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박선아 순천향대학교부천병원신경과 Update in Dementia Sun Ah Park, MD, PhD Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea The fields of Alzheimer s disease (AD) and related

1 박선아 순천향대학교부천병원신경과 Update in Dementia Sun Ah Park, MD, PhD Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea The fields of Alzheimer s disease (AD) and related dementia have been continually updated. The developments and applications of biomarkers and early diagnosis of AD followed by early interventions are considered to be the prime interests in clinical field of dementia. Although a number of promising new drugs have failed in proving the therapeutic efficacy, a few drugs improving nutrition and availability of acetylcholine showed positive results. Key Words: Alzheimer s disease, Biomarker, Criteria, Pathology, Prevenstion, Update 서론 알츠하이머병과연관치매에대한연구는많은연구자들에의해꾸준히업데이트되고있다. 효율높은치료법이아직개발되지않아기전규명및치료타겟개발위한기초연구, 조기진단및경과추정을위한바이오마커개발, 치료제개발, 신약임상시험, 그리고예방전략개발등다양하게연구가진행중이다. 더불어치매환자및가족들을위한복지정책등실용적분야에대한관심도높아지고있다. 본저자는임상가들의치매환자진료에도움을줄임상연구분야의최신지견을소개하고자한다. 본론 1. 알츠하이머병바이오마커연구 1) Global standardization measurement of CSF for Alzheimer s disease (AD) Sun Ah Park, MD, PhD Department of Neurology, Soonchunhyang University Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon, Korea Tel: , Fax: sapark@schmc.ac.kr 반복측정및측정실험실사이의변동이한계로지적된뇌척수액의베타아밀로이드단백 1-42(Aβ42), 총타우단백 (T-tau), 그리고인산화타우단백 (P-tau) 농도측정의질적향상을위해알츠하이머협회차원에서 external quality control (QC) program 을만들어국제협력연구를진행한결과가나왔다. 1 7차례에걸친공동분석의결과를정리하여 2012년 Alzheimer s Association International Conference(AAIC) 에서발표하였다. 실험실간동일샘플의측정값차이는 Aβ42 의경우 25%, T-tau 의경우 15% 그리고, P-tau의경우 20% 정도였다. 그러나뇌척수액바이오마커를반복해서꾸준히측정해온곳에서는측정값의변동이적었다. 아직은알츠하이머병진단을위한기준값은제공하지않았고, 이에대해서는추가연구가이루어질것이라고만밝혔다. 그러나이같은국제적공동노력들이앞으로진단의유용성이높은뇌척수액 Aβ42, T-tau, 그리고 P-tau의활용및이를이용한다기관국제공동연구에활력을줄것으로보인다. 2) 새로운알츠하이머병진단기준및바이오마커의임상적활용알츠하이머병바이오마커이용은그간연구목적이대부분이었으나, 최근에개정된 National Institute on Aging (NIA) 와 Alzheimer s Association (AA) 의알츠하이머병진 년대한신경과학회제 32 차학술대회 - 강의록 -

2 단기준 2-5 및뒷부분에기술된약물예방연구등 6 을통해볼때더이상연구만을위한수단이아닌유용한임상활용도구로다가오고있다. 개정된알츠하이머병진단기준은증상발현전매우초기부터의알츠하이머병관리필요성을제시하고있다. 즉 Dementia due to AD 외에그이전인 preclinical AD, mild cognitive impairment (MCI) due to AD 까지총 3단계로나눠알츠하이머병을접근하기를권하고있다. 