Copy number loss in SFMBT1 is common among Finnish and Norwegian patients with iNPH

ARTICLE OPEN ACCESS Copy numbe loss in SFMBT1 is common among Finnish and No wegian pa ien s wi h iNPH Ville E. Ko honen, BMed, Seppo Helisalmi, PhD, Aleksi Jokinen, BMed, Ila i Jokinen, BMed, Juha-Ma i Leh ola, BMed, Minna Oinas, MD, PhD, Kimmo L¨ onn o , MD, PhD, Cecilia A ellan, MD, Anna Ko kansalo, MD, Janek F an zen, MD, PhD, Jaakko Rinne, MD, PhD, An i Ronkainen, MD, PhD, Mikko Kauppinen, MD, An i Junkka i, MD, PhD, Mikko Hil unen, PhD, Hilkka Soininen, MD, PhD, Mi ja Ku ki, PhD, Juha E. J¨ a¨ askel¨ ainen, MD, PhD, Anne M. Koi is o, MD, PhD, Hideno i Sa o, MD, PhD, Takeo Ka o, MD, PhD, Anne M. Remes, MD, PhD, Pe K is ian Eide, MD, PhD, and Ville Leinonen, MD, PhD Neu ol Gene 2018;4:e291. doi:10.1212/NXG.0000000000000291 Co espondence M . Ko honen [email p o ec ed] Abs ac Objec i e To e alua e he ole o he copy numbe loss in SFMBT1 in a Caucasian popula ion. Me hods Fi e hund ed six y-se en Finnish and 377 No wegian pa ien s wi h idiopa hic no mal p essu e hyd ocephalus (iNPH) we e geno yped and compa ed wi h 508 Finnish elde ly, neu ologically heal hy con ols. The copy numbe loss in in on 2 o SFMBT1 was de e mined using quan- i a i e PCR. Resul s The copy numbe loss in in on 2 o SFMBT1 was de ec ed in 10% o Finnish (odds a io [OR] = 1.9, p= 0.0078) and in 21% o No wegian (OR = 4.7, p< 0.0001) pa ien s wi h iNPH compa ed wi h 5.4% in Finnish con ols. No copy numbe gains in SFMBT1 we e de ec ed in pa ien s wi h iNPH o heal hy con ols. The ca ie s a us did no p o ide any p ognos ic alue o he effec o shun su ge y in ei he popula ion. Mo eo e , no diffe ence was de ec ed in he p e alence o hype ension o T2DM be ween SFMBT1 copy numbe loss ca ie s and nonca ie s. Conclusions This is he la ges and he fi s mul ina ional s udy epo ing he inc eased p e alence o he copy numbe loss in in on 2 o SFMBT1 among pa ien s wi h iNPH, p o iding u he e idence o i s ole in iNPH. The pa hogenic ole s ill emains unclea , equi ing u he s udy. F om he Depa men o Neu osu ge y (V.E.K., A. Jokinen, I.J., J.-M.L., A. Junkka i, J.E.J., V.L.), Kuopio Uni e si y Hospi al and Uni e si y o Eas e n Finland; Ins i u e o Clinical Medicine- Neu ology (S.H., M.H., H. Soininen, A.M.K.), Uni e si y o Eas e n Finland, Kuopio; Depa men o Neu osu ge y (M.O., K.L.), Uni e si y o Helsinki and Helsinki Uni e si y Hospi al; Clinical Neu osciences (C.A., A.K., J.F., J.R.), Depa men o Neu osu ge y, Uni e si y o Tu ku and Tu ku Uni e si y Hospi al; Depa men o Neu osu ge y (A.R.), Tampe e Uni e si y Hospi al; Uni o Clinical Neu oscience (M. Kauppinen, V.L.), Neu osu ge y, Uni e si y o Oulu and Medical Resea ch Cen e , Oulu Uni e si y Hospi al; Ins i u e o Biomedicine (M.H.), Uni e si y o Eas e n Finland, Kuopio; Analy ical and T ansla ional Gene ics Uni (M. Ku ki), Depa men o Medicine, Massachuse s Gene al Hospi al; P og am in Medical and Popula ion Gene ics (M. Ku ki), B oad Ins i u e o MIT and Ha a d; S anley Cen e o Psychia ic Resea ch (M. Ku ki), B oad Ins i u e o Ha a d and MIT; Depa men o Neu ology (H. Sa o, T.K.), Hema ology, Me abolism, Endoc inology and Diabe ology, Yamaga a Uni e si y Facul y o Medicine, Japan; Medical Resea ch Cen e (A.M.R.), Oulu Uni e si y Hospi al, Finland; Uni o Clinical Neu oscience (A.M.R.), Neu ology, Uni e si y o Oulu, Finland; Depa men o Neu osu ge y (P.K.E.), Oslo Uni e si y Hospi al-Rikshospi ale ; and Ins i u e o Clinical Medicine (P.K.E.), Facul y o Medicine, Uni e si y o Oslo, No way. Funding in o ma ion and disclosu es a e p o ided a he end o he a icle. 