Cha ac e iza ion o isual cogni ion
in p e-mani es , mani es and
educed pene ance Hun ing on’s
disease
Rocio Del Pino1, Ma ia Ángeles Ace a1, Amaia O iz de Eche a ía1, Bea iz Tije o1,2,
Ma a Ruiz-Lopez1,2, Johanne Somme3, Ja ie Ruiz-Ma ínez5, And ea Gabilondo4,5,
Ioana M. C oi o u5, La a Pa dina5, Naia Ayo-Men xaka o e1, Ane Mu ue a-Goyena1,6,
Iñigo Gabilondo1,2,7, Rosa io Sanchez-Pe nau e1,7, Tama a Fe nández-Valle1,2,6 &
Juan Ca los Gómez Es eban1,2,6
Cogni i e and isual impai men a e common in Hun ing on’s Disease (HD) and may p ecede mo o
diagnosis. We in es iga e he ea ly p esence o isual cogni i e de ici s in 181 pa icipan s, including
HD ca ie s (40 p e-mani es , 30 ea ly mani es , 27 mani es , and 6 educed pene ance) and 78 heal hy
con ols (HC). Signi ican di e ences in isual memo y we e obse ed be ween educed pene ance
and p e-mani es g oups (p = .003), wi h p e-mani es showing wo se pe o mance. Age, educa ion,
CAG epea s, mo o s a us, execu i e unc ion, and e bal luency, accoun ed o up o 72.8% o he
a iance in gene al and isual cogni i e unc ions, wi h mo o s a us ha ing he s onges impac on
isual domains in HD ca ie s. In p e-mani es HD, isual cogni i e domains we e p ima ily in luenced
by execu i e unc ion, e bal luency, age, and CAG epea s, while in ea ly and mani es s ages mo o
s a us and e bal luency becomes mo e in luen ial. ROC analyses showed ha especially isuospa ial
abili ies, isual memo y, and isual a en ion (AUC = 0.927, 0.878, 0.874, espec i ely) e ec i ely
di e en ia ed HC and p e-mani es om ea ly and mani es HD. Ea ly assessmen o isual cogni i e
domains, pa icula ly isual memo y, could be an ea ly ma ke o cogni i e decline in HD. Ou indings
highligh he di e en p o iles o impai men in isual cogni ion ac oss HD ca ie s.
Keywo ds Hun ing on disease, Cogni ion, P e-mani es , Reduced pene ance, Visual cogni ion
Hun ing on’s Disease (HD) is a a e, au osomal dominan neu odegene a i e diso de caused by an expansion
o cy osine-adenine-guanine (CAG) epea s (> 35 epea s) in he Hun ing in (HTT) gene1,2. HD p ima ily
mani es s as an adul -onse diso de 3, and is cha ac e ized by a complex symp oma ology in ol ing p og essi e
mo o and cogni i e impai men , along wi h psychia ic symp oms, due o neu onal loss in he b ain2,4. The
diagnosis elies p ima ily on he p esence o mo o symp oms; howe e , non-mo o symp oms may appea be o e
clinical diagnosis. The numbe o CAG epea s is he p ima y ac o de e mining he a e o s ia al pa hology
p og ession, wi h indi iduals ha ing 40 o mo e CAG epea s de eloping HD du ing hei li e ime. S udies ha e
also iden i ied a ange o 36–39 CAG epea s, e e ed o as “ educed o incomple e pene ance” alleles, whe e
symp oms may appea la e in li e o no a all5,6. Howe e , he ac o s con ibu ing o his a iabili y emain
unclea , and p io s udies ha e been unable o p ecisely es ima e he pene ance isk7. Indi iduals wi h 40 o
mo e CAG epea s who do no ye mee he clinical c i e ia o HD a e o en e e ed o as p e-symp oma ic o
p e-mani es HD8,9.
Cu en ly, he e is no cu e o HD, and he disease ypically p og esses o e 15–20 yea s om onse , wi h
diagnosis p ima ily based on mo o impai men 1,10. Howe e , ecen li e a u e inc easingly sugges s ha he
1Neu odegene a i e Diseases G oup, Biobizkaia Heal h Resea ch Ins i u e, Plaza de C uces 12, Ba akaldo (Bizkaia),
Ba akaldo CP 48903, Spain. 2Neu ology Depa men , C uces Uni e si y Hospi al, Osakide za, Ba akaldo, Spain.
3Neu ology Depa men , A aba Uni e si y Hospi al, Vi o ia-Gas eiz, Spain. 4Ou pa ien Men al Heal h Ne wo k o
Gipuzkoa, San Sebas ián, Spain. 5Neu ology Depa men , Donos ia Uni e si y Hospi al, San Sebas ián, Gipuzkoa,
Spain. 6Depa men o Neu oscience, Uni e si y o he Basque Coun y (Uni e sidad del Pais Vasco/Euskal
He iko Unibe si a ea), Leioa, Spain. 7The Basque Founda ion o Science, IKERBASQUE, Bilbao, Spain. email:
[email p o ec ed]
OPEN
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onse o mo emen diso de alone does no ully ep esen he spec um o HD. The symp oms a e complex and
a y signi ican ly among CAG expansion ca ie s, in oducing unce ain y ega ding he appea ance o speci ic
signs, age o onse 2, and disease se e i y11.
Cogni i e impai men and isual abno mali ies a e common and unc ionally debili a ing in HD gene
ca ie s2,8,12, and o en appea be o e HD mo o diagnosis10. In ac , e inal hickness has po en ial as a good
bioma ke o cogni i e impai men in mani es HD, wi h a educ ion o pe ipapilla y e inal ne e ibe laye
hickness obse ed ega dless o disease s age13–15. In e ms o cogni ion, HD- ela ed decline p ima ily in ol es
p og essi e impai men in execu i e unc ion16–18, which is associa ed wi h educed unc ional capaci y and,
consequen ly, a decline in quali y o li e. As well as de ici s in a en ion and concen a ion, wo sened wo king
memo y, slowed psychomo o speed, language de ici s and impai ed language skills. Social cogni ion is also
a ec ed, leading o challenges in unde s anding and in e p e ing social cues, emo ions, and ela ionships19.
