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.
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Neu ology.o g/NG.
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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.
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