Cover Page

Cover Page

The following handle holds various files of this Leiden University dissertation:

http://hdl.handle.net/1887/74007

Author: Baake, V.

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Chapter 4

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cognitive performance in Huntington’s

disease

9HUHQD%DDNH

1,2

_{, REGISTRY Investigators of the European Huntington’s Disease}

Network

3

_{DQG5D\PXQG$&5RRV}

1

1_{/HLGHQ8QLYHUVLW\0HGLFDO&HQWHU'HSDUWPHQWRI1HXURORJ\/HLGHQ7KH1HWKHUODQGV} 2_{+XQWLQJWRQ&HQWHU7RSD]2YHUGXLQ.DWZLMN7KH1HWKHUODQGV} 3 _{Membership of the REGISTRY Investigators of the European Huntington’s Disease Network is provided}

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60

Chapter 4

Abstract

Background: In Huntington’s disease (HD), cognitive decline starts early

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FOLQLFDOWULDOHQGSRLQWLWLVHVVHQWLDOWRLGHQWLI\IDFWRUVZKLFKFDQLQÀXHQFHFRJQLWLYH

performance in HD. Medication treating non-cognitive neuropsychiatric disturbances

DQG WHWUDEHQD]LQH ZKLFK DUH JHQHUDOO\ NQRZQ WR KDYH D QHJDWLYH LQÀXHQFH RQ

cognition, are often prescribed in HD patients.

Objective: 7KLV VWXG\ HYDOXDWHV ZKHWKHU FRJQLWLYH SHUIRUPDQFH GLɣHUV EHWZHHQ

users and non-users of these drugs at HD clinics throughout Europe.

Methods: ,QWRWDOSDUWLFLSDQWVRIWKH5(*,675<VWXG\IXO¿OOHGWKHFULWHULDIRU

cognitive assessment and recorded medication use at their baseline visit. Participants

were grouped according to disease stage and medication use: i.e. benzodiazepines,

selective serotonin reuptake inhibitor (SSRI) antidepressants, antipsychotics, atypical

antipsychotics and tetrabenazine. Univariate general linear model analysis was

conducted.

Results: Medication use was common in the REGISTRY cohort. In total 42% of

WKHSDUWLFLSDQWVXVHGDQ\RIWKHSUHGH¿QHGGUXJVZKHUHDVSHUFHQWDJHRIPHGLFDWLRQ

used increased from 12% in the pre-motormanifest stage to 81% in the advanced

PRWRUPDQLIHVW VWDJHV $ VLJQL¿FDQW HɣHFW RI DQWLSV\FKRWLF XVH RQ WKH 6WURRS :RUG

Test was found in the early HD stages.

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61

Medication and cognition

Introduction

Huntington’s disease (HD) is an autosomal dominant inherited, progressive

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on chromosome 4

1

_{. HD is characterized by a triad of symptoms: motor abnormalities,}

behavioral signs and cognitive deterioration

2

_{$VWKHH[DFWORFDWLRQRIWKHH[SDQGHG}

gene is known, individuals at risk can be tested for the expanded HD gene before any

symptoms or signs appear.

Motor abnormalities are the most characteristic signs of HD, but gene-expansion

carriers and caregivers perceive cognitive decline and behavioral signs to be the

most burdensome

3, 4

_{. These can precede motor signs by several years}

5-13

_{$VFRJQLWLYH}

decline starts early and continues as the disease progresses, cognition is recognized as

a potential endpoint in clinical trials. Nowadays, a broad range of cognitive domains

is evaluated in almost all clinical trials

14

_{, including psychomotor speed which starts to}

slow down early on and continues to worsen throughout the later HD stages

15, 16

_{. It is}

HVVHQWLDOWRNQRZZKLFKIDFWRUVFRXOGSRVVLEO\LQÀXHQFHFRJQLWLYHSHUIRUPDQFHLQ+'

in order to evaluate whether potential interventions could stop or slow down cognitive

decline in HD.