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Published by Wol e s Kluwe Heal h, Inc. on behal o he Ame ican Academy o Neu ology. 1 Idiopa hic no mal p essu e hyd ocephalus (iNPH) is a la e- onse p og essi e neu ologic disease p esen ing ypically wi h gai difficul ies oge he wi h enla ged en icles and igh - ened pa asagi al co ical sulci, whe eas o he symp oms such as cogni i e impai men and u ina y incon inence a e o en p esen . 1,2 Recen ly, he 2 a ailable diagnos ic guidelines 1,2 ha e been c i icized, and u gen e ision and/o unifica ion o he diagnos ic manual ha e been eques ed. 3–5 Pa ien s wi h iNPH a e cha ac e ized by abno mal CSF ci cula ion and e idence o delayed ce eb al clea ance, as ecen ly shown in an MRI CSF ace s udy. 6 Al hough he e a e no bioma ke s o aid in he diagnos ics, and he e iology o iNPH emains unclea , he e is an inc easing amoun o p oo indica ing a po en ial gene ic componen in iNPH. 7–12 The p e alence o amilial iNPH, i.e., a leas 2 pa ien s wi h iNPH, in he fi s -deg ee ela i es has been epo ed o ange om 4.8% o 7%. 10,11 Da a also con ain a pai o iden ical wins ha ing iNPH 11 and a amily in which an au osomal dominan inhe i ance pa e n is obse ed. 9 A segmen al copy numbe loss in he SFMBT1 gene was epo ed in Japan o be p esen in 50% o pa ien s, who p esen concomi an ly wi h clinical ea u es o iNPH and enla ged en icles, 13 and in 26% o pa ien s wi h iNPH, who expe ienced a posi i e shun esponse. 14 These esul s ha e p e iously no been confi med ou side o Japan and wi h sufficien ly la ge coho s. Ou aim was o e alua e he p e - alence o he copy numbe loss o SFMBT1 in pa ien s wi h iNPH o Caucasian o igin. Me hods S anda d p o ocol app o als, egis a ions, and pa ien consen s This s udy was conduc ed in he Depa men o Neu osu ge y in Kuopio Uni e si y Hospi al, he B ain Resea ch Uni o he Uni e si y o Eas e n Finland, and he Depa men o Neu- osu ge y, Oslo Uni e si y Hospi al, Rikshospi ale , Oslo, No way, acco ding o he Decla a ion o Helsinki. Kuopio Uni e si y Hospi al Resea ch E hics Boa d app o ed he s udy (5/2008 and 276/2016). In No way, he s udy was app o ed by he Regional Commi ee o Medical and Heal h Resea ch E hics (REK) o Heal h Region Sou h-Eas , No way (2015/1313), and he Ins i u ional Re iew Boa d o Oslo Uni e si y Hospi al (2015/8128). The s udy consis ed o 567 Finnish (mean age 70 yea s; SD 8.3; men: n = 254; able 1) and 377 No wegian (mean age 68 yea s; SD 11; men: n = 190 (50%); able 2) pa ien s wi h possible iNPH. All pa ien s and con ols p o ided hei w i en in o med consen . All Finnish and No wegian pa ien s suspec ed o ha ing iNPH ha e been clinically e alua ed by a neu ologis and a neu o- su geon. The pa ien s we e e e ed o a neu osu geon by a neu ologis i he pa ien s we e obse ed o ha e a leas one o he co e symp oms associa ed wi h iNPH, which include gai difficul ies, cogni i e impai men , and u ina y incon inence oge he wi h enla ged en icles (E ans Index >0.30) 15 disp opo iona e o he size o he sulci o he ce- eb al con exi ies