Execu i e dys unc ion in HD also includes impai men s in a en ion, ini ia ing and planning ac i i ies,
o ganiza ional skills, p oblem-sol ing, decision-making, and cogni i e lexibili y, ul ima ely leading o di icul ies
in managing daily li e ac i i ies16. Indi iduals wi h HD o en ace challenges in s a ing and comple ing complex
asks, managing hei ime, and o ganizing hei hough s. They may also s uggle wi h accu a ely assessing
isks, leading o poo decision-making19. The deg ee and p og ession o cogni i e impai men in HD can a y
among indi iduals, bu cogni i e decline is gene ally obse ed o e ime as he neu odegene a ion associa ed
wi h HD ad ances. Cogni i e impai men can appea 10 o 15 yea s p io o he onse o mo o symp oms20,
and he e is inc easing e idence ha de ici s in isual cogni i e domains may se e as ea ly indica o s o
cogni i e decline in HD. This highligh s he impo ance o ecognizing and assessing hese isual cogni i e
impai men s, which can p ecede he clinical diagnosis o HD and signi ican ly a ec gene ca ie s. Howe e ,
he e m ‘ isual cogni ion’ is a ely used and no well-de ined21. Visual cogni ion encompasses complex men al
p ocesses engaged in in e p e ing, analysing, and comp ehending isual in o ma ion om ou su oundings.
Visual cogni ion is essen ial o he o ma ion o men al ep esen a ions o he isual en i onmen and o
he ex ac ion o signi ican in o ma ion om isual s imuli22,23. I encompasses a ious cogni i e unc ions,
including: isual a en ion ( he abili y o ocus on speci ic isual in o ma ion while il e ing ou dis ac ions);
isual pe cep ion ( he abili y o ecognize and in e p e isual s imuli, such as shapes, colo s, and mo ion);
isual memo y ( e ain and ecall isual in o ma ion, which can include isual images, spa ial ela ionships, and
pa e ns); isuospa ial abili ies (unde s anding he loca ion and mo emen o objec s in ela ion o onesel and
each o he ); isual p oblem-sol ing (using isual in o ma ion o analyze si ua ions, make decisions, and sol e
p oblems). The e o e, isual cogni ion plays a c ucial ole in how indi iduals in e ac wi h and unde s and hei
isual en i onmen , in luencing ac i i ies such as eading, na iga ing spaces, and ecognizing aces.
Neu opsychological s udies assessing isual cogni i e unc ion in HD ha e epo ed impai men s in se e al
s uc u es and ne wo ks in ol ed in he key s eps o isual in o ma ion pe cep ion and p ocessing. Speci ically,
hese s udies ha e iden i ied de ici s in asks ela ed o isual objec pe cep ion, acial emo ion ecogni ion,
isuospa ial p ocessing, and isual wo king memo y22,24. Changes in he isual co ex and isual cogni i e
de ici s ha e been epo ed in ea ly mani es HD gene ca ie s, bu no in p e-mani es gene ca ie s25. Al hough,
cogni i e decline is a well-known non-mo o symp om o HD associa ed wi h educed unc ional capaci y—
in e e ing wi h pa ien s’ wo k and social li es and subsequen ly wo sening hei quali y o li e— u he esea ch
is needed o unde s and isual cogni i e impai men s in p e-mani es HD. I is essen ial o iden i y which
speci ic cogni i e a eas a e mos a ec ed in his popula ion. Explo ing isual cogni ion also in he educed
pene ance ange is pa icula ly impo an , as i may p o ide insigh s in o he isk o pheno-con e sion26. This
in o ma ion can enhance gene ic counseling and in o m he apeu ic op ions when hey become a ailable. We
aimed o in es iga e he ea ly p esence o isual cogni i e de ici s in HD ca ie s ac oss he en i e spec um,
including p e-mani es , ea ly mani es , mani es HD, and pa icipan s wi h educed pene ance, compa ed o
heal hy con ols (HC).
Me hods
S udy design and Pa icipan
A o al o 181 pa icipan s we e ec ui ed, di ided in o 5 g oups: 40 p e-mani es HD, 30 ea ly mani es HD
(disease du a ion < 5 yea s om he diagnosis), 27 mani es HD (disease du a ion > 5 yea s om he diagnosis),
6 wi h educed pene ance (CAG epea ange o 36–39 CAG), and 78 HC. S udy subjec s we e mainly ec ui ed
in he Depa men o Neu ology o C uces Uni e si y Hospi al, bu also in A aba Uni e si y Hospi al and
Donos ia Uni e si y Hospi al (Spain). The HC g oup was ec ui ed h ough wo d o mou h, he Hun ing on’s
Disease Associa ion o Bizkaia (ASHUBI), and amily and iends o pa ien s who did no ca y pa hological
CAG epea s.
The inclusion c i e ia we e he ollowing: (1) Age > 18 yea s; (2) Volun a y pa icipa ion and signing he
in o med consen om; (3) Being able o ead and w i e; (4) In he case o gene ic ca ie s, ha ing a gene ic
es ha indica es he numbe o CAG epea s; (5) Classi ica ion o pa icipan s as p e-mani es (no clinical-
mo o HD diagnose bu a posi i e gene ic es ), ea ly mani es (disease du a ion < 5 yea s om he diagnosis),
mani es HD pa ien s (disease du a ion > 5 yea s om he diagnosis), and educed pene ance g oup (CAG
epea ange o 36–39). The exclusion c i e ia we e as ollows (1) P e ious his o y o physical o men al disease
ha signi ican ly comp omised he cogni i e unc ion o he pa ien ; (2) Visual o hea ing limi a ion ha could
no be compensa ed wi h glasses o hea ing aids; (3) Signi ican his o y o alcohol o d ugs abuse; (4) Lack o will
o incapaci y o he pa icipan o collabo a e wi h he s udy.
