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1 원저접수번호 :09-029(2 차 -0710) 단국대학교의과대학신경과학교실 Decreased Retinal Thickness in Patients With Alzheimer s Disease Bong-hui Kang, MD, Jae-il Kim, MD, PhD Department of Neurology, Dankook University Medical College, Cheonan, Korea Background: The loss of ganglion cells observed in Alzheimer s disease (AD) patients might be attributable to a neurodegenerative process involving the neuroretinal structure. The objective of this study was to determine the retinal thickness in patients with AD using optical coherence tomography (OCT). Methods: Neuro-ophthalmologic examinations were performed in eight AD patients and eight age-matched control subjects. The average thicknesses of the retinal nerve fiber layer (RNFL) and the ganglion cell inner plexiform layer (GCIPL) were measured using spectral-domain OCT in both subject groups, and the results were compared. Results: The RNFL was thinner in AD patients than in the age-matched controls (p<0.05), especially at the nasal and inferior retina, and the GCIPL was also significantly thinner (p<0.05). Conclusions: The decreased retinal thickness observed in AD patients suggests that OCT can be used as a biological marker of AD. The findings of this preliminary study suggest that the extent of the reduction in GCIPL and RNFL thicknesses should be investigated further. J Korean Neurol Assoc 31(3): , 2013 Key Words: Alzheimer s disease, Spectral-domain optical coherence tomography, Retinal nerve fiber layer, Ganglion cell inner plexiform layer 서 론 알쯔하이머병 (Alzheimer s disease: AD) 은가장흔한유형의치매로대뇌피질신경세포의점진적인소실로인하여기억장애를포함한광범위한인지기능장애가초래되고행동장애도나타나결국은환자가독립적으로생활할수있는능력이상실되는질환이다. AD 환자에서공통적으로심한뇌위축과피질세포의광범위소실, 신경원섬유매듭 (neurofibrillary tangle) 과아밀로이드베타 (Aß) 로구성된노년판 (senile plaque) 과같은병리이상이나타난다. 1 AD 환자중에서시력, 입체시, 색각, 공간대조감수성 (spatial contrast sensitivity) 에장애를호소 Received May 15, 2013 Revised May 29, 2013 Accepted May 29, 2013 *Jae-il Kim, MD, PhD Department of Neurology, Dankook University Hospital, Dankook University Medical College, 201 Manghyang-ro, Dongnam-gu, Cheonan , Korea Tel: Fax: neurokji@hanmail.net 하는경우가보고되었는데, 이는주로시각피질의신경퇴행으로설명되었다. 2 그러나앞쪽시각경로에도문제가있다는것이알려졌는데 AD 환자의사후망막병리에서정상인에비하여망막신경절세포의심한감소와망막세포주위의 Aß침착을확인하였고시신경변성과망막신경섬유의감소가보여뇌피질뿐아니라망막에도신경퇴행질환의변화가함께일어나는것을알수있다. 3,4 빛간섭단층촬영기 (optical coherence tomography, OCT) 는녹내장과여러안과질환에서망막신경섬유층 (retinal nerve fiber layer, RNFL) 의결손과시신경유두이상을발견하는우수하고비침습적인최신검사방법이다. 5 그중스펙트럼영역 (spectrum domain, SD) OCT는시간영역 OCT보다 50배이상빠르고민감하며고해상도의 2차원과 3차원망막영상을제공한다. 최근에는분할알고리즘 (segmentation algorithms) 의발전으로황반부망막의각층을시각화하고그두께를측정할수있게되었다. 이전의외국과국내보고에의하면정상 RNFL 두께는성별에영향을받지않고나이가증가함에따라감소하는것으로알려져있고인종간의차이도확인되었다. 6 AD J Korean Neurol Assoc Volume 31 No. 3,

