킨슨병으로진단받은환자 116명을연구대상으로선정하였다. 다음으로, 연구대상환자 (116명) 중파킨슨병진단이전부터치매를앓고있었거나파킨슨병진단과동시에치매를진단받은환자, 레보도파초기용량 (600 mg 이상 ) 이높은환자는제외하고였다. 16) 자료수집및분석방법 자료수집연구자료는대상환자들의의무기록을후향적으로검토하여수집하였다. 환자군의기초적분석은나이, 성별, 파킨슨병의진단일, 진단일을기준으로한파킨슨병의발병연령, 파킨슨병의초기증상을조사하여시행하였다. 환자들의약물복용과관련된정보는초기약물요법, 레보도파의투여시작시기, 복용한레보도파제제의종류, 레보도파 1일투여용량, 레보도파이외에복용한다른파킨슨병치료약물등을포함하였다. 연구대상환자는레보도파를복용하는동안이상운동증및비운동성장애인치매, 우울증, 불안장애, 불면증, 환각증상이발생했는지를조사하였고, 치매로진단받은환자는치매진단일, 인지기능검사도구인한국형간이정신상태검사 (Korean Mini Mental State Examintion; K-MMSE), 치매의심각도평가지표인임상치매척도 (Clinical Dementia Rating scale; CDR) 점수및치매를치료하기위해복용중인약물등의기록을검토하였다. 자료분석연구대상환자중파킨슨병치매환자들에서 MMSE 및 CDR 점수는평균치를계산하였고, 치매의치료를위하여복용중인약물의종류와처방비율을검토하였다. 파킨슨병장애평가척도 (Unified Parkinson s Disease Rating Scale; UPDRS) 와 Hoehn 및 Yahr 병기 (Hoehn and Yahr Stage, H&Y 병기 ) 의기록이있는경우분석에포함하였다. 파킨슨병치매환자들의레보도파초기용량은치매진단시복용한레보도파용량과비교하여레보도파용량의증감을확인하고그변화량을계산하였다. 연구대상환자는치매군과비치매군으로나누어성별, 파킨슨병발병연령, 레보도파초기용량, 연간평균 1일투여용량을검토하였고, 이상운동증, 우울증, 불안장애, 불면증및환각증상의발병비율등이치매-비치매군간에차이가있는지에대하여검토하였다. 통계연구자료는 SPSS 통계프로그램 (version 20.0) 을사용하여분석하였다. 연속변수는평균 ± 표준편차 (means ± SD) 로표시하였고비연속변수는빈도와백분율로표시하였다. 각변수들의비교는연속변수인경우독립 t-test, 비연속변수는 chi-square test를이용하여수행하였다. 파킨슨병치매군과비치매군의두군간에차이를보이는변수는파킨슨병치매환자의위험인자를예측하기위한이분형로지스틱회귀분석을시행하였으며, 두군간년차별레보도파용량변화의비교는일원배치 (one-way) 및이원배치 (two-way) 에따른 ANOVA 분석법을이용하여시행하였다. 각연구결과에대한분석은 p값이 0.05 미만일때유의한것으로평가하였다. 연구대상자보호본연구는충북대학교병원기관윤리심의위원회 (Institutional Review Board, IRB) 의승인을받아진행하였다 (IRB File No.: CBNUH 2015-12-012-001).