Clinical and neu opsychological assessmen
The clinical e alua ion p o ocol consis ed o measu ing: (1) Mo o s a us wi h he Uni ied Hun ing on’s Disease
Ra ing Scale (UHDRS)27; (2) Cogni i e gene al s a us wi h he Mon eal Cogni i e Assessmen (MoCA)28,29;
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(3) Visual A en ion wi h S oop Tes (Wo d, Colo , Wo d-Colo )30and T ail Making Tes (TMT)31–33pa A; (4)
Visual P ocessing speed and isual pe cep ion wi h he Sal house Pe cep ual Compa ison Tes (SPCT)34,35and
Symbol Digi Modali ies Tes (SDMT)33,36; (5) Visuospa ial abili ies wi h Visual Objec and Space Pe cep ion
Ba e y (VOSP)37cubes and do coun ing, G oo ed Pegboa d es (GPT)38, and Ben on Judgmen o Line
O ien a ion (BJLO)39,40; (6) Visual memo y wi h he Taylo Complex Figu e (TCF)41and he B ie Visuospa ial
Memo y Tes -Re ised (BVMT-R)42,43; (7) Execu i e unc ion wi h Modi ied Wisconsin Ca d So ing Tes
(M-WCST)44,45and TMT pa B; (8) Ve bal luency wi h he FAS Wo d Fluency and le e P46. Supplemen a y
Table 1 p esen s he assessmen p o ocol as well as he cogni i e unc ions. Howe e , i is impo an o no e ha ,
in neu opsychology, each es measu es mo e han one cogni i e domain simul aneously, which is a c i ical
conside a ion. Fo his eason, we conduc ed a con i ma o y ac o analysis o ensu e ha he measu es assessed
he cogni i e domains o in e es .
S a is ical analysis
S a is ical analyses we e ca ied ou using IBM SPSS S a is ics o Windows, e sion 20.0 (IBM-SPSS, A monk,
New Yo k) o all he analysis excep o he con i ma o y ac o analysis (CFA) o which he la aan package
(Rosseel, 2012) o he R s a is ical p og am (Co e Team 2021) was used. The assump ions o no mali y and
homogenei y o a iances o he a iables we e analyzed. Desc ip i e analyses we e pe o med o he mean and
s anda d de ia ion o each a iable. The sco es o T ail Making es (TMT) pa A and B, G oo ed Pegboa d Tes
ime, Modi ied Wisconsin Ca d So ing Tes (M-WCST) pe se e a i e and o al e o s we e in e ed. Cogni i e
composi es we e c ea ed by a e aging z-sco es o cogni i e es s in each domain [ isual a en ion: TMT-A
(in e ed), S oop Wo d, S oop Colo and S oop Wo d-Colo ; isual p ocessing speed/ isual pe cep ion:
Sal house Pe cep ual Compa ison Tes , Symbol Digi Modali ies Tes ; Visuospa ial abili ies: G oo ed Pegboa d
es , Visual pe cep ion wi h Visual Objec and Space Pe cep ion Ba e y (VOSP cubes and do -coun ing), Taylo
Complex Figu e-copy, Ben on Judgmen o Line O ien a ion; Visual Memo y: B ie Visuospa ial Memo y
Tes - e ised (BVMT-R o al sco e and delayed ecall), Taylo Complex Figu e-memo y; Execu i e Func ions:
Modi ied Wisconsin Ca d So ing Tes (M-WCST o al ca ego ies, pe se e a i e e o s and o al e o s), TMT
Pa B; Ve bal luency: le e s F, A, S, and P]. Con i ma o y ac o analysis was pe o med using he o al sample
o e i y he cons uc alidi y o hese 6 cogni i e domains ( isual a en ion, isual p ocessing speed/ isual
pe cep ion, isuospa ial abili ies, isual memo y, execu i e unc ions, and e bal luency) (Fig.1). The model
p esen ed adequa e i alues: Compa a i e Fi Index (CFI) = 0.90, Tucke -Lewis Index (TLI) = 0.88, and Roo
Mean Squa e.
One-way ANOVA and Tukey’s HSD Tes o mul iple compa isons we e pe o med o he sociodemog aphic
and clinical da a o in es iga e he di e ences be ween g oups. One-way ANCOVA, wi h age as co a ia e, was
conduc ed o pos hoc analysis o mo o s a us and cogni ion o compa e he di e ences be ween g oups.
Fig. 1. Con i ma o y ac o analysis o cogni i e domains. No e: Visual a en ion [TMT (T ail Making Tes )
pa A, S oop Wo d, S oop Colo , S oop Wo d-Colo ]; Visual p ocessing speed/ isual pe cep ion [Sal house
Pe cep ual Compa ison Tes (SPCT), Symbol Digi Modali ies Tes (SDMT)]; Visuospa ial abili ies: [G oo ed
Pegboa d es (GPT), Visual pe cep ion wi h Visual Objec and Space Pe cep ion Ba e y (VOSP cubes and
do -coun ing), Taylo Complex Figu e (TFC copy), Ben on Judgmen o Line O ien a ion (BJLO)]; Visual
Memo y: [B ie Visuospa ial Memo y Tes - e ised (BVMT-R o al sco e and delayed ecall), TFC memo y];
Execu i e Func ions: [Modi ied Wisconsin Ca d So ing Tes (M-WCST o al ca ego ies, pe se e a i e e o s
and o al e o s), TMT Pa B]; Ve bal luency: le e s F, A, S, and P.
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A s epwise linea eg ession (excluding he HC g oup) was ca ied ou o analyze he pe cen age o a iance
explained by age, yea s o educa ion, CAG epea s, mo o s a us (measu ed wi h he UHDRS), execu i e
unc ions, and e bal luency ac oss he ollowing isual cogni i e domains: isual a en ion, isual p ocessing
speed/ isual pe cep ion, isuospa ial abili ies, isual memo y. Fo he execu i e unc ions and e bal luency, we
also pe o med a s epwise linea eg ession including age, yea s o educa ion, CAG epea s, and mo o s a us as
p edic o s.
The ecei e -ope a ing cha ac e is ic (ROC) cu e analysis was used as a me hod o e alua e he abili y o
he cogni i e measu es o classi y and disc imina e be ween HC and mani es HD pa ien s (including bo h ea ly
mani es and mani es g oups), p e-mani es HD s. mani es HD (ea ly mani es and mani es g oups), and HC
and P e-mani es HD.