2 환자에서 OCT를통한 RNFL 두께의감소는이전의여러보고를통해확인되었으나 7-13 아직국내보고는없는상태이다. 또한황반부의망막신경절세포-안쪽얼기층 (ganglion cell-inner plexiform layer, GCIPL) 두께측정은최신의 SD-OCT 기계로만가능한데아직은녹내장같은안과질환에서만그재현성과유용성이연구되고있는상태이다. 14,15 저자들은본연구에서 SD-OCT 검사를이용하여정상대조군에비하여 AD 환자에서시신경유두주위 RNFL과황반부 GCIPL 두께감소를확인하고자하였다. 대상과방법 1. 대상 2012년 3월부터 2013년 2월까지본원신경과외래에내원하여 AD로진단받고외래추적중인환자중본연구에동의한환자를대상으로안과검사를진행하였다. 모든환자에게뇌자기공명영상, 서울신경심리검사 (Seoul neuropsychological screening battery, SNSB), 한국판간이정신상태검사 (Mini-Mental Status examination, MMSE), 임상치매척도 (clinical dementia rating, CDR), 치매단계평가척도 (global deterioration scale, GDS) 를하였고, NINCDS-ADRDA 진단기준을사용하여 AD진단을확정하였다. 16 본원안과에안구건조증같은증상때문에내원한환자중에서인지기능장애와신경계질환이없는대상을대조군으로하였다. 모든대상자에서나안시력과교정시력측정, 굴절검사, 세극등현미경을이용한전안부와전방각경검사 (gonioscopy), 검안경을이용한시신경유두검사, 골드만압평안압계 (Goldman s applanation tonometry) 를이용한안압검사, SD-OCT 검사를하였다. 이상의검사에서녹내장, 포도막염, 망막질환같은안질환이나눈에영향을줄만한전신질환이있는환자, 안수술이나외상의기왕력이있는사람은연구대상에서제외하였다. 또한협조가되지않아 OCT 검사를잘하지못하였거나수정체이상으로 OCT 검사를정확하게판단할수없는경우도분석대상에서제외하였다. 이에따라 AD 환자 8명과인지기능장애와신경계질환이없는정상대조군 8명에서양안을모두분석하였다. 본연구는연구에참여한모든환자에게연구동의서를받았고단국대학교병원의임상연구심의위원회를통과하였다. 2. 스펙트럼영역빛간섭단층촬영 (spectrum domain OCT) 본원에있는 Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, CA, USA) 를이용하여모든대상자를검사하였다. RNFL 두께측정은 Cirrus HD-OCT에내장된소프트웨어중 Optic Disc Cube 스캔을사용하였으며이는시신경유두를중심으로가로, 세로 6 mm 사각형부위를 200개로균등하게분할한후각단면당 200회의 A-스캔을통해얻어진자료에서시신경유두중심으로부터반경 1.73 mm 부위의측정치를추출하여측정값을구하고 4개의사분면 (4-quadrants), 즉귀쪽 ( 도 ), 위쪽 (46-135도), 코쪽 ( 도), 아래쪽 ( 도) 과평균 RNFL 두께측정값 (average thickness) 을제공한다. 양안에서측정된 RNFL은결과지에서거울상으로나타난다. GCIPL 두께측정은 Macular Cube 스캔을통하여얻어진중심오목 (fovea) 을중심으로 mm 부위의자료에서소프트웨어안에포함되어있는신경절세포복합체 (ganglion cell complex) 알고리즘을이용하여중심오목주위 mm 2 타원지역의평균 GCIPL 두께가자동으로계산된다. 3. 통계분석통계분석에 Prism 5 for Windows version 5.02 (GraphPad software Inc., California, USA) 프로그램을사용하였고통계방법으로독립 t검정중비모수방법인 Mann-Whitney test를이용하여 AD 환자군과대조군에서평균 RNFL과 GCIPL 두께의차이가있는지비교하였다. p값이 0.05 미만인경우에만통계적으로유의한것으로판정하였다. 결과 총 8명의 AD 환자군의평균나이는 71.5세 ( 최소 53세, 최대 81세 ) 로대조군평균나이 67.4세 ( 최소 63세, 최대 73세 ) 와비교하여통계학적으로차이가없었다 (p value>0.05). 모든환자는 SNSB 검사를통해비정상적인기억력저하와함께여러영역의인지기능저하를확인하였고평균 MMSE 17.75( 최소 8, 최대 25), CDR 1.125( 최소 0.5, 최대 2), GDS 4.5( 최소 3, 최대 6) 였다. 증상초기발병시점부터 OCT검사까지평균유병기간은대략 2.9년 ( 최소 0.5년, 최대 9년 ) 이었다. 성별구조는 AD 환자군과대조군에서모두남 4명, 여 4명으로동일하였다. AD 환자군에서평균시신경유두주위 RNFL 두께는정상대조군에비해통계학적으로유의하게감소되어있었다 (80.44 µm±16.73 vs µm±9.8, p=0.041). 사분면중에서코쪽과아래쪽의 RNFL 두께가통계학적으로의미있게감소되어있었다. 위쪽, 가쪽사분면의 RNFL 두께역시수치상으로는감소되어있으나통계학적인의미는없었다. 황반부 GCIPL 두 174 대한신경과학회지제 31 권제 3 호, 2013

3 Table. Mean retinal thickness results in patients with AD and age-matched normal controls Factors AD (n=16) Control (n=16) p value Mean ages (min-max) 71.5 (53-81) 67.4 (63-73) Average RNFL (µm) ± SD ± ± a Nasal ± ± a Inferior ± ± a Temporal ± ± Superior ± ± Average GCIPL (µm) ± SD ± ± a a Statistically significant. AD; Alzheimer s disease group, N; number of the eyes, RNFL; retinal nerve fiber layer, GCIPL; ganglion cell-inner plexiform layer, SD; standard deviation. A B 정리하였고 Fig. 에그래프로표시하였다. 