RESEARCH ARTICLE
Neu odegene a ion ajec o y in pedia ic and adul /la e
DM1: A ollow-up MRI s udy ac oss a decade
Ga azi Labay u
1,2,3
, An onio Jimenez-Ma in
4,5
, Es he Fe n
andez
6
, Jo ge Villanua
6
,
Mi en Zulaica
2,3
, Jesus M. Co es
4,7,8
, Ibai D
ıez
9,10,11
, Jo ge Sepulc e
9,10
,
Adol o L
opez de Munain
2,3,12,13
& Andone Sis iaga
1,2,3
1
Pe sonali y, Assessmen and psychological ea men depa men ; Psychology Facul y, Uni e si y o he Basque Coun y (UPV/EHU), San
Sebas i
an, Gipuzkoa, Spain
2
Neu oscience A ea, Biodonos ia Resea ch Ins i u e, Osakide za, Donos ia-San Sebas i
an, Gipuzkoa, Spain
3
Cen o de In es igaci
on Biom
edica en Red sob e En e medades Neu odegene a i as (CIBERNED), Ins i u e Ca los III, Mad id, Spain
4
Bioc uces-Bizkaia Heal h Resea ch Ins i u e, Ba akaldo, Bizkaia, Spain
5
Biomedical Resea ch Doc o a e P og am, Uni e si y o he Basque Coun y (UPV/EHU), Leioa, Spain
6
Osa ek, Donos ia Uni e si y Hospi al, Donos ia- San Sebas i
an, Gipuzkoa, Spain
7
Cell Biology and His ology Depa men , Uni e si y o he Basque Coun y (UPV/EHU), Leioa, Spain
8
IKERBASQUE, The Basque Founda ion o Science, Bilbao, Spain
9
Go don Cen e o Medical Imaging, Depa men o Radiology, Massachuse s Gene al Hospi al and Ha a d Medical School, Bos on,
Massachuse s
10
A hinoula A. Ma inos Cen e o Biomedical Imaging, Massachuse s Gene al Hospi al, Ha a d Medical School, Bos on, Massachuse s
11
Neu o echnology Labo a o y, Tecnalia Heal h Depa men , De io, Spain
12
Neu ology Depa men , Donos ia Uni e si y Hospi al, Donos ia- San Sebas i
an, Gipuzkoa, Spain
13
Neu oscience Depa men , Uni e si y o he Basque Coun y (UPV/EHU), Donos ia-San Sebas i
an, Gipuzkoa, Spain
Co espondence
Ga azi Labay u, Uni e si y o he Basque
Coun y, Psychology Facul y, A da. Tolosa,
70. 20018 Donos ia- San Sebas i
an,
Gipuzkoa, Spain. Tel: +00 34 94 301 8382;
Fax: +34 94 301 5670;
E-mail: [email p o ec ed]
Recei ed: 9 Ap il 2020; Re ised: 24 July
2020; Accep ed: 25 July 2020
Annals o Clinical and T ansla ional
Neu ology 2020; 7(10): 1802–1815
Funding In o ma ion
CIBERNED609 Eusko Jau la i zaPRE_
2016_1_0187PRE_2019_1_0070SAIO08-
PE08BF01 Ins i u e o Heal h Ca los III co-
ounded by Fondo Eu opeo de Desa ollo
Regional-FEDERPI17/01231 PI17/01841
doi: 10.1002/acn3.51163
Abs ac
Objec i e: To cha ac e ize he p og ession o b ain s uc u al abno mali ies in
adul s wi h pedia ic and adul /la e onse DM1, as well as o examine he
po en ial p edic i e ma ke s o such p og ession. Me hods: 21 DM1 pa ien s
(pedia ic onse : N =9; adul /la e onse : N =12) and 18 heal hy con ols (HC)
we e assessed longi udinally o e 9.17 yea s h ough b ain MRI. Addi ionally,
pa ien s unde wen neu opsychological, gene ic, and muscula impai men
assessmen . In e -g oup compa isons o o al and oxel-le el egional b ain ol-
ume we e conduc ed h ough Voxel Based Mo phome y (VBM); c oss-sec ion-
ally and longi udinally, analyzing he associa ions be ween b ain changes and
demog aphic, clinical, and cogni i e ou comes. Resul s: The pe cen age o GM
loss did no signi ican ly di e in any o he g oups compa ed wi h HC and
when assessed independen ly, adul /la e DM1 pa ien s and hei HC g oup su -
e ed a signi ican loss in WM olume. Regional VBM analyses e ealed subco -
ical GM damage in bo h DM1 g oups, e ol ing o on al egions in he
pedia ic onse pa ien s. Muscula impai men and he ou comes o ce ain
neu opsychological es s we e signi ican ly associa ed wi h ollow-up GM dam-
age, while isuocons uc ion, a en ion, and execu i e unc ion es s showed
sensi i i y o WM degene a ion o e ime. In e p e a ion: Dis inc pa e ns o
b ain a ophy and i s p og ession o e ime in pedia ic and adul /la e onse
DM1 pa ien s a e sugges ed. Resul s indica e a possible neu ode elopmen al o i-
gin o he b ain abno mali ies in DM1, along wi h he possible exis ence o an
addi ional neu odegene a i e p ocess. F on o-subco ical ne wo ks appea o be
in ol ed in he disease p og ession a young adul hood in pedia ic onse DM1
pa ien s. The in ol emen o a mul imodal in eg a ion ne wo k in DM1 is dis-
cussed.