Resul s
The gene al clinical cha ac e is ics o pa icipan s a e p esen ed in Table1. The pa icipan s we e p edominan ly
emale (56%). The mean age and educa ion o he o al sample we e 49.8 ± 12.0 yea s and 12.7 ± 3.7 yea s,
espec i ely. S a is ically signi ican di e ences we e ound be ween g oups in age (F = 4.9; p = .001), and he
numbe o CAG epea s (F = 14.0; p < .001). The p e-mani es g oup was younge han he o he g oups and he
mani es g oup who had he highes numbe o CAG epea s (44.1 ± 3.0). No di e ences we e ound be ween
g oups in educa ion o in age a onse o i s symp oms. As expec ed, he mani es HD g oup had highe mo o
impai men in he UHDRS (42.0 ± 21.7) compa ed o ea ly mani es HD pa ien s (25.0 ± 14.1, p < .001). We did
no ind s a is ical di e ences in gene al cogni ion (MoCA), nei he in he di e en isual cogni i e unc ions
be ween HC, educed pene ance and p e-mani es g oups, excep o isual memo y ha he e we e signi ican
di e ences be ween educed pene ance and p e-mani es (p = .003), and also ma ginal signi ican di e ences
be ween HC and educed pene ance (p = .074). Addi ionally, isual memo y was he only cogni i e domain ha
he e we e no signi ican di e ences be ween ea ly mani es and mani es (Table2; Fig.2. See supplemen a y
Table 2 o he aw da a o he cogni i e measu es).
P edic ed ac o s in gene al and isual cogni ion ac oss HD ca ie s
Acco ding o he s epwise linea eg ession, age, educa ion, CAG epea s, mo o s a us, execu i e unc ion
and e bal luency explained be ween 1.3 and 72.8% o he a iance in gene al cogni ion and isual cogni i e
unc ions (Table3; Fig.3) ac oss he spec um o HD g oups. Execu i e unc ion explained he highes pe cen age
HC Reduced Pene ance P e-mani es Ea ly mani es Mani es F
M (SD) M (SD) M (SD) M (SD) M (SD) ANOVA
Age (yea s) 50.8 (12.8) 52.0 (12.6) 43.0 (11.6) 51.6 (7.3) 54.4 (11.3) 4.9**
Educa ion (yea s) 13.0 (4.0) 13.7 (1.9) 12.8 (3.5) 12.6 (3.1) 11.7 (3.7) 1.0
Sex ( emale), n (%) 43 (55.1%) 3 (50.0%) 24 (60.0%) 19 (63.3%) 13 (48.1%)
CAG Repea s - 36.8 (1.8) 42.5 (2.4) 42.5 (2.2) 44.1 (3.0) 14.0***
Age a i s symp oms - - 47.1 (8.3) 48.9 (7.6) 44.5 (9.1) 1.3
ANCOVA
Mo o s a us (UHDRS) - 1.2 (1.5) 1.5 (2.3) 25.0 (14.1) 42.0 (21.7) 87.0***
Gene al cogni ion (MoCA) 26.3 (3.5) 27.3 (3.8) 25.9 (3.0) 21.8 (4.9) 18.8 (4.8) 21.2***
Visual a en ion 0.3 (0.5) 0.3 (0.6) 0.4 (0.6) −0.5 (0.7) −1.1 (1.0) 33.2***
Visual p ocessing speed/ isual pe cep ion 0.4 (0.7) 0.2 (0.7) 0.4 (0.8) −0.6 (0.8) −1.2 (0.7) 38.6***
Visuospa ial abili ies 0.4 (0.3) 0.3 (0.4) 0.3 (0.4) −0.5 (0.7) −1.0 (0.8) 38.3***
Visual memo y 0.4 (0.8) 0.9 (0.7) 0.2 (0.7) −0.7 (0.6) −1.0 (0.6) 35.6***
Execu i e unc ions 0.2 (0.6) 0.3 (0.4) 0.3 (0.6) −0.3 (1.0) −1.1 (1.1) 17.2***
Ve bal luency 0.4 (0.7) 0.7 (0.6) 0.1 (0.8) −0.5 (0.7) −0.8 (0.9) 14.5***
Table 1. Demog aphic, clinical, mo o and isual cogni i e domains da a in p e-clinical and clinical phases in
Hun ing on’s disease. *p < .05; **p < .01; ***p ≤ .001. No e: M = Mean, SD: S anda d de ia ion; Age, Educa ion,
CAG Repea s, Age a i s symp om, Mo o s a us, and Gene al cogni ion a e shown in aw da a. Visual
a en ion, isual p ocessing speed/ isual pe cep ion, isuospa ial abili ies, isual memo y, execu i e unc ions
and e bal luency a e shown in Z-sco es. Mo o s a us was assessed wi h he Uni ied Hun ing on’s Disease
Ra ing Scale (UHDRS): Gene al cogni ion was assessed wi h he Mon eal Cogni i e Assessmen (MoCA).
Visual a en ion [TMT (T ail Making Tes ) pa A, S oop Wo d, S oop Colo , S oop Wo d-Colo ]; Visual
p ocessing speed/ isual pe cep ion [Sal house Pe cep ual Compa ison Tes (SPCT), Symbol Digi Modali ies
Tes (SDMT)]; Visuospa ial abili ies: [G oo ed Pegboa d es (GPT), Visual pe cep ion wi h Visual Objec
and Space Pe cep ion Ba e y (VOSP cubes and do -coun ing), Taylo Complex Figu e (TFC copy), Ben on
Judgmen o Line O ien a ion (BJLO)]; Visual Memo y: [B ie Visuospa ial Memo y Tes - e ised (BVMT-R
o al sco e and delayed ecall), TFC memo y]; Execu i e Func ions: [Modi ied Wisconsin Ca d So ing Tes
(M-WCST o al ca ego ies, pe se e a i e e o s and o al e o s), TMT Pa B]; Ve bal luency: le e s F, A, S,
and P.