초기진단을위해서는바이오마커참조가요구되는데 (Table 1), Aβ 변화가있는지-없는지그리고신경퇴행의증거가있는지-없는지에따라초기알츠하이머병은추가로세분화된다. Preclinical AD 는바이오마커및인지기능추적결과에따라다음과같이분류되어, 1) Stage1 - Aβ 바이오마커의이상, 2) Stage2 - stage1와이에추가로신경퇴행의증거가있음, 3) Stage3 - stage2 와이에추가로이전에비해인지변화가있 Table 1. Biomarkers under examination for AD 2 Biomarkers of Aβ deposition CSF Aβ42 PET amyloid imaging Biomarkers of neuronal injury CSF tau/phosphorylated tau Hippocampal volume or medial temporal atrophy by volumetric measures or visual rating Rating of brain atrophy FDG PEG imaging SPECT perfusion imaging Less well validated biomarkers: fmri activation studies, resting BOLD functional connectivity, MRI perfusion, MR spectroscopy, diffusion tensor imaging, voxel based and multivariate measures Associated biochemical change Inflammatory biomarkers (cytokines) Oxidative stress (isoprostanes) Other markers of synaptic damage and neurodegeneration such as cell death Aβ: beta-amyloid protein; CSF, cerebrospinal fluid; PET, positron emission tomography; FDG, fluorodeoxyglucose; SPECT, single photon emission tomography; MRI, magnetic resonance imaging; fmri, functional magnetic resonance imaging; BOLD, blood oxygen level-dependent. 음이다. MCI due to AD 는임상진단및인지평가가여전히중요하여, 한가지이상의인지장애가연령및학력을고려했을때인지기능검사에서발견되지만, 일상생활수행능력은도움없이혹은경미한도움만으로유지가능하여치매가아닌임상진단기준에맞아야한다. 2 그러나, 추가로바이오마커까지고려하여 (Table 1) 분류하면 MCI를좀더세분화할수있다. 1) MCI-core clinical criteria, 2) MCI due to AD - intermediate likelihood, 3) MCI due to AD-high likelihood, 4) MCI-unlikely due to AD 이렇게 4 군으로분류할수있고 (Table 2), 이렇게해서 AD에가까운 MCI로분류된경우는향후 AD에의한치매로진행가능성이그렇지않은경우에비해매우높은것으로알려져있다. 6,7 이미치매가발병한후에도, 알츠하이머병에의한치매 ( 알츠하이머치매 ) 로진단하기위해서는임상적진단기준외에바이오마커결과를추가로고려할것을권고하고있다 (Table 3). 그러나, 아직까지는바이오마커의유용성에한계가있기에인지기능검사및뇌영상등임상정보통해다른퇴행성뇌질환과의감별후에바이오마커검사결과를해석해야알츠하이머병치매의진단및치매전단계환자에서의치매전환예측의정확도가높으니주의하여야한다. 8,9 2. 알츠하이머병병리진단기준개정 6, 년에만들어진알츠하이머병의병리학적진단기준인 NIA/Reagan Institute of the Alzheimer Association Consensus Recommendations for the Postmortem Diagnosis of AD 혹은 NIA-Reagan Criteria 11 가오랜만에개정되었다. 다음과같은이유들로인해개정이필요했다. 1) 임상적으로알츠하이머병의개념이임상증상전단계 (preclinical stage) 나경미한증상이있는경우까지포함하게되었고, 2 2) 정상인의경우도나이가들면알츠하아이머병병리소견을가지고있는경우가상당히있고, 5 3) 다른질환에서도알츠하이머병병리가관찰되는경우가많기때문이다. 새로운병리기준에서는 A β, Tau, 그리고 neuritic plaque 의정도와분포를각각고려 Table 2. Mild cognitive impairment (MCI) criteria incorporating biomarkers 2 Diagnostic category Biomarker probability of AD etiology Aβ (PET or CSF) Neuronal injury (tau, FDG, smri) MCI core clinical criteria Uninformative Conflicting/indeterminant/untested Conflicting/indeterminant/untested MCI due to AD intermediate likelihood Intermediate Positive Untested Untested Positive MCI due to AD high likelihood Highest Positive Positive MCI unlikely due to AD Lowest Negative Negative 2013 년대한신경과학회제 32 차학술대회 - 강의록 - 9