1802 ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion
This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial-NoDe i s License, which pe mi s use and
dis ibu ion in any medium, p o ided he o iginal wo k is p ope ly ci ed, he use is non-comme cial and no modi ica ions o adap a ions a e made.
In oduc ion
Myo onic Dys ophy ype 1 (DM1) is he mos common
o m o adul muscula dys ophy. I is an au osomal
dominan diso de a ec ing mul iple sys ems. The se e i y
o symp oms a ies acco ding o age o onse , wi h ea lie
onse pa ien s being mo e se e ely a ec ed.
Aside om he known p og essi e na u e o he mus-
cula impai men , many o he clinical symp oms ha e
been sugges ed o be pa o an accele a ed aging p ocess.
CNS s udies wi h a ocus on b ain pa hology ha e de ined
DM1 as a combina ion o auopa hy, spliceopa hy, and
RNAopa hy, all o which con ibu e o neu odegene a-
ion.
1
Fu he mo e, om a neu opsychological pe spec-
i e, ecen indings sugges ha cogni i e unc ions su e
a decline in se e al a eas, beyond ha expec ed in no mal
aging.
2–6
Al hough neu oimaging da a a e hough o suppo
he p e iously sugges ed hypo hesis o neu odegene a i e
p ocesses in DM1, o he bes o ou knowledge, he e
ha e been only wo p e ious a emp s o longi udinally
s udy a hypo hesized p og essi e impai men in b ain
s uc u es. While Gliem e al
7
did no ind a g ea e ol-
ume loss o e ime in DM1 o ei he g ay o whi e ma -
e issue, Con o i e al. ound a p og ession in whi e
ma e lesions along wi h g ea e b ain a ophy assessed
by he en icula /b ain a io.
8
The aim o his s udy was o longi udinally assess he
s uc u al b ain changes o DM1 pa ien s o e a pe iod o
mo e han 9 yea s and o delinea e he pa hway o disease
p og ession. Addi ionally, we aimed o examine he
po en ial gene ic, muscula , clinical, and cogni i e ma k-
e s o his p og ession.
Ma e ials and Me hods
Pa icipan s
The DM1 pa ien s analyzed in his wo k we e selec ed
om hose a ending he Neu ology Depa men o he
Donos ia Uni e si y Hospi al (Gipuzkoa, Spain). Heal hy
con ols (HC) included accompanying ela i es and non-
ela i es o DM1 pa ien s using he se ice.
Inclusion c i e ia o DM1 pa ien s included being
olde han 18 yea s wi h molecula con i ma ion o he
clinical diagnosis. Pa ien s we e excluded i any o he ol-
lowing c i e ia we e me bo h a baseline and a ollow-
up: congeni al o m, his o y o majo psychia ic o
soma ic diso de , acqui ed b ain damage o alcohol o
d ug abuse, p esence o co po al pa amagne ic body
de ices ha could impede an MRI s udy, and he p es-
ence o ce eb al anomalies ha could a ec he olume -
ic analysis. HC pa icipan s we e equi ed o sa is y he
same inclusion c i e ia, excep o he clinical diagnosis.
The DM1 pa icipan s we e classi ied in o wo g oups
acco ding o hei age o onse based on he mos ecen ly
p oposed classi ica ion (OMMYD-4): adul s wi h pedia ic
onse DM1 when age o onse was be ween 1-18 yea s
old, and adul s wi h adul and la e onse DM1 ( om now
on adul /la e DM1) when pa ien s had ei he adul onse
(18-40 yea s old) o la e onse (>40 yea s old).
Figu e 1 shows low cha o he ec ui men p ocess.
F om he heal hy olun ee s wi h a alid MRI a baseline,
only hose whose age, gende and yea s o educa ion we e
equal o closely simila o any e-scanned pa ien we e
in i ed o pa icipa e in o de o o m demog aphically
equi alen g oups. The i s 20 pa icipan s ha ag eed o
be e-scanned we e sui able o o ming wo g oups
equi alen in sex, age, and yea s o educa ion wi h a alid
sample size o pu poses o compa ison wi h each o he
DM1 g oups.