레보도파요법중인파킨슨병환자의인지장애위험인자연구 / 287 연구결과 대상환자의특성연구대상환자의특성은 Table 1에나타내었다. 분석대상환자는 76명이며, 이중여성이더많았으며 (67.1%), 파킨슨병의발병연령은평균 67.3(± 7.9) 세이었다. 파킨슨병진단시의초기증상은진전, 강직순으로빈도가높았다. 파킨슨병장애평가척도 (UPDRS) 점수는기록이없는환자가대부분이었고, Hoehn 및 Yahr 병기의기록이있는환자는총 25명이었다. 2회이상의기록이있는경우최종기록을이용하여평균 H&Y 병기를계산하였다. 파킨슨병치매환자 (9명) 에대한 H&Y 병기는평균 3.3, 비치매환자 (17명) 의평균은 2.9점이었다. 레보도파를복용하는동안대상환자중에서 21명이치매 (27.6%) 로진단을받았으며, 이상운동증 (17명) 과환각 (16명) 증상도나타내었다. 약물복용과관련된특성약물복용과관련한특성은 Table 2에나타내었다. 파킨슨병환자대부분은진단과동시에레보도파를치료약물로처방받았으나, 초기에약물처방이없는환자는 5명이었으며, 3명은브로모크립틴 (bromocriptine) 과트리헥신 (trihexine) 요법으로시작하였다. 그러나미복용환자 (5명) 는 1-4년사이에레보도파를복용하기시작하였으며, 브로모크립틴과트리헥신을복 용중이던환자들도 2 년이내에레보도파복용을시작하였다. 제제는마도파 ( 레보도파 / 벤세라자이드 ) 로시작한환자가가장많았고 (48명), 3가지제제를함께병용한환자도 1명이있었다. 레보도파이외에복용한파킨슨병치료약물중로피니롤 (ropinirole) 이가장많은처방비율 (54 명, 71.1%) 을나타내었다. 파킨슨병치매환자의특성파킨슨병치매환자 21명중검사를실시한환자 (20명) 의 K- MMSE 평균점수는 18.1(± 5.2) 점이었고, CDR 평균점수는 1.5(± 0.7) 점이었다. 학력에대한자료가있었던환자는 16명이며, 대졸 1명, 대학중퇴 1명, 고졸 2명, 중졸 1명, 초졸 2명, 초등학교중퇴 1명, 무학 7명으로초등학교이하의학력을가진환자들이가장많았다. 파킨슨병치매환자가치료를위하여주로복용한약물은도네페질 (donepezil) 과갈란타민 (galantamine) 이며, 두가지이상의약물을병용한환자들도있었다 ( 자료미제시 ). 파킨슨병치매환자 (21명) 의초기레보도파 1일투여용량 (mg) 은평균 284.5 (± 100.1), 치매진단시평균증가량은 295.5 (± 216.0) 이었고, 치매진단시용량의증가가없었던환자는 6명, 용량을감량한환자는 1명이었다. 치매군과비치매군의비교파킨슨병환자 (76명) 중에서치매진단을받은환자 (21명) 는파킨슨병치매환자군으로, 나머지는비치매군 (55명) 으로분 Table 1. Characteristics of patients with Parkinson's disease Characteristics PD-dementia, n (%) PD-non dementia, n (%) p-value Patients 21 (27.6) 55 (72.4) Gender 0.592 Men 8 (38.1) 17 (30.9) Women 13 (61.9) 38 (69.1) Age at PD onset (years) 70.5 ± 5.2 66.1 ± 8.4 0.027 Initial symptom Tremor 11 (21.2) 41 (78.8) 0.075 Rigidity 9 (20.0) 36 (80.0) 0.101 Bradykinesia 12 (27.9) 31 (72.1) 1.000 Gait disturbance 16 (57.1) 12 (42.9) <0.0001 Myerson's sign 2 (15.4) 11 (84.6) 0.330 Masked face 2 (22.2) 7 (77.8) 1.000 Postural instability 3 (37.5) 5 (62.5) 0.677 Stooped posture 2 (50.0) 2 (50.0) 0.570 PD duration (years) 7.8 ± 1.6 9.7 ± 3.6 0.002 Duration 0.042 6-10 years 19 (35.8) 34 (64.2) 11-15 years 2 (11.8) 15 (88.2) 16 years 0 (0) 6 (100) Data are expressed as the means ± SD. The values in the parentheses are expressed as percentages of the total patients with PD. PD, Parkinson s disease; PD-dementia, Parkinson s disease with dementia; PD-non dementia, Parkinson s disease without dementia.