in MRI o CT imaging scans. In addi ion, mos Finnish and No wegian pa ien s ha e unde gone, as ap ognos ic es o shun benefi , a 24-hou in a en icula p essu e moni o ing, spinal ap, ex ended lumba d ainage, o lumba in usion es . The No wegian pa ien s we e diagnosed, and he decision o pe o m he shun su ge y was done ollowing a p e- iously published p o ocol, 16 which included a clinical judgmen o he se e i y o iNPH symp oms using a Oslo iNPH G ading Scale ( anging om 3 o 15), 16 MRI o CT imaging scans o he e alua ion o he en iculomegaly, e alua ion o como bidi ies, and finally a diagnos ic o e - nigh ICP moni o ing. All he Finnish and No wegian pa ien s ulfilled he clinical diagnos ic c i e ia o possible iNPH. 1,2 The con ol g oup consis ed o 508 (mean age 70 yea s; SD 5.1; male: n =207) Finnish subjec s acqui ed o neu ogene ic s udies. All subjec s ha e unde gone clinical and neu opsychological Table 1 Clinical cha ac e is ics o he Finnish iNPH coho Va iables Mean o no. o cases SD o % Cases 567 Sex ( emale) 312 54.9 Como bidi ies High a e ial blood p essu e 339/564 59.7 Diabe es 169/565 29.8 Age a shun a 71 7.9 Posi i e subjec i e shun esponse b 458/528 86.8 Posi i e objec i e shun esponse c 97/203 49 a A ailable o 551 pa ien s. b Clinical e alua ion a 3-mon h ollow-up. c Calcula ed using he modi ied 12-poin Kubo scale, in which 1-poin de- c ease is conside ed o be clinically impo an . Glossa y CI = confidence in e al; iNPH = idiopa hic no mal p essu e hyd ocephalus; OR = odds a io. 2Neu ology: Gene ics | Volume 4, Numbe 6 | Decembe 2018 Neu ology.o g/NG es ing lead by an expe ienced neu ologis specialized in neu odegene a i e condi ions o exclude any signs o cogni i e impai men ( able 3). Genomic DNA was ex ac ed om enous blood samples using QIAamp DNA blood mini ex ac ion ki (QIAGEN). The copy numbe loss/gain in he in on 2 egion o SFMBT1 was de ec ed using quan i a i e PCR (qPCR) and he del a- del a me hod as p e iously desc ibed. 14 Ou collabo a o (T. Ka o) p o ided a posi i e con ol sample, and a comme cial nega i e con ol was used. All s a is ical analyses we e pe o med using SPSS s a is ic e sion 23 (IBM co p. USA). The χ 2 es was used o ca e- go ical dicho omous a iables o g oups >2. The Fishe exac es was used o pai wise compa ison. p< 0.05 was consid- e ed s a is ically significan . Powe calcula ions we e comple ed be o e he execu ion o he esea ch and we e based on he esul s o he s udy by Sa o e al. 14 in which he expec ed p e alence was di ided by a ac o o 2 (26/2% = 13%). Wi h a powe o 0.85, p= 0.05, he sample size was de e mined o be n ≥362. Bo h he Finnish and No wegian iNPH coho s and Finnish con ols ulfill his equi emen . Da a a ailabili y s a emen Acco ding o Finnish law, he ull indi idual clinical da a se canno be sha ed publicly. Howe e , he da a se can/will be sha ed by academic collabo a ion ag eemen upon eques . Resul s The copy numbe loss in SFMBT1 was de ec ed in 9.9% o he Finnish pa ien s wi h iNPH, in 21% o he No wegian pa ien s wi h iNPH, and in 5.4% o he Finnish con ols (figu es 1 and 2). S a is ically significan diffe ence was de ec ed be ween Finnish and No wegian pa ien s wi h iNPH (p< 0.0001). No copy numbe gains in SFMBT1 we e de ec ed in Finnish o No wegian pa ien s wi h iNPH o heal hy con ols. In he Finnish iNPH coho , 9/71 