A inal g oup o 21 DM1 pa ien s (9 pedia ic and 12
adul /la e) and one o 18 HC we e included o he analy-
sis. The 18 HC con ols we e hen subdi ided o o m he
wo compa ison g oups: one o compa isons wi h pedi-
a ic onse DM1 (HC-pedia ic: N =12) and one o
compa isons wi h adul /la e onse DM1 (HC-adul /la e:
N=14). The heal hy olun ee s we e included o o m
each con ol g oup in a con olled selec ion p ocess,
ensu ing gende equi alence, and mean age di e ences
be ween g oups o less han 4 yea s, which we e non-sig-
ni ican and wi h small e ec sizes. All pa icipan s we e
in o med o he objec i es and de ails o he s udy and
signed an in o med consen o m. The s udy was
app o ed by he E hics Commi ee o he Donos ia
Uni e si y Hospi al.
Clinical and neu opsychological assessmen
Clinical da a we e ex ac ed om medical eco ds. Addi-
ionally, bo h a baseline and a ollow-up, all pa ien s
we e clinically examined by a neu ologis wi h he Mus-
cula Impai men Ra ing Scale (MIRS)
9
and unde wen a
neu opsychological assessmen .
All pa ien s we e examined by an expe ienced neu-
opsychologis who was blind o he pa ien ’s clinical
condi ion (CTG expansion size, clinical o m, ma e nal
o pa e nal inhe i ance pa e n, muscula impai men ,
and MRI esul s). Neu opsychological assessmen
included he ollowing sub es s om he Wechsle Adul
In elligence Scale III (WAIS III)
10
: Block design, Digi
span, Objec assembly, A i hme ic, Simila i ies and
Vocabula y. An es ima ed IQ sco e was calcula ed om
a wo sub es sho o m (Block design and Vocabula y)
wi h high eliabili y (
xx
=.93) and alidi y ( =.87) based
on Sa le and Ryan.
11
O he cogni i e es s used we e:
ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion 1803
G. Labay u e al.Neu odegene a ion in DM1: A Follow-up MRI S udy
S oop es ,
12
Cali o nia Compu e ized Assessmen Pack-
age (CALCAP),
13
Rey Audi o y Ve bal Lea ning Tes
(RAVLT),
14
phonemic (P) and seman ic (animals) e bal
luency es ,
15,16
Rey-Os e ie h Complex Figu e es
(ROCF),
17
Ra en’s p og essi e ma ices,
18
Ben on’s
Judgemen o Line O ien a ion,
19
and he Wisconsin
Ca d So ing Tes .
20
Raw sco es we e con e ed in o
s anda dized T alues acco ding o Spanish no ms o
each es .
MRI acquisi ion and da a p ep ocessing
MR scanning was conduc ed on a 1.5 Tesla scanne
(Achie a No a, Philips). The cu en esul s a e based on
a high- esolu ion olume ic “ u bo ield echo” (TFE) se -
ies (Sagi al 3D T1 weigh ed acquisi ion, TR =7.2,
TE =3.3, lip angle =8, ma ix =256 x 232, slice hick-
ness 1mm, oxel dimensions o 1mm x 1mm x 1mm,
NSA =1, no slices 160, gap =0, o al scan du a ion 5´
34¨). All he scans, bo h a baseline and a ollow-up,
we e acqui ed on he same MR scanne .
To s udy oxel-based GM olume loss in DM1 pa ien s
and i s associa ion wi h di e en clinical and neu opsy-
chological ou comes, FSL ( e sion 6.01) Voxel Based
Mo phome y (VBM) was used,
21
which is an op imized
VBM p o ocol
22
ca ied ou wi h FSL ools.
23
Fi s , s uc-
u al images we e b ain-ex ac ed and GM-segmen ed
be o e being egis e ed o he MNI 152 s anda d space
using non-linea egis a ion.
24
The esul ing images we e
a e aged and lipped along he x-axis o c ea e a le - igh
symme ic, s udy-speci ic GM empla e. Second, all na i e
GM images we e non-linea ly egis e ed o his s udy-
speci ic empla e and "modula ed" o co ec o local
expansion (o con ac ion) due o he non-linea compo-
nen o he spa ial ans o ma ion. The modula ed GM
images we e hen smoo hed wi h an iso opic Gaussian
ke nel wi h a sigma o 3.
The same VBM p ocedu e was applied o he WM-seg-
men ed images.
To es ima e global GM and WM b ain issue olume,
no malized o subjec head size, he SIENAX ool was
used.
25
Figu e 1. Flow-cha o sample ec ui men om baseline o ollow-up. DM1 =Myo onic Dys ophy Type 1; HC =heal hy con ols.
1804 ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion
Neu odegene a ion in DM1: A Follow-up MRI S udy G. Labay u e al.