288 / Korean J Clin Pharm, Vol. 28, No. 4, 2018 Table 2. Characteristics of drugs used for PD patients Characteristics PD-dementia, n (%) PD-non dementia, n (%) p-value Levodopa Initial formulation Madopar (levodopa/benserazide) 10 (47.6) 38 (79.2) 0.112 Sinemet (Llevodopa/carbidopa) 9 (39.1) 14 (60.9) 0.168 Stalevo (levodopa/carbidopa/entacapone) 2 (40.0) 3 (60.0) 0.612 Formulation at enrollment Madopar 8 (20.5) 31 (79.5) 0.202 Sinemet 5 (41.7) 7 (58.3) 0.295 Stalevo 1 (12.5) 7 (87.5) 0.432 Madopar + Sinemet 3 (37.5) 5 (62.5) 0.677 Madopar + Stalevo 4 (57.1) 3 (42.9) 0.087 Sinemet + Stalevo 0 (0) 1 (100) 1.000 Madopar + Sinemet + Stalevo 0 (0) 1 (100) 1.000 Other anti-parkinson agents Ropinirole 16 (29.6) 38 (70.4) 0.587 Amantadine 10 (30.3) 23 (69.7) 0.796 Trihexyphenidyl 5 (16.1) 26 (83.9) 0.073 Bromocriptine 3 (10.7) 25 (89.3) 0.016 Propranolol 2 (14.3) 12 (85.7) 0.325 Entacapone 3 (37.5) 5 (62.5) 0.677 Pramipexole 1 (25.0) 3 (75.0) 1.000 Selegiline 0 (0) 4 (100) 0.328 Table 3. Comparisons of levodopa doses between PD-dementia and PD-non dementia groups Variables PD-dementia PD-non dementia p-value Patients, n 21 55 Levodopa (average daily dose) Initial dose (mg/day) 284.5 ± 100.1 298.4 ± 141.5 0.682 Dose at dementia onset (mg/day) 476.8 ± 225.3 - - Total dose (mg/day) 463.2 ± 175.8 422.2 ± 154.9 0.319 Average dose for 1st-year (mg/day) 345.0 ± 119.9 348.4 ± 152.1 0.928 Average dose for 2nd-year (mg/day) 426.7 ± 139.0 374.5 ± 174.3 0.223 Average dose for 3rd-year (mg/day) 473.4 ± 169.4 407.0 ± 173.5 0.138 Average dose for 4th-year (mg/day) 487.4 ± 207.2 436.6 ± 180.2 0.296 Average dose for 5th-year (mg/day) 526.2 ± 267.2 474.4 ± 211.8 0.379 Average dose for 6th-year (mg/day) 520.9 ± 294.5 492.2 ± 228.2 0.653 Levodopa (dose change) Dose change-2 (mg) 116.5 ± 25.40 26.1 ± 69.9 0.013* Dose change-3 (mg) 164.9 ± 36.00 058.7 ± 117.1 0.043* Dose change-4 (mg) 205.3 ± 44.80 088.3 ± 142.8 0.197 Dose change-5 (mg) 268.3 ± 58.50 126.0 ± 213.1 0.352 Dose change-6 (mg) 307.4 ± 67.10 143.9 ± 242.1 0.634 Total dose means average daily dose of levodopa for the 6-year drug therapy in patients with PD. PD-dementia, Parkinson s disease with dementia; PD-non dementia, Parkinson s disease without dementia. Dose change-2, dose change in the 2nd year from the 1st year; Dose change-3, dose change in the 3rd year from the 1st year; Dose change-4, dose change in 4th year from the 1st year; Dose change 5, dose change in the 5th year from the 1st year; Dose change 6, dose change in the 6th year from the 1st year. Data are expressed as the means ± SD. *p < 0.05 compared to PD-non dementia groups (t-test).