sus- pec ed amilial pa ien s, who a e ca ie s o he copy num- be loss, we e de ec ed, and he e o e, no agg ega ion o he copy numbe loss a ian was obse ed in amilial iNPH (12.1% s 10%, p= 0.5). The e was no significan diffe ence in age a onse , sex, shun ing p e alence, o shun esponse be ween Finnish and No wegian pa ien s. In addi ion, no diffe ence was de ec ed in he p e alence o hype ension o T2DM be ween SFMBT1 copy numbe loss ca ie s and nonca ie s ( able 4) o in he equency o he gene ic a - ian be ween shun - esponsi e and non esponsi e pa ien s in ei he Finnish (odds a io [OR] = 1.0, confidence in e al [CI] 95% 0.44–2.4, p= 0.93) o No wegian (OR = 0.68, CI 95% 0.31–1.5, p= 0.33) coho . Discussion This is he fi s s udy on he p e alence o he copy numbe loss in SFMBT1 among pa ien s wi h iNPH o non-Asian o igin. Al hough he e a e s udies desc ibing amilial agg e- ga ion 11 and e en in some a e cases au osomal dominan inhe i ance pa e n, 9 SFMBT1 is he fi s gene o be associa ed wi h iNPH. Ou findings a e p incipally in line wi h he Jap- anese esul s p o iding compelling u he e idence on he ole o he copy numbe loss in SFMBT1 in iNPH. The copy numbe loss in SFMBT1 is de ec ed only in 10%–20% o he pa ien s wi h iNPH, which would sugges ha iNPH has bo h a polygene ic and mul i ac o ial o igin. E h- nici y seems o modi y he p e alence o his gene ic a ian be ween Finnish and No wegian iNPH pa ien s bu su p is- ingly is simila be ween selec ed No wegian and Japanese popula ions. In addi ion, a small pe cen age o cogni i ely in- ac con ols ca y he gene ic a ian p o iding u he e i- dence on he copy numbe loss in SFMBT1 o being only a possible isk-inc easing geno ype. In he Japanese s udy, a small pe cen age o pa ien s and con ols we e ound o ca y a copy numbe gain a ian , bu no s a is ically significan di - e ence be ween pa ien s wi h iNPH and con ols was de ec- ed. 14 O in e es , in he No dic coho s, no copy numbe gain a ian s we e de ec ed in ei he pa ien s wi h iNPH o heal hy con ols. The e o e, i appea s ha he copy numbe loss in Table 2 Clinical cha ac e is ics o he No wegian iNPH coho Va iables Mean o no. o cases SD o % Cases 377 Sex ( emale) 187/377 49.6 Shun 297/377 78.8 Como bidi ies A e ial hype ension 156/377 41.4 Diabe es 58/377 15.4 Age a shun 69 9.9 Posi i e shun esponse a 258/297 86.95 No shun esponse 39/297 13.1 Los o ollow-up 7/297 2.4 Abb e ia ion: iNPH = idiopa hic no mal p essu e hyd ocephalus. a Clinical e alua ion a 6–12 mon hs a e su ge y. Calcula ed using he Oslo NPH scale. 16 Table 3 Finnish con ol cha ac e is ics Va iables Mean o no. o cases SD o % Con ols 508 Sex ( emale) 301 59.3 Age a inclusion 69.8 5.1 Neu ology.o g/NG Neu ology: Gene ics | Volume 4, Numbe 6 | Decembe 2018 3 SFMBT1 is associa ed wi h iNPH, and he esul s a e no influenced by genomic ins abili y in he SFMBT1 in on egion. Hype ension, T2DM, schizoph enia, and Alzheime disease a e common among pa ien s wi h iNPH. 17–22 The p esen esul s could eflec a highe occu ence o hype ension and T2DM in iNPH, as p e iously demons a ed. Howe e , in his s udy coho , we ound no s a is ically significan diffe - ence in he p e alence o hype ension o T2DM be ween SFMBT1 copy numbe loss ca ie s and nonca ie s, u he alida ing i s independen associa ion wi h iNPH. In he p esen s udy, bo h shun - esponsi