S a is ical analysis
Fo all s a is ical analyses lis wise dele ion was used o
deal wi h missing alues. Demog aphic (sex, age a base-
line, age a ollow-up, yea s o educa ion) and clinical
(CTG epea s, inhe i ance pa e n, and MIRS sco e)
da a we e analyzed using he SPSS (IBM SPSS S a is ics
24) s a is ical package. In e -g oup compa isons we e
conduc ed o compa e DM1 pa ien s and HC, as well as
he wo DM1 g oups, using con ingency analysis (Chi-
squa e) o ca ego ical da a and pa ame ic ( - es ) o
non-pa ame ic (Mann–Whi ney U) o in e al da a,
whe e app op ia e. In o de o dismiss he possibili y o
a highe unc ioning sample in he e- es ed g oups (se-
lec i ea i ion), hesameanalyseswe eemployed o
compa e hose pa ien s ha ailed o e- es a ollow-
up and hose who we e e es ed. In a-g oup analysis o
he longi udinal e olu ion o clinical and neu opsycho-
logical da a was conduc ed using he Wilcoxon signed-
ank es .
In o de o add ess he gene al objec i e o his s udy,
h ee main analyses we e ca ied ou (no e ha no di ec
s a is ical compa ison was made be ween pedia ic onse
and adul /la e onse DM1 g oups):
To al GM and WM olume analyses: C oss-
sec ional and longi udinal: In a-g oup and in e -
g oup compa isons
To al GM and WM olume compa isons, bo h in e -
g oup and in a-g oup, we e analyzed using he SPSS
s a is ical package. All analyses we e conduc ed by co -
ec ing he olume wi h he head size. In e -g oup
c oss-sec ional compa isons o o al GM and WM ol-
umes we e conduc ed o compa e DM1 pa ien s and
HC a baseline and a ollow-up, using a pa ame ic -
es ( he da a me he assump ions o pa ame ic es s).
Longi udinal analyses o GM and WM olumes we e
sepa a ely assessed o DM1 pa ien s and HC using he
Wilcoxon signed- ank es . Finally, he pe cen age o
olume loss om baseline o ollow-up in each g oup
was calcula ed and compa isons we e made be ween
each DM1 g oup and hei HC g oup, using a uni a i-
a e ANOVA es co ec ed o ime be ween he baseline
and he ollow-up scan.
Regional GM and WM olume analysis om
baseline o ollow-up: VBM in e -g oup analysis
A gene al linea model was used o compu e he in e -
g oup s a is ical analysis using FSL, con olling o age
and head size. All he esul s we e ob ained using wo-
ailed es s and co ec ed o mul iple compa isons using
he Mon e Ca lo simula ion clus e -wise co ec ion, as
implemen ed in he AFNI so wa e ( e sion 19.3.00)
(h ps://a ni.nimh.nih.go /) wi h 10,000 i e a ions o es i-
ma e he p obabili y o alse posi i e clus e s wi h a P
alue <0.05. Only clus e s o mo e han 50 con iguous
oxels we e epo ed.
Associa ion be ween b ain olume and
demog aphic, clinical, and neu opsychological
ou comes: VBM in a-g oup analysis
To s udy he po en ial p edic i e capaci y o demo-
g aphic, clinical, and neu opsychological a iables a base-
line, h ee sepa a e analyses we e conduc ed.
Fi s , in o de o assess he p edic i e capaci y o
hese a iables a baseline (CTG, MIRS, yea s o educa-
ion, disease inhe i ance, and neu opsychological
sco es) o olume loss ( olume a ia ions be ween ol-
low-up and baseline), pa ial co ela ion analyses con-
olling o age, head size, and ime span om baseline
o ollow-up scan we e conduc ed. The esul s we e
u he co ec ed by mul iple compa isons using he
alse disco e y a e (FDR) s a egy. These analyses we e
conduc ed sepa a ely o pedia ic and adul /la e onse
DM1 g oups.
Second, in o de o assess he p edic i e capaci y o
he same a iables o he image a ollow-up, pa ial
co ela ion analyses we e conduc ed, con olling o
age, head size and ime om baseline assessmen o
ollow-up scan, be ween p edic i e a iables and global
GM and WM olume a ollow-up. These analyses
we e conduc ed sepa a ely o pedia ic and adul /la e
onse DM1 g oups.