$V WKHUH LV QR FXUH IRU +' PHGLFDWLRQ LV SUHVFULEHG WR PDQDJH +' V\PSWRPV

Many HD gene expansion carriers take psychotropic medication for behavioral and

depressive signs; i.e. medication targeting non-cognitive neuropsychiatric signs

2, 17

_.

)RULQVWDQFHRQHVWXG\VKRZHGWKDWLQD(XURSHDQ+'SRSXODWLRQRI+'SDWLHQWV

received symptomatic treatment

18

_{. Unfortunately, there is only low level of evidence}

RQWKHHɣHFWDQGVLGHHɣHFWVRIXVLQJFHUWDLQPHGLFDWLRQLQ+'PRVWSUHVFULSWLRQVDUH

based on clinical experience

19, 20

_{. Depression is common in HD and is often treated with}

DQWLGHSUHVVDQWVZLWKD¿UVWFKRLFHRIVHOHFWLYHVHURWRQLQUHXSWDNHLQKLELWRUV665,VRU

serotonin-norepinephrine reuptake inhibitors (SNRIs). There is some evidence that

VRPH665,VPLJKWKDYHDSRVLWLYHHɣHFWRQFRJQLWLRQLQWKHSURGURPDOSKDVHRI+'

LHEHIRUHDQ\GH¿QLWH+'V\PSWRPVDUHSUHVHQW

21

_{%HKDYLRUDOV\PSWRPVHJDQ[LHW\}

are often treated with benzodiazepines

20

_{+RZHYHUWKHHɣHFWRIEHQ]RGLD]HSLQHRQ}

cognitive performance in HD is not well documented. We do know from other studies

that the higher the intake of benzodiazepines the greater risk of cognitive impairment

and in the elderly population it is related to a higher risk of dementia

22, 23

_{,QD)UHQFK}

study it was shown that also the use of antipsychotics is common in HD and some

KDYHDQHJDWLYHHɣHFWRQFRJQLWLRQ

24

_{. In another study it was found that HD patients}

using antipsychotic medication (classical and atypical) or tetrabenazine had a faster

disease progression

25

_{%\WDNLQJWKHVHUHSRUWVWRJHWKHUWKHUHLVVRPHLQGLFDWLRQWKDW}

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62

Chapter 4

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FRJQLWLYHSHUIRUPDQFHEXWQRWWKHHQWLUHPHGLFDWLRQJURXSZDVHYDOXDWHG%XWIRU

many clinical trials individuals are not allowed to take any of these drugs because it

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Therefore, the aim of this observational, explorative study is to investigate whether

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using medication targeting non-cognitive neuropsychiatric signs or tetrabenazine

compared to non-users in a clinical HD population. We expect that the SSRI group

KDVWKHVDPHFRJQLWLYHSHUIRUPDQFHDVQRQXVHUV)RUDOORWKHUPHGLFDWLRQJURXSVZH

expect that users display a more impaired cognitive performance. This is evaluated in

a large HD population seen at several specialized HD clinics throughout Europe, no

medication use was adapted for this study.

Methods

Participants

REGISTRY is a European, multicenter, longitudinal, observation study, facilitated

E\WKH(XURSHDQ+XQWLQJWRQ¶V'LVHDVH1HWZRUN(+'1$WRWDORIFRQ¿UPHG

+'JHQHH[SDQVLRQFDUULHUVZLWKD&$*!RIWKH5(*,675<VWXG\ZHUHLQFOXGHGDOO

completed the cognitive assessment at baseline. Participants without any motor signs,

DVGH¿QHGE\DWRWDOPRWRUVFRUH706RI”RQWKH8QL¿HG+XQWLQJWRQ¶V'LVHDVH

Rating Scale (UHDRS)