e and non esponsi e pa ien s we e included, and no diffe ence was obse ed be ween hese g oups ega ding he ca ie s a us o he copy numbe loss in SFMBT1. The o iginal disco e y was done in subjec s wi h enla ged b ain en icles, 13 and he Japanese s udy on copy numbe loss in SFMBT1 14 included only shun - esponsi e iNPH pa ien s, and he e o e, he p e alence o he copy numbe loss in SFMBT1 among pa ien s who a e non esponsi e o shun su - ge y is unknown in he Japanese popula ion. 14 Because o he simila p e alence be ween bo h shun - esponsi e and non- esponsi e pa ien g oups, SFMBT1 seems obelinkedwi h enla gemen o b ain en icles bu no wi h shun esponse. The diagnosis o iNPH is p esen ly based on ypical clinical cha ac e is ics and adiologic p esen a ion. In addi ion, diffe en p ognos ic es s a e used o e alua e he po en ial shun benefi , bu no bioma ke s ha e been ound o help in he diffe en ial diagnos ics. The cu en ague diagnos ic c i e ia o iNPH 1,2 should be no ed in he in e p e a ion o he cu en esul s and u he gene ic s udies on iNPH. These include he defini ion o he diagnosis, he e ogenei y o he disease cou se and a iable adiologic ea u es, and common como bid neu odegene a i e diseases. 4 This poses a challenge o he diffe en ial diagnos ics o iNPH, and bo h alse and missed diagnoses a e likely o be common. Po en ially, he gene ic in o ma ion could, in he u- u e, be included in diffe en isk calcula o s (e.g., e e ence 23) o p o ide clinician ools ha help decide e e als conce ning hese ypes o uncommon diseases. Figu e 1 Flowcha o he s udy coho Flowcha showing he Finnish and No wegian coho s. No di e ence was de ec ed be ween he equency o he gene ic a ian be ween shun - e- sponsi e and non esponsi e pa ien s in ei he Finnish (OR = 1.0, CI 95% 0.44–2.4, p= 0.93) o No wegian (OR = 0.68, CI 95% 0.31–1.5, p= 0.33) coho . a Los o ollow-up (n = 7). b Los o ol- low-up esponse (n = 63). CI = con i- dence in e al; OR = odds a io. Figu e 2 The p e alence o he copy numbe loss in he SFMBT1 among Finnish and No wegian pa ien s wi h iNPH Thep e alenceo hecopynumbe lossinSFMBT1 among No wegian iNPH pa ien s is 21% (n = 79/377), 9.9% (n = 56/567) among Finnish iNPH pa ien s, and 5.4% (n = 27/508) among Finnish con ols. S a is ical signi icance was ob- se ed; No wegian iNPH pa ien s s Finnish con ols (OR = 4.7, CI 95% 3.0–7.5, p< 0.001), Finnish iNPH pa ien s s Finnish con ols (OR = 1.9, CI 95% 1.2–3.1, p= 0.0078), and No wegian iNPH pa ien s s Finnish iNPH pa ien s (OR = 2.5, CI 95% 1.7–3.6, p<0.001).p< 0.05 was conside ed s a is ically signi ican . The Fishe exac es was used o pai wise compa isons. CI = con idence in e al; iNPH = idiopa hic no mal p essu e hyd ocephalus; OR = odds a io. 4Neu ology: Gene ics | Volume 4, Numbe 6 | Decembe 2018 Neu ology.o g/NG The SFMBT1 locus has been p e iously iden ified o be in- ol ed in ele a ed se um u a e le els, as ing glucose, and high blood p essu e. 24–26 The physiologic ole o he SFMBT1 p o ein is poo ly unde s ood bu ela es o his one binding and is in ol ed in diffe en ansc ip ion co ep esso ac i i ies. 27,28 Howe e , he SFMBT1 p o ein seems o be p esen in ana- omical s uc u es in ol ed wi h CSF de elopmen and ci cu- la ion such as he cho oid plexus, he ependymal cell lining o he en icles, and he smoo h muscle and endo helial cells o he a e ies. 13 A CSF ace s udy has e ealed dis u bed CSF ci cula ion and delayed CSF ace clea ance wi hin he b ains o pa ien s wi h iNPH. 6 An inc easing body o e idence links he pa hophysiology behind iNPH o p o- cesses aking place a he glia- ascula in e ace. I has been shown ha pa ien s wi h iNPH showed e idence o al e - a ions in he b ain capilla y ul as uc u e, including al e - a ions in pe icy es and endo helial cells. 