레보도파요법중인파킨슨병환자의인지장애위험인자연구 / 289 Table 5. Comparison of comorbidities between the PD-dementia and PD-non dementia groups Variables PD-dementia, n (%) PD-non dementia, n (%) p-value Patients, n 21 55 Dyskinesia 3 (14.3) 14 (25.5) 0.369 Hallucinations 9 (42.9) 7 (12.7) 0.007* Insomnia 4 (19.0) 10 (18.2) 1.000 Anxiety 3 (14.3) 10 (18.2) 0.751 Depression 2 (9.5) 7 (12.7) 1.000 *p < 0.05 compared to PD-non dementia groups (chi-square test). Fig. 1. Effects of levodopa doses on the development of PDdementia. PD-dementia, PD patients with dementia; PD-non dementia, PD patients with non-dementia. Dose-1 to dose-6 means average daily dose (mg) of levodopa at the 1st-year to 6th-year. *p < 0.05, # p < 0.05 compared to Dose-1 in each group (one-way ANOVA test); p < 0.05 compared to PD-non dementia (two-way ANOVA test) 류하였다. 치매환자 (21 명 ) 중남자는 8 명 (38.1%), 비치매환자 (55명) 중남자는 17명 (30.9%) 으로두군에서모두여자비율이높았으나, 두군간에서성별차이는없었다. 파킨슨병발병연령은치매군이평균 70.5(± 5.2) 세, 비치매군이평균 66.1(± 8.4) 세로치매군에서유의적으로높게나타났다 (p = 0.027)(Table 1). 치매환자군의치매진단시레보도파의 1일투여용량은평균 476.8(± 225.3) mg이었고, 6년동안의전체평균 1일투여용량 (total average daily dose) 은비치매군 (422.2 mg) 보다치매군 (463.2 mg) 에서높았으나두군간의차이는유의하지않았다 (Table 3). 레보도파복용 6년동안연간평균 1일복용량은치매군및비치매군모두에서투여기간동안증가하였으며, 치매군에서더높게나타났으나유의한차이를나타내지는않 았다 (Table 3). 그러나치매군과비치매군간의 6년동안레보도파투여용량은치매군이비치매군보다유의적으로높게나타났다 (Fig. 1). 다음으로레보도파복용량에대하여복용첫해로부터 6년간의평균용량증가량을년도별로비교하였다. 2년째증가량 (2년째평균용량에서 1년째평균용량을뺀것 ) 을비교하면치매군은평균 116.5(± 25.4) mg, 비치매군은 26.1(± 69.9) mg (p = 0.013) 이었고, 3년째의증가량 (3 년째평균용량에서 1년째평균용량을뺀것 ) 의비교에서는치매군은평균 164.9(± 36.0) mg, 비치매군은 58.7(± 117.1) mg (p =0.043) 으로두군간에각각유의한차이를나타냈다 (Table 3). 또한, 투여기간 (6년) 동안레보도파투여용량과증가량은치매군이비치매군에비하여더증가하였다 (Fig. 1). 그리고치매군과비치매군의평균비교에서유의한차이를나타낸파킨슨병발병연령과 2년째및 3년째증가량은이분형로지스틱회귀분석에서도치매발병과의상관관계를나타내었다 (Table 4). 레보도파요법중인파킨슨병환자의이상운동증, 우울증, 불안장애및불면증의발생은치매군 -비치매군의두군간에서차이를나타내지않았으나, 환각증상은치매군 (p =0.007) 에서더높게나타났다 (Table 5). Table 4. Logistic regression analysis of predictors of PD patients with dementia to PD patients with non-dementia Variables p-value Exp (B) 95%, CI Levodopa (dose change-2) Sex (1: male, 2: female) 0.825 1.141 (0.356-3.660) PD onset age 0.052 1.091 (0.999-1.192) Mean dose change 0.036 * 1.007 (1.000-1.013) Levodopa (dose change-3) Sex 1: male, 2: female) 0.681 1.274 (0.401-4.049) PD onset age 0.030* 1.111 (1.010-1.221) Mean dose change 0.030* 1.004 (1.000-1.008) The logistic regression analysis was performed using total PD patients (n = 76). Exp (B), expectency; CI, confidence interval. Dose change-2, dose change in the 2nd from the 1st year; Dose change-3, dose change in the 3rd year from the 1st year. *p < 0.05.