14

_{, were considered pre-motormanifest. These participants}

ZHUH IXUWKHU GLYLGHG LQWR µIDU IURP HVWLPDWHG GLVHDVH RQVHW¶ SUH$ DQG µFORVH WR

HVWLPDWHGGLVHDVHRQVHW¶SUH%FDOFXODWHGE\WKH/DQJEHKQIRUPXOD

26-29

_{and split at}

WKHPHGLDQRI\HDUV3DUWLFLSDQWVZLWKXQHTXLYRFDOPRWRUV\PSWRPV706!

were further divided into disease stages based on total functional capacity scale

30

_{. The}

last two disease stages were merged into one due to the small number of participants

in these two groups, stages 4 and 5. Ethical approval was obtained for all sites and

all participants gave written informed consent. The study was conducted by trained

SURIHVVLRQDOVDQGDOOGDWDZHUHPRQLWRUHG)RUDIXOOGHVFULSWLRQRIWKHVWXG\VHH2UWK

et al.

31

_.

Assessments

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63

Medication and cognition

ÀXHQF\WHVWWRWDOQXPEHUFRUUHFWLQRQHPLQXWHIRUWKUHHOHWWHUVDVWKHVWXG\ZDV

DGPLQLVWHUHGLQGLɣHUHQWFRXQWULHVWKHOHWWHUVDOVRGLɣHUHGE\FRXQWU\6WURRS&RORU

Word-Interference Test: word-reading, color-naming and interference condition

(total number correct for each condition in 45 seconds; here the colors are red, blue

and green), and the Symbol Digit Modalities Test (total number correct in 90 seconds).

$OOPHGLFDWLRQVXVHGZHUHUHFRUGHGLQWKH5(*,675<VWXG\)RUDQDO\VLVSXUSRVHV

participants were grouped as follows: taking benzodiazepines, selective serotonin

reuptake inhibitor (SSRI) antidepressants, antipsychotics, atypical antipsychotics or

WHWUDEHQD]LQH)RUPRUHLQIRUPDWLRQRQWKHH[DFWPHGLFDWLRQWDNHQVHHVXSSOHPHQWDU\

appendix 1. Participants were allowed to take other medication prescribed for other

conditions such as hypertension.

Statistical analysis

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appropriate, a chi-square test was used.

Univariate general linear model was applied to evaluate whether medication users

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RIGLVHDVHVWDJHDQGPHGLFDWLRQXVHZDVDOVRDGGHGWRWKHPRGHO)RUWKHPXOWLSOH

FRPSDULVRQDQDO\VLVDFRQVHUYDWLYHVLJQL¿FDQWOHYHOZDVXVHGS GLYLGHGE\WKH

QXPEHURIWHVWVSHUIRUPHGLHS 



PreA

N=283

N=239

PreB

Stage 1

N=712

Stage 2

N=619

Stage 3

N=378

Stage 4+5

N=58

Age

a

_{34 (8) 42 (10)}

_{47 (11)}

_{51 (12)}

_{53 (11)}

_{54 (11)}

CAG repeat length

a

_{42 (2)}

_{44 (3)}

_{44 (3)}

_{44 (3)}

_{44 (3)}

_{45 (4)}

Years of education

a

_{13 (3)}

_{13 (7)}

_{12 (5)}

_{11 (4)}

_{11 (6)}

_{10 (3)}

Sex (Male/Female)

b

_{96/187 104/135 384/328 304/315 189/189 20/38}

PreA: pre-motormanifest A; PreB: pre-motormanifest B

a_{Mean (standard deviation)} b_{Total number}

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64

Chapter 4

Results

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)  S \HDUV RI HGXFDWLRQ )  S &$*

UHSHDW OHQJWK )  S DQG JHQGHU ǒð  S, see

table 1.

In total 58% of the participants did not use any medication. If disease stage was

considered, the percentage of participants not taking medication gradually declined

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LQFUHDVHG IURP SUH$  WR VWDJHV  DQG   $ERXW  RI WKH PHGLFDWLRQ

users were already on medication for at least 2 months with stable doses.