29 Fu he mo e, he pe i ascula exp ession o he wa e channel aquapo in-4 (AQP4) was educed in iNPH. 30 Ou s udy has conside able s eng hs including a well- cha ac e ized la ge mul ina ional coho consis ing o bo h shun ed and nonshun ed pa ien s. The mos subs an ial limi a ion in he cu en s udy is ha no heal hy No wegian con ol indi iduals we e a ailable and ha no in e nal alida ion was used. The p e alence o he copy numbe a ian could be diffe en among neu ologically heal hy popula ion. In addi ion, in he cu en s udy, asymp oma ic en iculomegaly was no ou inely e alua ed om he heal hy Finnish con ols. The e o e, i is possible ha he some o he heal hy con ols ha a e ca ie s o he copy numbe loss a ian in SFMBT1 ha e enla ged en icles bu a e asymp oma ic. This migh skew he cu en esul , and he associa ion be ween iNPH and he copy numbe loss in SFMBT1 could be e en s onge han epo ed. Al- hough a s ong associa ion be ween he copy numbe loss in SFMBT1 and iNPH was ound in bo h he Japanese and he Caucasian coho s, he e a e s ill limi a ions o he s udies concen a ing on he copy numbe loss in SFMBT1 and iNPH. Fi s , no na ionwide da a exis on he p e alence o he copy numbe loss in SFMBT1, and he e o e, he con ols used p o ide only a ough es ima ion o he p e alence in he no mal popula ion. Second, he ole o he SFMBT1 gene in he de- elopmen o ca dio ascula diseases needs o be in es iga ed in dep h. In addi ion, he ole o SFMBT1 should be s udied in o he neu odegene a i e diseases o find whe he he gene ic a ia ion in SFMBT1 is unique o iNPH. Thi d, he p esen esul s need s ill o be confi med in la ge mul ina ional coho s bo h in c oss-sec ional and p ospec i e s udy se ings. No mal p essu e hyd ocephalus is di ided in o 3 diffe en g oups: idiopa hic, whe e he e iology is unclea , seconda y when he e is a p edisposing ac o o be ound, and mos ecen ly de ec ed amilial ype, whe e iNPH is seen also in he fi s -deg ee ela i es. 9,11 So a , no diffe ence in he pheno ype has been obse ed be ween iNPH and amilial NPH. Because copy numbe a ia ion o SFMBT1 was no en iched in a- milial iNPH, i does no seem o explain amilial agg ega ion o iNPH, and he e o e, o he gene ic a ia ions a e expec ed o associa e wi h iNPH. The effec o he copy numbe loss in SFMBT1 o he clinical pheno ype should be desc ibed. This migh shed ligh in o he diffe en o ms o iNPH wi h so a undis inguishable pheno ypes. I has been epo ed ha some o he asymp oma ic people wi h en iculomegaly a e ca ie s o he copy numbe loss in SFMBT1. 13 Ven iculomegaly is a key adiologic finding in iNPH, and E ans Index >0.3 is included as a equi emen in he diagnos ic c i e ia o iNPH, 1,2 al hough i has been ecen ly sugges ed ha he cu off alue o en icula enla gemen shouldbe age and sex dependen and he pa hologic lowe limi o E an’s Index inc eased o >0.32. 