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HC
(1) Reduced Pene ance
(2) P e-mani es (3) Ea ly
mani es (4) Mani es
(5) Pos Hoc Tukey’s (p)
Es ima es [95% Con idence In e al] 1 s2 1 s3 1 s4 1 s5 2 s3 2 s4 2 s5 3 s4 3 s5 4 s5
Age (yea s) [48.2, 53.4] [42.7, 61.3] [39.4, 46.7] [47.4, 55.8] [50.0, 58.8] -0.001 - - - - - 0.003 < 0.001 -
Educa ion (yea s) [12.2, 13.9] [10.7, 16.6] [11.6, 13.9] [11.3, 14.0] [10.2, 13.0] - - - - - - - - - -
CAG Repea s -[34.8, 38.8] [41.7, 43.3] [41.5, 43.4] [43.1, 45.1] - - - - < 0.001 < 0.001 < 0.001 -0.015 0.017
Age a i s symp oms - - [42.6, 51.5] [45.7, 52.1] [40.8, 48,1] - - - - - - - - - -
Mo o s a us (UHDRS) -[−7.1, 9.4] [−1.7, 4.9] [21.3, 28.7] [38.0, 45.9] - - - - - < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
Gene al cogni ion (MoCA) [25.5, 27.2] [24.4, 30.6] [24.2, 26.7] [20.6, 23.3] [17.6, 20.5] - - < 0.001 < 0.001 -0.002 < 0.001 < 0.001 < 0.001 0.005
Visual a en ion [0.2, 0.5] [−0.2, 0.8] [0.1, 0.5] [−0.7, −0.3] [−1.3, −0.8] - - < 0.001 < 0.001 -0.006 < 0.001 < 0.001 < 0.001 0.001
Visual p ocessing speed/ isual pe cep ion [0.3, 0.6] [−0.3, 0.8] [0.0, 0.4] [−0.8, −0.3] [−1.3, −0.8] - - < 0.001 < 0.001 -0.005 < 0.001 < 0.001 < 0.001 0.017
Visuospa ial abili ies [0.3, 0.5] [−0.1, 0.4] [0.1, 0.4] [−0.7, −0.3] [−1.1, −0.7] - - < 0.001 < 0.001 -< 0.001 < 0.001 < 0.001 < 0.001 0.001
Visual memo y [0.3, 0.6] [0.4, 1.5] [−0.1, 0.3] [−0.9, −0.5] [−1.1, −0.6] - - < 0.001 < 0.001 0.003 < 0.001 < 0.001 < 0.001 < 0.001 -
Execu i e unc ions [0.1, 0.4] [−0.2, 0.9] [0.0, 0.5] [−0.5, 0.0] [−1.3, −0.7] - - 0.030 < 0.001 -0.05 < 0.001 0.004 < 0.001 < 0.001
Ve bal luency [0.2, 0.6] [0.1, 1.4] [−0.1, 0.4] [−0.8, −0.2] [−1.2, −0.6] - - < 0.001 < 0.001 -< 0.001 < 0.001 0.001 < 0.001 -
Table 2. Pos -hoc analyses be ween p e-clinical and clinical phases in Hun ing on’s disease. No e: M = Media, SE: S anda d e o ; HC = 1: Heal hy con ols; 2: Reduced pene ance; 3: p e-mani es HD; 4: Ea ly mani es HD; 5: Mani es HD; Mo o s a us was assessed wi h he Uni ied
Hun ing on’s Disease Ra ing Scale (UHDRS): Gene al cogni ion was assessed wi h he Mon eal Cogni i e Assessmen (MoCA). Visual a en ion [TMT (T ail Making Tes ) pa A, S oop Wo d, S oop Colo , S oop Wo d-Colo ]; Visual p ocessing speed/ isual pe cep ion [Sal house
Pe cep ual Compa ison Tes (SPCT), Symbol Digi Modali ies Tes (SDMT)]; Visuospa ial abili ies: [G oo ed Pegboa d es (GPT), Visual pe cep ion wi h Visual Objec and Space Pe cep ion Ba e y (VOSP cubes and do -coun ing), Taylo Complex Figu e (TFC copy), Ben on
Judgmen o Line O ien a ion (BJLO)]; Visual Memo y: [B ie Visuospa ial Memo y Tes - e ised (BVMT-R o al sco e and delayed ecall), TFC memo y]; Execu i e Func ions: [Modi ied Wisconsin Ca d So ing Tes (M-WCST o al ca ego ies, pe se e a i e e o s and o al e o s),
TMT Pa B]; Ve bal luency: le e s F, A, S, and P.
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o a iance in gene al cogni ion (56.8%), while mo o s a us explained he highes in he es o he cogni i e
domains, anging om 37.2% in execu i e unc ion o 72.8% in isuospa ial abili ies.
The esul s om he s epwise linea eg ession analysis by g oup (Fig.4) showed di e ences be ween g oups.
In he p e-mani es g oup, execu i e unc ion was he only a iable explaining gene al cogni ion (31.2%) and
isuospa ial abili ies (38.2%). Age, educa ion, CAG epea s, mo o s a us, execu i e unc ion and e bal luency
explained be ween age (9.6%)- execu i e unc ions (38.2%) o he a iance in he di e en isual cogni i e
unc ions. Visual p ocessing speed was mos ly explained by e bal luency (30.3%) and age (25.1%), isual
memo y by age (24.6%) and CAG epea s (12.8%) in p e-mani es g oup, while e bal luency was jus explained
by educa ion (19.4%), and execu i e unc ions by educa ion (22.3%) and mo o s a us (20.1%). In he ea ly
mani es g oup, gene al cogni ion was mos ly explained by execu i e unc ions (54.9%) bu also by mo o s a us
(9.8%), while he isual cogni i e unc ions we e explained by e bal luency ( om 12.4 o 55.7%), mo o s a us
( om 14.1 o 52.5%), and execu i e unc ions (19.1%). Las ly, in he mani es g oup, e bal luency explained
he 52.4% o gene al cogni ion, and isual cogni i e unc ions we e also explained by e bal luency ( om 55.3
o 60.5%), mo o s a us ( om 5.5 o 66.9%), and age ( om 8.4% o 19,2%).