Finally, o assess he associa ion be ween he p e ious
a iables and egional GM olume a ollow-up, a gene al
linea model analysis was applied o e alua e he ela ion-
ship be ween GM olume and CTG, MIRS clinical scale,
yea s o educa ion, and inhe i ance pa e n o he disease,
as well as he ou comes o neu opsychological es s. The
esul s we e con olled o age, head size and ime span
be ween he baseline scan and he ollow-up (excep o
neu opsychological a iables, which we e adjus ed o
ime be ween he baseline neu opsychological assessmen
and he ollow-up scan). The s a is ical es s we e wo-
ailed and co ec ed o mul iple compa isons using
Mon e Ca lo simula ions wi h clus e -wise co ec ion
a e 10,000 i e a ions o es ima e he p obabili y o alse
posi i e clus e s wi h a P alue <0.05. A e co ec ions,
a mask was applied using he esul s o he g oup
di e ence o look o any o e lap wi h he egions whe e
DM1 pa ien s show a signi ican GM olume loss
compa ed wi h con ols. Only clus e s o mo e han 50
con iguous oxels we e epo ed. Analyses we e
ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion 1805
G. Labay u e al.Neu odegene a ion in DM1: A Follow-up MRI S udy
conduc ed sepa a ely o pedia ic and adul /la e onse
DM1 g oups.
Resul s
S a is ically signi ican di e ences we e ound be ween he
excluded and he included DM1 pa ien s o he ollowing
a iables: CTG expansion size a baseline ( (34) =3.276; p=
.002, d=1.1) wi h mo e epe i ions in he excluded DM1
(mean =1002.88, SD =432.88) han he included DM1
(mean =534.4, SD =421.21) and MIRS sco e a baseline
(U=45.5; P=0.001; =0.58), wi h he excluded DM1 p e-
sen ing g ea e muscula impai men (mean =3.62,
SD =0.87, mean ank =24.5) han he included DM1
(mean =2.29, SD =0.96 mean ank =13.17). No di e ence
was ound be ween he excluded and he included DM1
pa ien s in e ms o sex, inhe i ance pa e n, yea s o educa-
ion, age, and IQ es ima e.
The demog aphic and clinical cha ac e is ics o he sam-
ple a e summa ized in Tables 1 and 2. None o he DM1
pa ien g oups di e ed om he co esponding HC g oups
in e ms o sex, age a baseline, age a ollow-up o yea s o
educa ion. Pedia ic onse DM1 pa ien s we e signi ican ly
younge and had a g ea e CTG expansion a bo h baseline
and ollow-up compa ed wi h adul /la e onse DM1 pa ien s.
Bo h g oups showed a signi ican inc ease in MIRS sco e
and CTG epea size om baseline o ollow up. The mean
ime om baseline o ollow-up was 9.17 (SD =0.47) yea s
o he comple e sample. Neu opsychological ou comes o
he DM1 g oups a e shown in Supplemen a y Table S1.
Table 1. Baseline and ollow-up demog aphic cha ac e is ics o he sample di ided in o 4 subg oups: pedia ic DM1, adul /la e DM1, HC-pedi-
a ic, HC-adul /la e.
Pedia ic DM1 (N =9) HC-pedia ic (N =12)
S a is ic PE ec sizeMean/N(%) (SD) Mean/N(%) (SD)
Sex
Male 4 (44.4%) 5 (41.7%) X
2
=.016 0.899 V=.028
Female 5 (55.6%) 7 (58.3%)
Age a baseline 30 (6.59) 33.5 (8.32) =1.039 0.312 d=.46
Age a ollow-up 39.67 (6.61) 42.5 (8.06) =0.858 0.401 d=.36
Yea s o educa ion 14.22 (4.26) 18.89 (6.49) U=22.5 0.111 =.35
Adul /la e DM1 (N =12) HC-adul /la e (N =14)
S a is ic PE ec sizeMean/N(%) (SD) Mean/N(%) (SD)
Sex
Male 6 (50%) 8 (57.1%) X
2
=0.133 0.716 V=0.071
Female 6 (50%) 6 (42.9%)
Age a baseline 45.83 (9.05) 43.64 (8.11) =0.651 0.521 d=0.26
Age a ollow-up 55.17 (8.89) 52.71 (8.27) =0.728 0.473 d=0.29
Yea s o educa ion 13.42 (6.68) 17.64 (5.93) =0.976 0.340 d=0.41
Pedia ic DM1 (N =9) Adul /la e DM1 (N =12)
S a is ic PE ec sizeMean/N(%) (SD) Mean/N(%) (SD)
Sex
Male 4 (44.4%) 6 (50%) X
2
=0.064 0.801 V=0.055
Female 5 (55.6%) 6 (50%)
Age a baseline 30 (6.59) 45.83 (9.05) =4.427 0.000 d=1.95
Age a ollow-up 39.67 (6.61) 55.17 (8.89) =4.387 0.000 d=1.93
Inhe i ance
Ma e nal 6 (66.7%) 3 (27.3%) X
2
=3.104 0.078 V=0.394
Pa e nal 3 (33.3%) 8 (72.7%)
CTG a baseline 851.89 (444.77) 362.83 (325.54) =2.916 0.009 d=1.29
CTG a ollow-up 1044.44 (444.43) 500.75 (504.03) U=21.500 0.021 =0.05
MIRS a baseline 2,56 (0.88) 2.08 (1) U=41.000 0.382 =0.22
MIRS a ollow-up 3.11 (1.17) 2.67 (1.37) U=46.500 0.602 =0.12
No e: DM1: Myo onic Dys ophy Type 1; HC: Heal hy con ols; SD: S anda d De ia ion. Desc ip i e da a a e shown as mean and SD o age a
baseline, age a ollow-up and yea s o educa ion. F equency (N) and pe cen age (%) a e shown only o sex.