290 / Korean J Clin Pharm, Vol. 28, No. 4, 2018 Table 6. Comparisons of levodopa doses between hallucinators and non-hallucinatotors Variables Total Hallucinators Non-hallucinators p-value PD-dementia Patients, n 21 9 12 Men, n (%) 8(38.1) 6 (66.7) 2 (16.7) 0.032* Age at PD onset (years) 70.5 ± 5.20 72.3 ± 5.10 69.2 ± 5.00 0.169 Initial daily dose (mg) 284.5 ± 100.1 352.8 ± 100.3 233.3 ± 65.10 0.004* PD-non dementia Patients, n 55 7 48 Men, n (%) 17(30.9) 3 (42.9) 14 (29.1) 0.370 Age at PD onset (years) 66.1 ± 8.40 64.6 ± 5.00 66.31 ± 8.800 0.203 Initial daily dose (mg) 298.41 ± 141.50 364.3 ± 184.2 288.8 ± 133.9 0.083 Data are expressed as the means ± SD. *p < 0.05 compared to non-hallucinators (t-test or chi-square test). 치매군에서환각의유무에따른레보도파용량비교비운동성증상중치매군에서발생빈도가높았던환각증상의유무와레보도파초기용량및치매진단시용량을비교분석한결과를 Table 6에나타내었다. 파킨슨병치매환자 (21명) 중에서환각증상을나타낸환자 ( 환각군 ) 는 9명, 환각증상을나타내지않은환자 ( 비환각군 ) 는 12명이었다. 환각군은남자의비율이높았으며 (p = 0032), 레보도파의초기복용량은환각군이평균 352.8(± 100.3) mg, 비환각군이평균 233.3(± 65.1) mg 으로환각군에서유의하게높았고 (p =0.004), 치매발병시의레보도파의복용량은환각군에서더높았으나유의한차이를보이지는않았다. 비치매군에서의레보도파초기복용량은환각군과비환각군간에유의한차이를나타내지않았다. 고 본연구는파킨슨병으로레보도파를복용한환자들을대상으로비운동성증상의유무및레보도파의복용량과파킨슨병에서치매발병과의상관관계에대하여조사하였다. 파킨슨병은치매, 우울, 불안, 정신병적증상, 자율신경계이상, 수면장애등과같은다양한비운동성증상을동반한다. 17) 본연구에서도파킨슨병환자 (76명) 중 40명 (52.6%) 의환자가치매, 우울, 불안, 수면장애중한가지이상의비운동성증상을나타냈으며, 이중에서치매와환각의빈도가높았다. 파킨슨병에서나타나는행동심리증상은치매를동반한파킨슨병환자에서더자주나타난다. 파킨슨병치매환자 (500명 ) 를대상으로실시한연구에의하면, 파킨슨병치매환자 89% 는한가지이상의비운동성증상을포함한행동심리증상이나타났고, 이중에서우울증, 무감동, 불안, 환각이가장많이나타난증상이었다. 18) 국내연구에서는특발성파킨슨병환자에게인지기능관련신경심리검사를시행하여, 정상인지기능을보이는파킨슨병환자는정상대조군과행동심리증상의빈도 찰 나점수에서유의한차이를나타내지않으므로, 파킨슨병에서행동심리증상의발생은인지기능저하의시작일가능성이있고, 모든행동심리증상의유병율은파킨슨병치매군에서경도인지장애를동반한파킨슨병군보다더높았으며, 특히발생률이높았던망상, 환각, 이상운동 (aberrant motor behavior) 증상이나타나는경우파킨슨병치매로의진행을의심해야함을제안하였다. 19) 본연구에서는우울, 불안, 환각, 불면중한종류이상의증상을나타낸비율이파킨슨병치매환자에서는 66.7%, 치매가없는환자에서는 47.3% 로, 파킨슨병치매환자에서더높게나타났으나그비율은낮았다. 