고 찰 C Figure. The RNFL and GCIPL thickness and the RNFL result in an AD patient. (A, B) The graphs show that the average thickness of RNFL and GCIPL in AD group was significantly lower than that of healthy controls (*; P-value < 0.05). (C) The RNFL thickness of three quadrants (OD: superior, inferior, nasal, OS: superior, inferior, temporal) is reduced to the 0-1 percentile for age (red) and that of one quadrant (OD: temporal, OS: nasal) is reduced to the 1-5 percentile for age (yellow). RNFL; retinal nerve fiber layer, GCIPL; ganglion cell-inner plexiform layer, AD; Alzheimer s disease, OD; right eye, OS; left eye, S or SUP; superior, I or INF; inferior, T or TEMP; temporal, N or NAS; nasal. 께도 AD 환자군에서의미있게감소하였다 (67.31 µm±15.85 vs µm±11.99, p=0.046). 구체적인결과값과 p값을 Table 에 본예비연구의결과를보면알쯔하이머병환자에서평균시신경유두주위망막신경섬유층 (RNFL) 두께는동일연령대조군에비하여감소되어있고이전에는연구되지않았던황반부망막신경절세포-안쪽얼기층 (GCIPL) 두께또한감소되어있음을알수있다. 망막신경절세포는빛수용기 (photoreceptors) 로부터시각정보를받아긴축삭을내보내뇌의담당부위, 예를들어시상외측무릎체 (lateral geniculate body), 시각피질에그정보를보내는역할을담당한다. 즉시신경을이루는신경섬유의세포체로서그의축삭다발이시신경이되는것이다. 해부학적으로인간의망막신경절세포는개인차가있지만대략백만개이상존재하는데그중 50% 가량이중심오목의 4.5 mm 안에집중되어있다. GCIPL은 SD-OCT 검사를통하여측정할수있는신경절세포의세포체, 그의축삭과가지돌기를포함하는망막의가장안쪽구조물이다. 따라서시신경위축은 RNFL두께감소로나타나고이는이론적으로세포체손상을의미할수있다. 황반부 GCIPL 두께는신경절세포의소실을반영하는수치가될수있겠고황반부전체두께보다이를더잘반영할수있을것으로생각한다. 결과에언급하지는않았으나본연구에서두군사이에황반부전체두께의차이는없었다. 각사분면의 RNFL두께평균치를좀더자세히살펴보면본연구에서는코쪽, 아래쪽에서통계학적으로의미있게정상에비하여감소된것으로나타났다. 그러나외국의다른보고에서는다른분면에서도감소되었는데, 7-10,12 특히위쪽사분면의감소소견이많이보고되었으나 9 특정한패턴을보이거나특별히보존되는구역은없는것으로판단할수있다. AD J Korean Neurol Assoc Volume 31 No. 3,

4 와경도인지장애 (mild cognitive impairment, MCI) 환자를대상으로 OCT를이용한 RNFL 두께를비교한연구에대한메타분석이최근보고되었는데, 모든사분면에서정상에비해의미있게감소하였다. 13 최근에는 AD 환자에서뿐아니라 MCI 환자에서도 RNFL 두께감소를보고한연구들이있다. 8,11 그러나현재 MCI의임상진단방법으로는정상적인노화에의한인지기능저하와초기의치매환자가중복될수있다. 17 또한치매의원인이다양하듯, MCI의원인과아형이다를수있으므로 AD와같은퇴행질환의경과를보일지는의문이다. 따라서지금까지 MCI 환자에대한연구는아직신뢰하기어렵다. 또한이연구에서질병의심각도와 RNFL 두께감소의정도가비례하는지를확인하고자하였으나연구마다결과는일치하지않았다. 8,11 위에서언급한대로 MCI의임상진단기준때문에이와같은결과는어쩌면당연한것일지모르며아직연구대상이적어결론을내리기어렵다. AD 환자의임상적인질병의중증도가나이, 교육정도, 평가당시신체와심리적인상태에영향을많이받기때문에 MMSE 같은점수만으로이를쉽게판단할수는없는문제이다. 본연구에서도연구대상이적고연구방법의어려움때문에질병의중증도와의연관성에대해분석할수없었다. 나이와질환의심한정도에따라망막신경절세포손실과시신경위축이좀더뚜렷이나타날것이고이는결과해석에영향을줄수있기에이전연구중일부에서는치매유병기간과 MMSE를기준으로초기 AD 환자만을대상으로 RNFL 두께를확인하였고그역시정상대조군에비해통계학적으로의미있는두께감소를보고하였다. 9,10 Cirrus OCT Normative Database Study Group의연구에따르면연령을보정하였을때인종간에시신경유두와망막신경섬유층두께지표차이가나타난다. 18 이렇듯지역간, 인종간차이를파악하는것은역학적으로중요하며이런점에서한국인을대상으로한이번연구가의미있을것으로생각한다. 또한본연구는 AD 환자에서 GCIPL 두께감소를처음보고한연구로도의미가있다. 본연구와이전의외국연구를고찰하여보면 SD-OCT 검사가 AD 환자의진단에도움이될수있는비침습적인방법으로특히초기진단에도움이될수있을것이다. 한국 AD 환자에게이진단방법의중요성을확인하기위해후속연구가필요할것이며, 특히 MCI 환자대상연구와질병중증도와의연관성에대한전향적인코호트연구가필요하다고생각한다. REFERENCES 1. Hyman BT, Trojanowski JQ. Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease. J Neuropathol Exp Neurol 1997;56: Schlotterer G, Moscovitch M, Crapper-McLachlan D. Visual processing deficits as assessed by spatial frequency contrast sensitivity and backward masking in normal ageing and Alzheimer's disease. Brain 1984;107: Blanks JC, Schmidt SY, Torigoe Y, Porrello KV, Hinton DR, Blanks RH. Retinal pathology in Alzheimer's disease. II. Regional neuron loss and glial changes in GCL. Neurobiol Aging 1996;17: Guo L, Duggan J, Cordeiro MF. Alzheimer's disease and retinal neurodegeneration. Curr Alzheimer Res 2010;7: Hoh ST, Greenfield DS, Mistlberger