1806 ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion
Neu odegene a ion in DM1: A Follow-up MRI S udy G. Labay u e al.
To al GM and WM olume analyses: c oss-
sec ional and longi udinal: In a-g oup and
in e -g oup analyses
Wi h ega d o c oss-sec ional compa isons o b ain ol-
ume, pa ien s in he pedia ic onse g oup p esen ed lowe
olumes o bo h GM and WM compa ed wi h con ols, bo h
a baseline and a ollow up. Con e sely, he adul and la e
onse g oup ob ained lowe olumes only o GM when
compa ed wi h con ols (Table 3). Longi udinal analyses o
GM and WM olume loss o e ime showed ha none o he
g oups su e ed a signi ican dec ease in GM olume, and
only adul /la e DM1 pa ien s and hei HC g oup su e ed a
signi ican loss in WM olume. None heless, when compa -
ing he longi udinal a ia ions be ween g oups, he pe cen -
age o olume loss did no di e be ween pedia ic onse
DM1 and hei con ols, o be ween adul /la e onse DM1
and hei con ols. Howe e , he global GM olume dec ease
in he pedia ic g oup eached 3.86% compa ed wi h a
0.63% dec ease in HC, and, despi e being non-signi ican ,
he e ec size was la ge (ES =0.94). Simila ly, a medium
e ec size (ES =0.57) was ound o he di e ence be ween
he pe cen age o GM olume loss in adul /la e onse DM1
(2.71%) and HC-adul /la e (0.85%). Acco dingly, mode a e
e ec sizes we e ound in pa ien s’ GM olume loss when
in a-g oup analyses we e conduc ed o bo h pedia ic and
adul /la e onse pa ien s ( =0.43 and =0.4, espec i ely).
Regional GM and WM olume analysis om
baseline o ollow-up: VBM in e -g oup
analysis
Resul s om he GM VBM analyses a e depic ed in Fig-
u e 2 (and Supplemen a y Tables S2, S3, and S4 o a
de ailed epo on signi ican clus e s). A baseline, a eas
whe e pedia ic onse DM1 showed a dec ease in GM ol-
umes compa ed wi h he HC-pedia ic g oup we e he
bila e al halamus, cauda e, pu amen, pa ahippocampal
gy us, igh hippocampus, igh lingual gy us, le
Rolandic ope culum, le middle and supe io empo al
gy us, le Heschl’s gy us, le pa ie al ope culum, le
sup ama ginal gy us, and le pos cen al gy us. A ol-
low-up, hese a eas we e s ill dec eased in pa ien s and,
addi ionally, new co ical a eas we e in ol ed, pa icula ly
he le p ecen al gy us, bila e al in e io on al gy us
( iangula pa and o bi al pa ), igh in e io on al
gy us (ope cula pa ), bila e al pa ie al ope culum, and
le insula. Adul /la e onse DM1 pa ien s a baseline
showed GM dec ease in he bila e al cauda e, pu amen
and halamus and le insula in compa ison wi h he HC-
adul /la e g oup, and a ollow-up, hese a eas expanded
o adjacen egions such as he igh hippocampus and
pa a-hippocampal gy us, oge he wi h he ce ebellum.
Addi ionally, a dec ease was ound in he HC-adul /la e
g oup compa ed wi h adul /la e onse DM1 pa ien s,
loca ed a baseline in he ollowing a eas o he le hemi-
sphe e: in e io , middle and supe io empo al gy i, mid-
dle and supe io empo al poles, usi o m gy us, in e io
and middle on al gy i (o bi al pa ), pa ahippocampal
gy us, and he ce ebellum. A ollow-up, a signi ican
dec ease emained in only some o hese a eas in he HC-
adul /la e g oup compa ed wi h adul /la e DM1 pa ien s,
again in he ollowing egions o he le hemisphe e: he
middle and supe io empo al lobes, usi o m gy us, and
he pa ahippocampal gy us.