이것은본연구의대상환자수가적었고, 특정측정도구를이용한정확한검사결과가아닌의무기록검토를통한증상의검토에의한것으로사료된다. 그러나환각증상의발생은치매군에서비치매군보다유의하게더높게나타나고치매발병과의상관성이있음을나타내었다 (Table 5). 또한환각증상이발생한치매환자의초기레보도파복용량은환각이발생하지않은치매환자의용량에비하여유의하게높게나타났으나비치매군에서는환각군과비환각군간에유의한차이를나타내지않았다 (Table 6). 이결과들은파킨슨병환자가레보도파요법을시행하는경우, 레보도파의초기복용량이높으면환각이발생할수있음을제시하고있다. 파킨슨병치매의위험인자로는고연령, 심한파킨슨병증상, 자세불안정, 보행장애가심할경우, 파킨슨병시작시기에경도인지장애가있는경우가제시되고있다. 20) 이외에도성별 ( 남자 ), 낮은교육수준, 환각, 우울증이제시되고있으나, 이에대한연구결과는일치되지않고있다. 21-23) 본연구에서는치매군과비치매군에서성별의차이는없었으나, 파킨슨병발병연령은치매군이비치매군보다유의하게더높았다. 그러나이상운동증, 우울증, 불안증상은치매군보다오히려비치매군에서더높았고, 불면증의발생비율은치매군에서더높게나타났으나두군간에차이는없었다. 또한, 파킨슨병치매환
레보도파요법중인파킨슨병환자의인지장애위험인자연구 / 291 자는중-초등학교이하의학력을가진환자들이많았으나 (20 명중 16명 ), 비치매군에서는이와관련한기록이누락되어유의성은평가할수없었다. Rosdinom(2011) 등은파킨슨병의인지기능장애와파킨슨병의심각도가유의한상관성이있음을보고하였다. 24) 본연구의대상환자 (76명) 중에서 H&Y 병기의기록이있었던환자는 25명이며, 이중치매로진단받은환자 (9명) 의평균 H&Y 병기는 3.3, MMSE 24점미만인환자가 7명으로 Rosdinom (2011) 등의연구결과와비슷한경향을확인할수있었다. 파킨슨병환자에서치매발병의위험요인을평가한연구의일부는레보도파용량과치매발병과의연관성이없음을보고하고있다. 25,26) Hughes 등의연구에서는 1일투여용량에따라 4개그룹으로나누어파킨슨병환자군과대조군을비교했을때치매발생률에차이가없었다. 젊은연령에파킨슨병이발병한환자군과고연령에발병한환자군을비교한 Hietanen 등의연구에서는고연령에발병한파킨슨병환자군에서레보도파복용한군이기억력및인지기능이떨어졌지만평균레보도파용량은두연령그룹에서비슷했다. 본연구에서도파킨슨병진단후초기 6년동안의연간레보도파평균 1일복용량은치매군에서높은경향을보이기는하였으나비치매군의복용량에비해통계적으로유의한차이를나타내지는않았다. 레보도파의초기복용량이 450 mg/day 보다높은용량은파킨슨병치매발병의위험요인으로보고되고있다. 31) 본연구에서는파킨슨병치매환자의평균초기 1일투여용량은파킨슨병이진행됨에따라증가되었지만 (14명), 치매진단시초기투여용량과비교하여용량의증가가없었던환자 (6명) 도있었으며, 투여용량이감량된환자 (1명) 도있었다. 레보도파투여용량감량의이유는증상의호전이었다. 레보도파의초기 1일투여용량이 450 mg 이상인환자수가치매군에비하여비치매군에서더많았으며, 평균 1일투여용량이오히려비치매군에서높았다. 이러한이유는레보도파의투여용량은파킨슨병의운동증상의심한정도와관련이있으므로, 20,24) 진단시에증상이심한환자들이많았거나, 본원에서파킨슨병진단후약물복용을시작한환자들을선별하였고, 분석대상환자를초기 1일복용량이 600 mg 이하인환자들로선별하였지만, 내원이전에다른병원에서부터약물복용을시작한환자들이포함되어있을가능성을배제할수없다. 파킨슨병환자를대상으로실시한 5년간의전향적연구에서치매증상이없었던환자 (261명) 중평균추적기간 2.56년후에 68명 (26.1%) 에서치매증상이나타났으며, 콕스회귀 (Cox regression) 분석에서평균일일레보도파용량이치매발병의위험인자로나타났다. 