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7HVW) S VXJJHVWLQJWKDWSDUWLFLSDQWVXVLQJDQWLSV\FKRWLFV

VFRUHGZRUVHRQWKH6WURRS:RUG7HVWWKDQQRQXVHUVVHH¿JXUH$QWLSV\FKRWLFV

users in group stage 2 and stage 3 scored on average lower than then non-users

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WKH LQWHUDFWLRQ HɣHFW RI DOO GLVHDVH VWDJHV )   S  7KH XVH RI

benzodiazepines, SSRI antidepressants, atypical antipsychotics or tetrabenazine had

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Discussion

This study shows that about half of the HD-REGISTRY population used medication

targeting non-cognitive neuropsychiatric disturbances and/or tetrabenazine. The

percentage of HD gene carriers taking these medications increased from

pre-motormanifest to the advanced HD. The most logical explanation for this increase

throughout the disease stages is that advanced HD individuals have severe symptoms

 PreA

N=283 N=239 PreB Stage 1 N=712 Stage 2 N=619 Stage 3 N=378 Stage 4+5 N=58

No medicationa _{251 (88%) 202 (85%) 463 (65%) 283 (46%) 113 (30%) 11 (19%)} Benzodiazepinesa _{6 (2%) 5 (2%) 23 (3%) 29 (4%) 9 (2%) 2 (3%)} SSRIa _{16 (6%) 24 (10%) 84 (12%) 78 (13%) 43 (12%) 3 (5%)} Antipsychoticsa _{1 (<1%) Ɋ 8 (1) 10 (2%) 14 (4%) Ɋ} Atypical antipsychoticsa _{1 (<1%) Ɋ 62 (9%) 86 (14%) 66 (17%) 13 (23%)} Tetrabenazinea _{Ɋ 1 (1%) 6 (1%) 13 (2%) 9 (2%) 1 (2%)} Mixa _{8 (3%) 7 (2%) 66 (9%) 120 (19%) 124 (33%) 28 (48%)}

PreA: pre-motormanifest A; PreB: pre-motormanifest B

a_{Total number (%)}

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65

Medication and cognition

which need to be managed with medication. In addition, the pre-motormanifest

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¿UVWEHH[SORUHGLQWUHDWLQJV\PSWRPV

20

_{. Throughout disease progression symptoms}

become more severe, global functioning decreases and medication treatment becomes

useful, supported by adjunctive therapies, to manage all symptoms

32

_{. Polypharmacy is}

common in HD due to the complexity of the disease and several symptoms which need

to be addressed

20

_{which is supported by our results that about 40% of all medication}

XVHUVXVHGDPL[RIWKHSUHGH¿QHGPHGLFDWLRQJURXSV

%\HYDOXDWLQJWKHHɣHFWRIPHGLFDWLRQXVHRQFRJQLWLYHSHUIRUPDQFHZHRQO\IRXQG

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WKDW LV WKH 6WURRS :RUG 7HVW LQ WKH HDUO\ +' SKDVH 7KLV LV DQ LPSRUWDQW ¿QGLQJ

IRUIXWXUHFOLQLFDOWULDOVHVSHFLDOO\EHFDXVHWKHHɣHFWZDVIRXQGLQWKHHDUO\VWDJHV

)XWXUH FOLQLFDO WULDOV ZLOO PRVW OLNHO\ IRFXV RQ SUHPRWRUPDQLIHVW DQGRU HDUO\ +'

JHQHFDUULHUVWRHYDOXDWHZKHWKHUWUHDWPHQWLQÀXHQFHVGLVHDVHSURJUHVVLRQLQDQHDUO\

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66

Chapter 4

stage of the disease to ensure the highest quality of life for the HD gene carriers. With

RXU¿QGLQJVZHZRXOGUHFRPPHQGWREHFDXWLRXVWRLQFOXGH+'JHQHFDUULHUVXVLQJ

antipsychotic medication if cognition is an important outcome measure of a clinical

trial.