Resul s om WM VBM analysis a e shown in Supple-
men a y Tables S5 and S6. A baseline, a eas whe e pedi-
a ic onse DM1 showed a dec ease in WM olumes
compa ed wi h he HC-pedia ic g oup we e he bila e al
pos e io limb o in e nal capsule, le e olen icula pa
o in e nal capsule and bila e al ce eb al peduncle. A ol-
low-up, hese a eas we e s ill dec eased in pa ien s and,
addi ionally, new a eas we e in ol ed: le an e io co ona
adia a, le sagi al s a um, le o nix and s ia e mi-
nalis and igh e olen icula pa o in e nal capsule.
Adul /la e onse DM1 pa ien s a baseline showed WM
dec ease in he igh an e io co ona adia a and he genu
o co pus callosum. A ollow-up, hese a eas we e s ill
Table 2. Longi udinal e olu ion o clinical ea u es in pedia ic DM1 and adul /la e DM1 g oups.
N
Baseline Follow-up
S a is ic P
E ec
sizeMean (SD) Mean (SD)
Pedia ic DM1
CTG 9 851.89 (444.77) 1044.44 (444.43) =3.181 0.013 d=1.5
MIRS 9 2.56 (0.88) 3.11 (1.17) =3.162 0.013 d=.75
Adul /la e DM1
CTG 12 362.83 (325.54) 500.75 (504.03) Z=2.31 0.021 =.47
MIRS 12 2.08 (0.99) 2.67 (1.37) Z=2.33 0.020 =.48
No e: DM1: Myo onic Dys ophy Type 1; HC: Heal hy con ols; SD: S anda d De ia ion.
ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion 1807
G. Labay u e al.Neu odegene a ion in DM1: A Follow-up MRI S udy
Table 3. C oss-sec ional (in e -g oup) and longi udinal (in a-g oup and in e -g oup) compa isons o GM and WM olume.
N
Mean SD
DM1 e sus
HC Mean SD
DM1
e sus
HC
In a-g oup Follow-
up - Baseline
In e g oup compa ison o pe cen age o olume
loss
ZPMean FPg
Hedges
Baseline Follow-up
Pedia ic DM1 e sus
HC-pedia ic
GM olume =4.208 =5.071
DM1 9 728492.55 (59435.88) p=0.000 703854.60 (53407.41) P=0.000 1.836 0.066 3.86
¶
3.497 0.078 0.94
HC 12 829069.52 (50050.01) d=1.86 819800.71 (50693.01) d=2.24 1.569 0.117 0.63
¶
WM olume
DM1 9 656340.98 (45830.39) =4.334 658010.04 (28468.26) =4.643 0.296 0.767 0.25
¶
0.097 0.759 0.16
HC 12 721993.51 (22597.64) p=0.000 712342.09 (25040.87) p=0.000 1.412 0.158 0.77
¶
d=1.91 d=2.05
Adul /la e DM1
e sus HC-adul /la e
GM olume =2.172 =2.324
DM1 12 756500.85 (42058.37) p=.040 737651.22 (52119.48) p=0.029 1.961 0.050 2.71
$
1.721 0.203 0.57
HC 14 787456.64 (30440.24) d=.85 779936.16 (40616.75) d=0.91 1.475 0.140 0.85
$
WM olume
DM1 12 703532.11 (40638.08) =1.582 685715.24 (36237.65) =1.256 3.059 0.002 2.63
$
0.106 0.748 0.14
HC 14 727201.95 (35684.99) p=0.127 704947.47 (41037.58) p=0.221 2.856 0.004 2.97
$
d=0.62 d=0.49
No e: DM1: Myo onic Dys ophy Type 1; HC: Heal hy con ols; SD: S anda d De ia ion. Longi udinal in e -g oup compa isons o pe cen age o olume loss a e calcula ed using ime o ollow-up
as a co a ia e.
¶
Co a ia e alue: 9.1624.
$
Co a ia e alue: 9.0973.
1808 ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion
Neu odegene a ion in DM1: A Follow-up MRI S udy G. Labay u e al.
dec eased in pa ien s and, addi ionally, new a eas we e
in ol ed: le an e io co ona adia a, bila e al supe io
co ona adia a, body o co pus callosum and le supe io
longi udinal asciculus.
Associa ion be ween b ain olume and
demog aphic, clinical, and
neu opsychological ou comes: VBM in a-
g oup analysis
Fo pedia ic and adul /la e onse DM1 pa ien s, none o
he clinical (MIRS sco e, CTG expansion size, inhe i ance
pa e n) o demog aphic (yea s o educa ion) a iables a
baseline we e signi ican ly associa ed wi h he pe cen age
o GM and WM olume loss om baseline o ollow-up.
Howe e , among he neu opsychological es s, he ROCF
copy and wo CALCAP measu es (Sequen ial 1 eac ion
ime (RT) and Sequen ial 2 RT) we e posi i ely co ela ed
wi h he pe cen age o WM olume loss only in adul /la e
onse DM1 pa ien s (Figu e 3). Lowe sco es on neu-
opsychological es s we e associa ed wi h a g ea e pe -
cen age o o al WM olume loss.