3 박선아 Table 3. Alzheimer s disease (AD) dementia criteria incorporating biomarkers 4 Diagnostic category Biomarker probability of AD etiology Aβ (PET or CSF) Probable AD dementia Based on clinical criteria Uninformative Unavailable, conflicting, or With three levels of evidence of AD pathophysiological process Neuronal injury (CSF tau, PDG-PET, smri) Unavailable, conflicting, or Intermediate Unavailable or Positive Intermediate Positive Unavailable or High Positive Positive Possible AD dementia (atypical clinical presentation) Based on clinical criteria Uninformative Unavailable, conflicting, or Unavailable, conflicting, or With evidence of AD High but does not rule out Positive Positive pathophysiological process second etiology Dementia-unlikely due to AD Lowest Negative Negative 하여 A, B, C로나누어점수를매긴후 (Table 4) 알츠하이머병리, A1, B0, C0 으로표시하고, 이에따라 not, low, intermediate 또는 high 로분류하게된다 (Table 5). 추가로레비소체, 뇌혈관질환, 해마경화증, 그리고 TDP-43 에대한병리기준도제시하여, 알츠하이머병과동반될수있는병리기준에대해서도명기하였다. 3. 알츠하이머치매예방에대한관심 알츠하이머병의치료제가예상과달리알츠하이머치매환자를대상으로한임상연구에서연달아실패하면서, 알츠하이머병병리가진행하기훨씬이전부터이를예방할수있는전략에대한관심이높아졌다. 특히, 1) 인지활동, 사회활동, 여가활동, 영양, 운동등생활습관, 2) 제2형당뇨, 고지혈, 고혈압, 동맥경화, 심장질환, 흡연, 그리고음주등뇌혈관질환의위험인자들, 3) 뇌손상, 우울증, 및기타뇌질환등교정가능한위험인자들이치매예방을위한중요한공략대상으로제시되고있다. 이같은교정가능한치매위험인자관리는알츠하이머병리가길게보면 20년전부터뇌에서시작된다는점을고려하면, 우리가막연히생각하고있는시기보다훨씬이전부터관리가되어야한다는주장이알츠하이머병연구자나임상가들에의해널리받아들여지고있다. 6,12 4. 알츠하이머병조기치료및예방연구 6 미국을중심으로진행되고있는국제연구인 Dominantly Inherited Alzheimer s Network (DIAN), Anti-Amyloid Treatment of Asymptomatic Alzheimer s Disease (A4), 그리고 Alzheimer s Prevention Initiative (API) 의움직임이 Table 4. Classification of Alzheimer s disease (AD) neuropathologic change based on ABC score calculated by three parameters (Amyloid, Braak, CERAD) Aβ plaque score (modified from Thal등 15 ) A0 no Aβ or amyloid plaques A1 Thal phases 1 or 2 A2 Thal phases 3 A3 Thal phases 4 or 5 NFT stage (modified from Braak과 Braak 16 ) for silver-based histochemistry or phospho-tau immunohistochemistry) B0 no NFTs B1 Braak stage I or II B2 Braak stage III or IV B3 Braak stage V or VI Neuritic plaque score (modified from CERAD) 17 C0 no neuritic plaques C1 CERAD score sparse C2 CERAD score moderate C3 CERAD score frequent 주목할만하다. 1) Dominantly Inherited Alzheimer s Network (DIAN, dian-info.org) 체염색체우성가족형알츠하이머병원인유전자를갖는알츠하이머병환자의자녀를대상으로하는연구이다. 이같은유전자변이는 30 ~ 50 대알츠하이머병발병을유도한다. 알츠하이머병임상증상이나타나기전의정보, 생화학적변화를추적하고, 뇌병리로인해비가역적변화가오기전개발중인알츠하이머병치료약물을시도하는 Therapeutic Trial Unit (TTU) 를 DIAN 내에만들어알츠하이머병원인유전자를갖는사람들의발병연기, 예방그리고인지저하의회 년대한신경과학회제 32 차학술대회 - 강의록 -

4 Table 5. Level of Alzheimer s disease (AD) neuropathologic changes B: NFT score (Braak stage) A: Aβ/amyloid plaque score (Thal phases) C: Neuritic plaque score (CERAD) B0 or B1 (None or I/II) B2 (III/IV) B3 (V/VI) A0 (0) C0 (none) Not Not Not A1 (1/2) C0 or C1 (none to sparse) Low Low Low C2 or C3 (mod to freq) Low Intermediate Intermediate A2 (3) Any C Low Intermediate Intermediate A3 (4/5) C0 or C1 (none to