32) 본연구에서도파킨슨병환자에서치매군과비치매군간의초기 6년동안레보도파투여용량은치매군이비치매군보다유의적으로높게나타났다 (Fig. 1). 파킨슨병치매환자들은 1년째 1명, 2년째 4명, 3년째 4명, 4년째 1명, 5년째 6명, 6년째 5명이치매진단을받았다. 또한, 복용첫해로부터 2 년째및 3 년째증가된레보도파용량 ( 레보도파의증가량 ) 이비치매군보다치매군에서유의하게높았으며, 두군간에차이를나타낸연령과레보도파의증가량은회귀분석에서도치매발병의위험요인으로나타났다. 이러한결과로부터, 파킨슨병환자의약물요법과정에서레보도파의복용량의증가는치매증상발현의요인이라는것을제시하고있다. 본연구는단일기관에서후향적으로시행한연구로서대상환자의수가적어결과를일반화하는데는한계가있다. 또한, 비운동성증상들의수집이환자및보호자들의진술에의한진료기록에의해서만이루어졌고, 관련증상의평가도구를이용한점수에따른정확한결과가아니었다. 또한레보도파의복용량증가는운동증상의심각도와관련이있으나결측치가많아증상의심각도를배제하지못한점이한계로제시될수있다. 본연구의결과를종합하면, 파킨슨병환자의레보도파약물요법과정에서레보도파의 2년째와 3년째복용량의증가량이비치매군보다치매군에서유의하게더높았으며, 레보도파의용량증가량과치매증상의발현은상관관계를나타내었다. 그러므로파킨슨병진단증상조절을위하여레보도파의복용량을증량하는경우에는치매발병의위험성이고려되어야한다. 감사의말씀 본연구는한국연구재단 ( 과제번호, 2013R1A1A2058230, 2015-2016; 2016R1D1A3B03930722, 2016-2017) 의지원에의하여수행되었음. 참고문헌 1. Fahn S. Description of Parkinson s disease as a clinical syndrome. Ann N Y Acad Sci 2003; 991: 1-14. 2. Williams-Gray CH, Foltynie T, Brayne CE, et al. Evolution of cognitive dysfunction in an incident Parkinson s disease cohort. Brain 2007; 130: 1787-98. 3. Aarsland D, Andersen K, Larsen JP, et al. Risk of dementia in Parkinson s disease: a community-based, prospective study. Neurology 2001; 56: 730-6. 4. Cheng N, Maeda T, Kume T, et al. Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons. Brain Res 1996; 743: 278-83. 5. Bianchine JR. Drug therapy of parkinsonism. N Engl J Med 1976; 295: 814-8. 6. Ludin HP, Bass-Verrey F. Study of deterioration in long-term treatment of parkinsonism with L-dopa plus decarboxylase inhibitor. J Neural Transm 1976; 38: 249-58. 7. Marsden CD, Parkes JD. On-off effects in patients with Parkinson s disease on chronic levodopa therapy. Lancet 1976; 1: 292-6. 8. Marttila RJ. Diagnosis and epidemiology of Parkinson s disease. Acta Neurol Scand Suppl 1983; 95: 9-17.
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