31 I has been sugges ed ha people who a e asymp oma ic wi h enla ged en icles a e a an inc eased isk o de eloping iNPH, and i has been epo ed Table 4 P e alence o hype ension and diabe es Finnish iNPH pa ien s No wegian iNPH pa ien s SFMBT1 ca ie , n (%) SFMBT1 nonca ie , n(%) pValue (CI 95%) SFMBT1 ca ie , n (%) SFMBT1 nonca ie , n(%) pValue (CI 95%) Hype ension a Yes 29 (52) 309 (61) NS (0.4–1.2) 31 (39) 125 (42) NS (0.5–1.5) No 27 (48) 198 (39) 48 (61) 173 (58) Diabe es b Yes 12 (21) 156 (31) NS (0.3–1.2) 10 (13) 48 (16) NS (0.4–1.6) No 43 (77) 356 (69) 69 (87) 250 (84) Abb e ia ions: CI = con idence in e al; iNPH = idiopa hic no mal p essu e hyd ocephalus. NS: nonsigni ican p> 0.05. p alues a e calcula ed using he Fishe exac es wi hou co ec ion o mul iple es ing. a Da a missing om 4 Finnish pa ien s. b Da a missing om 3 Finnish pa ien s. Neu ology.o g/NG Neu ology: Gene ics | Volume 4, Numbe 6 | Decembe 2018 5 ha in he Japanese popula ion, 25% o people wi h asymp- oma ic en iculomegaly will e en ually de elop iNPH. 32 Howe e , he coho sizes ha e been limi ed in he s udies in which he connec ion be ween AVIM and iNPH has been p oposed. The e o e, no uni e sal consensus on his ma e exis s. The p e alence o he copy numbe loss in SFMBT1 could be inc eased among he amilies in which iNPH is equen ly obse ed, and he e o e, fi s -deg ee ela i es o pa ien s wi h iNPH should be included in u u e gene ic s udies. I migh be ha he copy numbe loss in SFMBT1 is a isk gene o iNPH bu equi es o he unknown igge ing isk ac o s o esul in clinical disease. Fu u e s udies a e s ill u gen ly needed o elucida e he ge- ne ics o iNPH. Unde s anding e en some o he pa hologic p ocesses causing iNPH p o ides possibili ies o de elop a ge ed o e en p e en i e he apies in he u u e. This s udy encou ages unc ional s udies on SFMBT1 o cla i y he ole in he disease p ocess o iNPH. Au ho con ibu ions V.E. Ko honen: s udy concep and design, da a acquisi ion, da a analysis and in e p e a ion, and d a ing o he manu- sc ip . S. Helisalmi: s udy concep and design, da a acquisi- ion, and c i ical e ision o he manusc ip o impo an in ellec ual con en . A. Jokinen, I. Jokinen, J.-M. Leh ola, M. Oinas, K. L¨onn o , C. A ellan, A. Ko kansalo, J. F an zen, J. Rinne, A. Ronkainen, M. Kauppinen, and A. Junkka i: da a acquisi ion and c i ical e ision o he manusc ip o impo - an in ellec ual con en . M. Hil unen and H. Soininen: c i ical e ision o he manusc ip o impo an in ellec ual con en . M. Ku ki: c i ical e ision o he manusc ip o impo an in ellec ual con en (s a is ics). J.E. J¨a¨askel¨ainen, A.M. Koi- is o, H. Sa o H, and T. Ka o: c i ical e ision o he manu- sc ip o impo an in ellec ual con en . A.M. Remes: s udy concep and design and c i ical e ision o he manusc ip o impo an in ellec ual con en . P.K. Eide and V. Leinonen: s udy concep and design, da a acquisi ion, c i ical e ision o he manusc ip o impo an in ellec ual con en , and s udy supe ision. Acknowledgmen The au ho s acknowledge Ma jo Lai inen o he help in se ing up he qPCR me hod and RN Ma i a Pa iainen o managing he KUH iNPH egis e . S udy unding This wo k was suppo ed by he Academy o Finland (no 307866), he Sig id Juselius Founda ion, he Kuopio Uni- e si y Hospi al Resea ch Fund, he Kuopio Uni e si y Hos- pi al VTR und, he Emil Aal onen Founda ion, he Cul u al Founda ion o Finland, he No h Sa o Regional