sparse) Low Intermediate Intermediate C2 or C3 (mod to freq) Low Intermediate High Table 6. Nutritional composition of Fortasyn Connect, the nutrient combination in Souvenaid 13 Component Amount per daily dose* Eicosapentaenoic acid, mg 300 Docosahexaenoic acid, mg 1200 Phospholipids, mg 106 Choline, mg 400 Uridine monophosphate, mg 625 Vitamin E (alpha-tocopherol equivalents), mg 40 Vitamin C, mg 80 Selenium, μg 60 Vitamin B12, μg 3 Vitamin B6, mg 1 Folic acid, μg 400 *Souvenaid (125mL [125 kcal] daily dose) contains Fortasyn Connect. Souvenaid is a registered trademark of Nutricia N.V. Fortasyn is a trademark of Nutricia N.V. 복등을위한새로운약물시도를고려하고있다. 알츠하이머병병인을공략하는치료법이알츠하이머병환자를대상으로한임상연구에서실패한이유가수십년전부터진행된알츠하이머병병리로인해이미신경세포는비가역적변화가왔기때문이라고추정되고있다. 따라서, DIAN-TTU 연구에서원인유전자로인해향후알츠하이머병이발병될대상자들에게알츠하이머병병리가시작되는초기에이같은약물로알츠하이머병병리를억제했을때알츠하이머병이예방될수있을지혹은진행을막고, 발병을연기시킬수있을지, 그연구결과에대한많은관심이집중되고있다. 2) Anti-Amyloid Treatment of Asymptomatic Alzheimer s Disease (A4) Alzheimer disease cooperative study에서알츠하이머병과연관된바이오마커에서양성이나온정상노인들을대상으로하여알츠하이머병약물치료를시행하여인지기능변화및바이어마커의변화를 outcome 으로분석하여 3년간 투여될치료제효과여부를판단하겠다는연구를계획하였다 ( AAIC 2012 Press Release). 2013년중순부터는대상자모집을시작하려고계획하고있다. 대상자수집에이용될바이오마커는아밀로이드양전자방출단층촬영 (positron emission tomography, PET) 에서양성그리고 / 또는뇌척수액 Aβ42의유의한감소가이용될예정이다. 이연구는알츠하이머병발생의원인이 Aβ 단백이기에, 이를초기에공략하면 Aβ에의해유도될세포사멸, 시냅스소실그리고인지장애등이예방될수있다는 아밀로이드가설 에이론적근거를둔다. 3) Alzheimer s Prevention Initiative (API, endalznow.org) 45세경에알츠하이머병이발병하는콜롬비아의큰가족형알츠하이머병가계를대상으로시작된예방적치료연구가진행중이다. 특히우성유전의알츠아이머병원인유전자를갖지만, 임상증상이없는약 300명의콜롬비아가계로부터의대상자와약 24명정도의미국인들을대상으로대뇌 A β 농도를줄이는단클론항체인 crenezumab (Genetech, South San Francisco, CS, USA) 투여를계획하고있다. 이같은가족형알츠하이머병유전자를가지고있는환자들을대상으로한예방전략연구가 DIAN, API 등을중심으로진행중이다. 앞으로몇년후나오게될이들을대상으로한연구결과는알츠하이머병치료의돌파구로서 알츠하이머병리초기치료 의효과를판가름하는중요한근거를제시할것이다. 알츠하이머병이대부분노년기에발생하고, 원인유전자변이가없이발생하는경우가훨씬더많지만, 가족형알츠하이머병이나노년기산발성알츠하이머병모두비슷한알츠하이머병병리, 임상적특징, 및임상경과를공통적으로보이기에, 가족형알츠하이머병원인유전자환자에서임상연구결과는곧알츠하이머병이나연관치매의치료 2013 년대한신경과학회제 32 차학술대회 - 강의록 - 11

5 박선아 지침을세우는데중요한해결책을제시하리라기대된다. 5. 약물개발임상시험결과 1) Souvenaid 48주간초기알츠하이머치매환자를대상으로진행되었던연구에서 Souvenaid 투여가기억력호전에효과가있다는연구결과가나왔다. Souvenaid 는시냅스형성과기능을도와주게만든영양음료이다 (Table 6). 하루한번 125 ml 의 Souvenaid 를복용은부작용거의없고복용순응도가높았다. 13 2) EVP 명의초기 - 중기알츠하이머치매환자를대상으로 EVP-6124 (EnVivo Pharmacueticals, Watertownm, MA) 를이용 6개월간진행된 phase2b 임상결과가 2012년 AAIC에서발표되었다. 선택적 alpha-7 nicotinic agnosist 인 EVP mg이알츠하이머치매환자의인지기능을통계적으로유의한수준으로호전시켰고, 소화기계부작용도적은것으로보고되어, 곧 phase3 임상연구가진행될예정이다. 3) 기타 Citicoline 은보조식품으로아세틸콜린, norepinephrine, 그리고도파민등일부신경전달물질및세포막의성분인 phospholipid 의대뇌이용을돕는것으로알려져있다. 9개월간진행된 265명의 vascular cognitive impairment 환자대상 citicoline 투여가이들의 minimental state examination (MMSE) 점수를약간호전시킴이보고되었다. 