ROC cu e analysis o cogni i e domains be ween Hun ing on’s disease ca ie s and heal hy
con ols
The ROC cu e analyses e ealed ha all cogni i e domains, pa icula ly he isual domains, e ec i ely
disc imina ed be ween HC and mani es HD pa ien s (including bo h ea ly mani es and mani es g oups), as
well as be ween p e-mani es and mani es HD pa ien s (ea ly mani es and mani es g oups) (Fig.5). The a eas
unde he cu e (AUC) o hese g oups anged om 0.72 o execu i e unc ions o 0.92 o isuospa ial abili ies
in bo h compa isons. Among he isual domains, isuospa ial abili ies demons a ed he highes disc imina i e
powe be ween HC and mani es HD, as well as be ween p e-mani es and mani es HD, ollowed by isual
memo y, isual a en ion, and isual p ocessing speed/ isual pe cep ion. In con as , he disc imina ion be ween
HC and p e-mani es HD was lowe , wi h AUC alues anging om 0.43 o execu i e unc ions o 0.57 o
e bal luency and isual memo y, ollowed by isuospa ial abili ies and gene al cogni ion.
Discussion
This s udy aimed o in es iga e he ea ly p esence o isual cogni i e de ici s in HD ca ie s, including p e-
mani es , ea ly mani es and mani es HD pa ien s, and also pa icipan s wi h educed pene ance by e alua ing
di e ences in hei cogni i e and isual pe o mance, compa ed o HC. Ou s udy e ealed no signi ican
di e ences in gene al cogni ion, among p e-mani es , educed pene ance, and HC g oups, sugges ing ha
gene al cogni i e unc ion emains ela i ely in ac un il la e s ages o HD. Howe e , he esul s highligh ed
signi ican di e ences in isual memo y be ween p e-mani es and educed pene ance g oups, showing he p e-
mani es g oup a lowe isual memo y pe o mance han he educed pene ance g oup. While no di e ences
Fig. 2. Cogni i e di e ences be ween g oups. *p < .05; **p < .01; ***p ≤ .001. No e: HC = Heal hy Con ols;
RP = Reduced Pene ance g oup. The igu e shows he boxplo s om he ANCOVA and pos hoc analysis
pe o med be ween g oups o each cogni i e domain. Gene al Cogni ion: MoCA o al sco e; Visual a en ion:
[TMT (T ail Making Tes ) pa A, S oop Wo d, S oop Colo , S oop Wo d-Colo ]; Visual p ocessing speed/
isual pe cep ion [Sal house Pe cep ual Compa ison Tes (SPCT), Symbol Digi Modali ies Tes (SDMT)];
Visuospa ial abili ies: [G oo ed Pegboa d es (GPT), Visual pe cep ion wi h Visual Objec and Space
Pe cep ion Ba e y (VOSP cubes and do -coun ing), Taylo Complex Figu e (TFC copy), Ben on Judgmen o
Line O ien a ion (BJLO)]; Visual Memo y: [B ie Visuospa ial Memo y Tes - e ised (BVMT-R o al sco e and
delayed ecall), TFC memo y]; Execu i e Func ions: [Modi ied Wisconsin Ca d So ing Tes (M-WCST o al
ca ego ies, pe se e a i e e o s and o al e o s), TMT Pa B]; Ve bal luency: le e s F, A, S, and P.
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we e shown be ween ea ly mani es and mani es HD pa ien s in his isual domain, sugges ing ha isual
memo y was al eady impai ed. The e o e, isual memo y may se e as an ea ly indica o o cogni i e decline in
HD, wa an ing u he explo a ion in o he speci ic isual cogni i e domains a ec ed in he p e-mani es s age.
Acco ding o p e ious s udies, p e-mani es pa ien s showed lowe cogni i e pe o mance in e bal luency,
execu i e unc ion, and memo y, including sho - e m and delayed ecall, isuospa ial abili ies, isual p ocessing
speed47–50. Howe e , none o hese s udies ocused speci ically on isual cogni ion o isual cogni i e unc ions.
As expec ed, he mani es HD g oup displayed highe mo o , gene al and isual cogni i e impai men
compa ed o ea ly mani es pa ien s, which aligns wi h he es ablished clinical unde s anding o he p og ession
o HD2,51. Howe e , no such di e ences we e no ed in isual memo y o e bal luency be ween hese wo
mani es g oups. This inding is no ewo hy, as i sugges s ha ce ain cogni i e domains may decline in a mo e
uni o m manne ac oss di e en s ages o he disease. The absence o signi ican di e ences in isual memo y
be ween hese wo mani es g oups indica es ha isual memo y de ici s may eme ge ea ly in he disease
cou se and emain ela i ely s able as he disease p og esses. Simila ly, he lack o dis inc ion in e bal luency
sugges s ha language- ela ed cogni i e abili ies may ollow a simila p og ession, po en ially connec ing o
mo o speech issues such as ana h ia and dysa h ia52,53. While e bal luency is adi ionally conside ed a es
o language abili y, i s pe o mance is also in luenced by execu i e unc ions. Gi en he cogni i e symp oms
Func ional Domain P edic o s BSE β
Visual
A en ion Mo o s a us − 0.02 0.00 − 0.37 −5.10 Rad=0.76. F(4.86) = 72.6***
Ve bal luency 0.39 0.08 0.38 4.93
Age − 0.02 0.00 − 0.23 −4.00
Execu i e unc ions 0.15 0.07 0.16 2.14
Visual p ocessing speed/
isual pe cep ion
Mo o s a us − 0.011 0.003 − 0.231 3.220 Rad=0.77. F(4.84) = 75.6***
Ve bal luency 0.483 0.081 0.445 5.956
Age − 0.031 0.005 − 0.372 6.600
Visuospa ial abili ies Execu i e unc ions 0.153 0.073 0.154 2.101 Rad=0.79. F(3.84) = 109.6***
Mo o s a us − 0.025 0.003 − 0.622 9.347
Ve bal luency 0.258 0.057 0.288 4.509
Age − 0.013 0.004 − 0.185 3.538
Mo o s a us − 0.025 0.003 − 0.622 9.347
Visual Memo y Mo o s a us − 0.014 0.004 − 0.310 3.343 Rad=0.66. F(4.85) = 43.2***
Execu i e unc ions 0.271 0.071 0.303 3.818
Age − 0.029 0.006 − 0.377 4.582
CAG epea s − 0.071 0.026 − 0.237 2.763
Gene al cogni ion Execu i e unc ions 1.758 0.413 0.346 4.252 Rad=0.72. F(4.86) = 57.6***
Mo o s a us − 0.078 0.020 − 0.313 3.925
Ve bal luency 1.518 0.461 0.274 3.292
Age − 0.056 0.027 − 0.127 2.046
Execu i e unc ions Mo o s a us − 0.028 0.004 − 0.573 7.263 Rad=0.45. F(2.88) = 37.5***
Educa ion (yea s) 0.088 0.023 0.298 3.777
Ve bal luency Mo o s a us − 0.021 0.003 − 0.491 6.043 Rad=0.51. F(3.92) = 33.3***
Educa ion (yea s) 0.073 0.020 0.267 3.663
CAG epea s − 0.073 0.025 − 0.234 2.891
Table 3. P edic ed e ec s o sociodemog aphic and clinical da a on cogni ion in HD. *p < .05; **p < .01;
***p ≤ .001. Da a in able ep esen s esul s om s epwise hie a chical eg ession analyses ela ing ou comes
om isual cogni ion es s (dependen a iables) wi h ou comes om age, educa ion, clinical da a (mo o
s a us and CAG epea s), execu i e unc ions and e bal luency in HD. Only eg ession models wi h
s a is ically signi ican F es s a e displayed in able. Abb e ia ions: B: non-s anda dized Be a eg ession
coe icien (e ec size o he a iable in he model); SE: S anda d E o o B; β: s anda dized Be a eg ession
coe icien ; Rad: co ec ed R squa ed (coe icien o de e mina ion o goodness o i ) o he eg ession model.