No associa ion was ound be ween any clinical, demo-
g aphic, o neu opsychological a iable wi h he o al GM
and WM olume a ollow-up in ei he DM1 g oup.
Howe e , he ou comes o some neu opsychological es s
we e signi ican ly co ela ed wi h speci ic egions o
educed GM and WM a ollow-up. In he pedia ic onse
DM1 g oup he esul s we e inconclusi e due o he
educed sample size a ailable in mos o he neu opsycho-
logical es s, which s ongly a ec ed he sensi i i y o he
s a is ical p ocedu e. Only he esul s o he S oop ask
(colo -wo d and in e e ence) we e egionally co ela ed
wi h dec eased GM a ollow-up (da a no shown).
Resul s in he adul /la e onse g oup o GM a e shown
in Supplemen a y Figu e S1 (see Supplemen a y Table S7
o a de ailed epo on signi ican clus e s) and o WM
in Supplemen a y Table S8. To ocus on he associa ion
be ween neu opsychological ou comes and a ec ed b ain
GM a eas, he egions de ined by he ollow-up mask o
g oup di e ences be ween adul /la e DM1 and HC-adul /
la e a e indica ed by black anspa en shading.
The MIRS scale was he only clinical a iable ha sig-
ni ican ly co ela ed wi h lowe GM and WM olume a
ollow-up. The speci ic a eas whe e lowe GM olumes a
ollow-up we e associa ed wi h he MIRS sco e we e he
bila e al pu amen, halamus, le cauda e, igh amygdala,
hippocampus, le ol ac o y co ex, igh an e io cingu-
lum, le Rolandic ope culum, le supe io empo al
gy us, le Heschl’s gy us, le pa ie al ope culum (pa icu-
la ly he OP4 a ea), le sup ama ginal gy us, le pos cen-
al gy us, igh medial and supe io on al o bi al gy us
Figu e 2. Voxel-Based Mo phome y analyses showing signi ican ly dec eased egions in pa ien s compa ed wi h HC a bo h baseline (blue) and
ollow-up ( ed). The depic ed egions a e hose ha su i ed mul iple compa isons adjus ed o age and b ain size. Panel 2A) shows he masks
whe e pedia ic onse pa ien s ob ained lowe g ay ma e alues han hei co esponding HC-pedia ic g oup. Panel 2B) shows he masks whe e
adul /la e onse pa ien s had lowe g ay ma e alues han hei co esponding HC-adul /la e g oup. The mask a baseline is ep esen ed wi h
anspa ency in o de o isualize he a eas o o e lap be ween baseline and ollow-up (da k blue and da k b own) and he non-o e lapping a eas
(ligh blue and ligh b own).
ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion 1809
G. Labay u e al.Neu odegene a ion in DM1: A Follow-up MRI S udy
and bila e al gy us ec us. The speci ic a eas whe e lowe
WM olumes a ollow-up we e associa ed wi h he MIRS
sco e we e he le an e io co ona adia a, bila e al supe-
io co ona adia a, body o co pus callosum and igh
supe io longi udinal ascisulus (see Figu e 4 and Supple-
men a y Table S9 o a de ailed epo on signi ican clus-
e s on GM and Supplemen a y Table S10 o WM).
Discussion
This s udy es s he hypo hesis o a neu odegene a i e p o-
cess in DM1, examining o he i s ime, he di e en p o-
iles o s uc u al b ain in ol emen in pedia ic and adul /
la e DM1. Fo his pu pose, he same pa ien s and con ols
we e ollowed ac oss a imespan o almos a decade.
Figu e 3. Pa ial co ela ion analyses o neu opsychological T sco es wi h pe cen age o WM olume loss om baseline o ollow-up in adul /la e
onse DM1 pa ien s. Only he esul s ha su i ed a alse disco e y a e (FDR) co ec ion a e p esen ed.
Figu e 4. G ay ma e (GM) olume dec ease a ollow-up associa ed wi h MIRS sco e o adul /la e DM1 pa ien s a baseline. The T-s a is ic
showing he ela ionship be ween GM olume and MIRS sco e is displayed. Only esul s su i ing mul iple compa isons a e shown, co ec ing o
age, head size, and ime om baseline assessmen o ollow-up scan. A black- anspa ency mask is displayed o show he damage mask o adul /
la e onse DM1 compa ed wi h HC-adul /la e a ollow-up.
1810 ª2020 The Au ho s. Annals o Clinical and T ansla ional Neu ology published by Wiley Pe iodicals LLC on behal o Ame ican Neu ological Associa ion
Neu odegene a ion in DM1: A Follow-up MRI S udy G. Labay u e al.