6 그외에도많은신약임상연구가진행중이지만, 14 앞서열거한것들을제외하고아직뚜렷한좋은결과를보이는것들이드물다. 결론 현재알츠하이머병및연관치매분야에서는조기발견, 조기치료, 예방치료의중요성이강조되고있다. 치매환자대상신약연구에서는기전타겟팅한특이치료보다는오히려영양상태나, 인지기능개선등을전략으로세운치료법이좋은결과를보여주고있다. 앞으로지속해서나오게될후속연구결과들이기대된다. REFERENCES 1.Carrillo MC, Blennow K, Soares H, Lewczuk P, Mattsson N, Oberoi P, et al. Global standardization measurement of cerebral spinal fluid for Alzheimer's disease: An update from the Alzheimer's Association Global Biomarkers Consortium. Alzheimers Dement 2013;9: Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer s disease: Recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement 2011;7: Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7: McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement : Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer s disease: Recommendations from the National Institute on Aging-Alzheimer s Association workgroups on diagnostic guidelines for Alzheimer s disease. Alzheimers Dement 2011;7: Alzheimer Association. Highlights of Alzheimer s Association news and events of interest to the medical and scientific community. Alzheimer s & Dementia 2012;8: Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer s disease neuroimaging initiative subjects. Ann Neurol 2009;65: Schoonenboom NS, Reesink FE, Verwey NA, Kester MI, Teunissen CE, van de Ven PM, et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 2012;78: Vos SJ, van Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund LO, et al. Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI. Neurology 2013 Feb 27 [Epub, PMID: ] 10.Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 2012;8: 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 as 년대한신경과학회제 32 차학술대회 - 강의록 -

6 sessment of Alzheimer disease. J Neuropathol Exp Neurol 1997;56: Polidori MD and Pientka L. A brief update on dementia prevention. Z Gerontol Geriat 2012;45: Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, et al. Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial. J Alzheimers Dis 2012;31: Misra S and Medhi B. Drug development status for Alzheimer s disease: present scenario. Neurol Sci 2013 Feb 8 [E pub, PMID ] 15. Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002;58: Braak H, Braak E. Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathol. 1991;82: Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;112: 년대한신경과학회제 32 차학술대회 - 강의록 - 13

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Dementia2 Today s Topics Memory Impairment & Dementia Age Associated Memory Impairment Dementia Definition of dementia Depression Schizophrenia Mental retardation Delirium : Not final diagnosis term, but symptomatologic