A, Liebmann JM, Ishikawa H, Ritch R. Optical coherence tomography and scanning laser polarimetry in normal, ocular hypertensive, and glaucomatous eyes. Am J Ophthalmol 2000;129: Lee JY, Hwang YH, Lee SM, Kim YY. Age and retinal nerve fiber layer thickness measured by spectral domain optical coherence tomography. Korean J Ophthalmol 2012;26: Hedges TR 3rd, Perez Galves R, Speigelman D, Barbas NR, Peli E, Yardley CJ. Retinal nerve fiber layer abnormalities in Alzheimer's disease. Acta Ophthalmol Scand 1996;74: Kesler A, Vakhapova V, Korczyn AD, Naftaliev E, Neudorfer M. Retinal thickness in patients with mild cognitive impairment and Alzheimer's disease. Clin Neurol Neurosurg 2011;113: Kirbas S, Turkyilmaz K, Anlar O, Tufekci A, Durmus M. Retinal nerve fiber layer thickness in patients with Alzheimer disease. J Neuroophthalmol 2013;33: Lu Y, Li Z, Zhang X, Ming B, Jia J, Wang R, et al. Retinal nerve fiber layer structure abnormalities in early Alzheimer's disease: evidence in optical coherence tomography. Neurosci Lett 2010;480: Paquet C, Boissonnot M, Roger F, Dighiero P, Gil R, Hugon J. Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer's disease. Neurosci Lett 2007;420: Parisi V, Restuccia R, Fattapposta F, Mina C, Bucci MG, Pierelli F. Morphological and functional retinal impairment in Alzheimer's disease patients. Clin Neurophysiol 2001;112: He XF, Liu YT, Peng C, Zhang F, Zhuang S, Zhang JS. Optical coherence tomography assessed retinal nerve fiber layer thickness in patients with Alzheimer's disease: a meta-analysis. Int J Ophthalmol 2012;5: Mwanza JC, Oakley JD, Budenz DL, Chang RT, Knight OJ, Feuer WJ. Macular ganglion cell-inner plexiform layer: automated detection and thickness reproducibility with spectral domain-optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci 2011;52: Sato S, Hirooka K, Baba T, Tenkumo K, Nitta E, Shiraga F. Correlation between the ganglion cell-inner plexiform layer thickness measured with cirrus HD-OCT and macular visual field sensitivity measured with microperimetry. Invest Ophthalmol Vis Sci 2013;54: McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan 176 대한신경과학회지제 31 권제 3 호, 2013

5 EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34: Petersen RC. Mild cognitive impairment: current research and clinical implications. Semin Neurol 2007;27: Knight OJ, Girkin CA, Budenz DL, Durbin MK, Feuer WJ; Cirrus OCT Normative Database Study Group. Effect of race, age, and axial length on optic nerve head parameters and retinal nerve fiber layer thickness measured by Cirrus HD-OCT. Arch Ophthalmol 2012;130: J Korean Neurol Assoc Volume 31 No. 3,

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<31302D31362D C8B2BFB5C8C62DB1E8B9CEB0E E687770> 대한안과학회지 2017 년제 58 권제 4 호 J Korean Ophthalmol Soc 2017;58(4):437-442 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) https://doi.org/10.3341/jkos.2017.58.4.437 Original Article 시신경유두좌우뒤바뀜이있는눈의망막신경섬유층및황반부신경절세포두께