Fund, he Ol i Founda ion, and he Finnish Medical Associa ion. In No way, he s udy was suppo ed by g an s om Heal h Sou h-Eas , No way (g an 2011067). Disclosu e V.E. Ko honen has ecei ed esea ch suppo om he Kuo- pio Uni e si y Hospi al Resea ch Fund, he Mai e Taponen Founda ion, he Uni e si y o Eas e n Finland, he Ol i Founda ion, he Emil Aal onen Founda ion, he Finnish Cul u al Founda ion, he No h Sa o Regional und, and he Finnish Medical Associa ion. S. Helisalmi, A. Jokinen, I. Jokinen, J.-M. Leh ola, M. Oinas, and K. L¨onn o epo no disclosu es. C. A ellan has ecei ed esea ch suppo om he Mai e Taponen Founda ion, Las en au ien u kimuss¨a¨a i¨o, S i elsen Do o hea Oli ia, Ka l Wal e och Ja l Wal e Pe kl´ens minne, and S enska kul u onden. A.E. Ko kansalo epo s no disclosu es. J. F an zen se es/has se ed on he scien ific ad iso y boa d o and as a consul an o Bonali e Bioma e ials L d. J. Rinne, A. Ronkainen, and M. Kauppinen epo no disclosu es. A. Junkka i has ecei ed esea ch sup- po om he s a e esea ch und (VTR), Kuopio Uni e si y Hospi al (KUH), he Uni e si y o Eas e n Finland (UEF), he Finnish Cul u al Founda ion, and he Mai e Taponen Founda ion. M. Hil unen se es/has se ed on he edi o ial boa ds o he Jou nal o Alzheime ’s Disease,Jou nal o Alz- heime ’s Disease & Pa kinsonism, and The Scien ific Wo ld Jou nal. H. Soininen se es/has se ed on he scien ific ad- iso y boa d o AC Immune and se es/has se ed on he edi o ial boa d o he Jou nal o Alzheime ’s Disease. M. Ku ki epo s no disclosu es. J.E. J¨a¨askel¨ainen se es/has se ed on he edi o ial boa d o Ac a Neu ochi u gica; has ecei ed e- sea ch suppo om he Finnish Academy o Sciences, he Juho Vainio Founda ion P¨ai ikki, he Saka i Sohlbe g Foun- da ion, and Kuopio Uni e si y Hospi al. A.M. Koi is o, H. Sa o, T. Ka o, A.M. Remes, and P.K. Eide epo no dis- closu es. V. Leinonen has ecei ed unding o a el and/o speake hono a ia om B. B aun Aesculap; se es/has se ed on he edi o ial boa d o he Jou nal o Alzheime ’s Disease; and has ecei ed esea ch suppo om Neu oVision Imaging, LLC, and Kuopio Uni e si y Hospi al. Full disclosu e o m in o ma ion p o ided by he au ho s is a ailable wi h he ull ex o his a icle a Neu ology.o g/NG. Publica ion his o y Recei ed by Neu ology: Gene ics May 30, 2018. Accep ed in final o m Oc obe 9, 2018. Re e ences 1. Relkin N, Ma ma ou A, Klinge P, Be gsneide M, Black PM. INPH guidelines, pa II: diagnosing idiopa hic no mal-p essu e hyd ocephalus. Neu osu ge y 2005;57:4–16. 2. Mo i E, Ishikawa M, Ka o T, e al. Guidelines o managemen o idiopa hic no mal p essu e hyd ocephalus: second edi ion. Neu ol Med Chi (Tokyo) 2012;52: 775–809. 3. Williams MA, Relkin NR. Diagnosis and managemen o idiopa hic no mal-p essu e hyd ocephalus. Neu ol Clin P ac 2013;3:375–385. 4. Espay AJ, Da P a GA, Dwi edi AK, e al. 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The E ans’Index e isi ed: new cu -offle els o use in adiological assessmen o en icula enla gemen in he elde ly. Eu J Radiol 2017;95:28–32. 32. Iseki C, Kawanami T, Nagasawa H, e al. Asymp oma ic en iculomegaly wi h ea- u es o idiopa hic no mal p essu e hyd ocephalus on MRI (AVIM) in he elde ly: a p ospec i e s udy in a Japanese popula ion. J Neu ol Sci 2009;277:54–57. Neu ology.o g/NG Neu ology: Gene ics | Volume 4, Numbe 6 | Decembe 2018 7