Mo o s a us was assessed wi h he Uni ied Hun ing on’s Disease Ra ing Scale (UHDRS): Gene al cogni ion
was assessed wi h he Mon eal Cogni i e Assessmen (MoCA). Visual a en ion [TMT (T ail Making Tes )
pa A, S oop Wo d, S oop Colo , S oop Wo d-Colo ]; Visual p ocessing speed/ isual pe cep ion [Sal house
Pe cep ual Compa ison Tes (SPCT), Symbol Digi Modali ies Tes (SDMT)]; Visuospa ial abili ies: [G oo ed
Pegboa d es (GPT), Visual pe cep ion wi h Visual Objec and Space Pe cep ion Ba e y (VOSP cubes and
do -coun ing), Taylo Complex Figu e (TFC copy), Ben on Judgmen o Line O ien a ion (BJLO)]; Visual
Memo y: [B ie Visuospa ial Memo y Tes - e ised (BVMT-R o al sco e and delayed ecall), TFC memo y];
Execu i e Func ions: [Modi ied Wisconsin Ca d So ing Tes (M-WCST o al ca ego ies, pe se e a i e e o s
and o al e o s), TMT Pa B]; Ve bal luency: le e s F, A, S, and P.
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associa ed wi h HD, i is easonable o assume ha execu i e unc ions and psychomo o speed may signi ican ly
a ec he pe o mance o o he cogni i e domains. This aises impo an ques ions ega ding he na u e o
cogni i e decline in HD and sugges s ha in e en ions aimed a suppo ing hese speci ic cogni i e a eas migh
be necessa y h oughou he disease cou se.
The indings highligh ed he mul i ace ed na u e o cogni i e impai men in HD and he signi ican
p edic o s in gene al cogni ion and isual cogni i e unc ions among HD ca ie s. A ange o ac o s—including
age, educa ion, CAG epea s, mo o s a us, execu i e unc ion, and e bal luency—con ibu ed o he isual
cogni i e p o iles ac oss he spec um o HD. No ably, mo o s a us had he highes p edic i e powe in isual
cogni i e unc ions, e bal luency and execu i e unc ions. This is pa icula ly in iguing as i emphasizes he
in e connec edness o mo o and isual cogni i e impai men s in HD. The mo o aspec includes an oculomo o
componen , ma ked by educed gaze ixa ion and diminished isual analysis capaci y. In addi ion, he high
pe cen age o a iance explained by mo o s a us in isuospa ial abili ies may also e lec he unde lying
neu obiological mechanisms linking mo o con ol and isual pe cep ion. As mo o unc ion declines, so oo
may he abili y o p ocess and in e ac wi h isual s imuli, leading o signi ican challenges in daily ac i i ies ha
equi e isuospa ial awa eness, such as na iga ing en i onmen s o ecognizing objec s17,54. On he o he hand,
execu i e unc ion eme ged as he s onges p edic o in gene al cogni ion, aligning wi h exis ing li e a u e ha
highligh s execu i e dys unc ion as a hallma k o cogni i e decline in HD16,18, impac ing a ange o abili ies
essen ial o daily unc ioning, including planning, p oblem-sol ing, and cogni i e lexibili y. Age and CAG
epea s a e well-es ablished p edic o s o disease onse and p og ession55, and he in luence o educa ion and
e bal luency on cogni ion unde sco es he po en ial o modi iable ac o s o impac cogni i e ou comes56.
Fo ins ance, highe le els o educa ion may p o ide cogni i e ese e, po en ially mi iga ing some e ec s o
neu odegene a ion. Unde s anding hese ela ionships could in o m a ge ed in e en ions ha add ess speci ic
cogni i e de ici s while conside ing indi idual pa ien p o iles.
On he o he hand, he indings among he di e en HD g oups di e ed om he o al HD ca ie ’s sample.
In he p e-mani es g oup, execu i e unc ion eme ged as he sole signi ican p edic o o bo h gene al cogni ion
and isuospa ial abili ies, sugges ing ha e en be o e he onse o mo o symp oms, execu i e unc ion may
se e as a c i ical ma ke o cogni i e decline in HD ca ie s, especially in isuospa ial abili ies. No ably, isual
p ocessing speed was p ima ily accoun ed o by e bal luency and age, while isual memo y was in luenced
also by age and CAG epea s57. This sugges s ha while execu i e unc ion is pa amoun in he p e-mani es
s age, o he ac o s, pa icula ly age and CAG epea s, also play essen ial oles in shaping cogni i e ou comes51,56.
In he ea ly mani es g oup, execu i e unc ions emained he p ima y p edic o o gene al cogni ion,
highligh ing he p og essi e na u e o cogni i e impai men associa ed HD. Addi ionally, mo o s a us began o
con ibu e o gene al cogni ion, showing a possible link be ween physical symp oms and cogni i e pe o mance.
The p edic o s o isual cogni i e unc ions in he ea ly mani es g oup b oadened o include e bal luency
Fig. 3. P edic ed e ec s o age educa ion, clinical da a, execu i e unc ion and e bal luency in cogni ion. The
igu e illus a es he pe cen age o a iance explained by age educa ion and clinical da a in each model. No e:
Mo o s a us was assessed wi h he Uni ied Hun ing on’s Disease Ra ing Scale (UHDRS): Gene al cogni ion
was assessed wi h he Mon eal Cogni i e Assessmen (MoCA). Visual a en ion [TMT (T ail Making Tes )
pa A, S oop Wo d, S oop Colo , S oop Wo d-Colo ]; Visual p ocessing speed/ isual pe cep ion [Sal house
Pe cep ual Compa ison Tes (SPCT), Symbol Digi Modali ies Tes (SDMT)]; Visuospa ial abili ies: [G oo ed
Pegboa d es (GPT), Visual pe cep ion wi h Visual Objec and Space Pe cep ion Ba e y (VOSP cubes and
do -coun ing), Taylo Complex Figu e (TFC copy), Ben on Judgmen o Line O ien a ion (BJLO)]; Visual
Memo y: [B ie Visuospa ial Memo y Tes - e ised (BVMT-R o al sco e and delayed ecall), TFC memo y];
Execu i e Func ions: [Modi ied Wisconsin Ca d So ing Tes (M-WCST o al ca ego ies, pe se e a i e e o s
and o al e o s), TMT Pa B]; Ve bal luency: le e s F, A, S, and P.
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and mo o s a us, e lec ing a mo e complex in e play o ac o s in luencing cogni i e ou comes a his s age.
The inclusion o e bal luency as a signi ican p edic o indica ed ha language skills may also begin o decline
as HD p og esses and he e o e, mo o aspec s o language, con ibu ing o o e all cogni i e impai men 58,59.
De ici s in e bal luency could se e as an ea ly indica o o b oade cogni i e decline and may wa an u he
assessmen in clinical se ings.
Finally, in he mani es g oup, e bal luency eme ged as he mos subs an ial p edic o in gene al and isual
cogni i e unc ions. This shi unde sco es he inc easing p ominence o language and e bal skills in he la e
s ages o HD59, po en ially e lec ing he b oade cogni i e decline expe ienced by pa ien s as hey na iga e mo e
complex cogni i e demands. Mo o s a us also showed a wide ange o in luence on isual cogni i e unc ions,
especially in isuospa ial abili ies, indica ing a ela ionship be ween he impai men o mo o symp oms and
he decline in isual cogni i e abili ies. Age emained also a ele an ac o , u he emphasizing he ongoing
impac o aging in conjunc ion wi h he p og ession o HD. These indings illus a ed he dynamic na u e o
cogni i e impai men in HD, wi h di e en p edic o s gaining o losing impo ance as he disease ad ances.
The emphasis on execu i e unc ions in he ea ly s ages shi ed owa d a mo e mul i ace ed model in he la e
s ages, whe e e bal luency and mo o s a us also signi ican ly in luence cogni i e ou comes. This p og ession
sugges s ha a ge ed in e en ions add essing execu i e dys unc ion in he p e-mani es and ea ly mani es
s ages may be bene icial, while in e en ions in he mani es s age could ocus mo e on enhancing e bal luency
and managing mo o symp oms.
Cogni ion and speci ically isual cogni i e domains eme ged as pa icula ly e ec i e in disc imina ing
be ween mani es HD pa ien s—encompassing bo h ea ly mani es and mani es g oups—and HC22,24,60.
Visuospa ial abili ies we e he mos disc imina i e domain be ween g oups, ollowed by isual memo y and
isual a en ion. Ou indings sugges ha isual cogni i e impai men s, pa icula ly isuospa ial abili ies a he
han execu i e unc ions as migh be expec ed, we e p ominen ea u es in he mani es a ion o HD. The ac
ha isuospa ial abili ies we e he mos dis inguishing domain be ween HC and mani es HD, as well as be ween
p emani es HD and mani es HD, a he han execu i e unc ion, is a signi ican inding, especially since he
measu es used o assess execu i e unc ion also included aspec s o isual abili ies. This suppo s he idea ha
Fig. 4. P edic ed e ec s o age, educa ion, CAG epea s, mo o s a us, execu i e unc ions and e bal luency
in cogni ion by g oups. P e-mani es pa ien s. Ea ly mani es HD pa ien s. Mani es HD pa ien s. The igu e
illus a es he pe cen age o a iance explained by age educa ion and clinical da a in each model sepa a ely
by p e-mani es HD, ea ly mani es HD, and mani es HD g oup. No e: Mo o s a us was assessed wi h he
Uni ied Hun ing on’s Disease Ra ing Scale (UHDRS): Gene al cogni ion was assessed wi h he Mon eal
Cogni i e Assessmen (MoCA). Visual a en ion [TMT (T ail Making Tes ) pa A, S oop Wo d, S oop
Colo , S oop Wo d-Colo ]; Visual p ocessing speed/ isual pe cep ion [Sal house Pe cep ual Compa ison Tes
(SPCT), Symbol Digi Modali ies Tes (SDMT)]; Visuospa ial abili ies: [G oo ed Pegboa d es (GPT), Visual
pe cep ion wi h Visual Objec and Space Pe cep ion Ba e y (VOSP cubes and do -coun ing), Taylo Complex
Figu e (TFC copy), Ben on Judgmen o Line O ien a ion (BJLO)]; Visual Memo y: [B ie Visuospa ial
Memo y Tes - e ised (BVMT-R o al sco e and delayed ecall), TFC memo y]; Execu i e Func ions: [Modi ied
Wisconsin Ca d So ing Tes (M-WCST o al ca ego ies, pe se e a i e e o s and o al e o s), TMT Pa B];
Ve bal luency: le e s F, A, S, and P.
Scien i ic Repo s | (2025) 15:4707 9
| h ps://doi.o g/10.1038/s41598-025-88406-5
www.na u e.com/scien i ic epo s/