Secondly, our study showed that the use of benzodiazepine, SSRI antidepressant,

DW\SLFDODQWLSV\FKRWLFRUWHWUDEHQD]LQHKDVQRHɣHFWRQSHUIRUPDQFHRIWKH8+'56

FRJQLWLYHEDWWHU\LQWKHFOLQLFDOVHWWLQJ2XU¿QGLQJWKDWWHWUDEHQD]LQHKDVQRHɣHFW

on cognition is in line with the 80 week open label study of tetrabenazine in HD in

which cognitive decline resembled the natural deterioration in HD

33

_{. Regarding future}

clinical trials targeting cognition in HD, we advise that the use of benzodiazepine,

SSRI antidepressant, atypical antipsychotic or tetrabenazine should be allowed if

participants are on a stable dose and if there is no suggestion that these medications

FRXOGKDYHDQDGYHUVHHɣHFWLQFRPELQDWLRQZLWKWKHLQYHVWLJDWLRQDOGUXJ7KLVVKRXOG

make it easier to recruit participants for clinical trials as many HD gene carriers use

these medications. It also allows to test an investigational drug in a cohort which more

FORVHO\UHSUHVHQWVWKHSRSXODWLRQVHHQLQFOLQLFVUDWKHUWKDQLQDVWULFWO\SUHGH¿QHG

population and improves the chance to have a successful phase III study.

One of the limitations of this study is that we grouped together the most commonly

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SRVVLEOHWKDWRQHSDUWLFXODUGUXJPLJKWKDYHDUHODWLYHO\VWURQJHUHɣHFWRQFRJQLWLYH

SHUIRUPDQFHEXWWKDWWKLVHɣHFWLVPDVNHGE\JURXSLQJVHYHUDOPHGLFDWLRQVWRJHWKHU

In addition, we chose to group the medication based on relatively broad categorization

as used by the Dutch regulatory agency. These categorization is based on broad

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of the acting agent. The reason for this is that most studies are based on animal or cell

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or even in the diseased human brain. It might be of interest for future studies to explore

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medication, not at the exact doses taken, although we do know that the majority was

on a stable dose. In addition, participants were allowed to take co-medications, such

DV DQWLK\SHUWHQVLYH GUXJV FRPELQDWLRQV ZKLFK FRXOG DɣHFW FRJQLWLYH SHUIRUPDQFH

On a positive note, the REGISTRY database provides an opportunity to look at

real-OLIHPHGLFDWLRQXVHDQGLWVHɣHFWRQFRJQLWLYHSHUIRUPDQFHVHHQDWWKHFOLQLFV

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Medication and cognition

Acknowledgment list

REGISTRY 2004- 2014

Registry Steering committee:  $QQH&DWKHULQH %DFKRXG/pYL $QQD5LWD %HQWLYRJOLR ,GD %LXQQR 5DSKDHO 0 %RQHOOL -XOLDQD %URQ]RYD -HDQ0DUF %XUJXQGHU 6WHSKHQ % 'XQQHWW -RDTXLP - )HUUHLUD-DQ)ULFK-RH*LXOLDQR2OLYLD-+DQGOH\$UYLG+HLEHUJ6HUJH\,OODULRVKNLQ7RUVWHQ ,OOPDQQ-LUL.OHPSLU*%HUQKDUG/DQGZHKUPH\HU-DPLH/HYH\7LP0F/HDQ-¡UJHQ(1LHOVHQ 6XVDQD3UR.RLYLVWR0DUNNX3lLYlULQWD6YHQ3nOKDJHQ2OLYHU4XDUUHOO0DULD5DPRV$UUR\R 5D\PXQG $& 5RRV &DUVWHQ 6DIW $QD 5RMR 6HEDVWLiQ 6DUDK - 7DEUL]L :LP 9DQGHQEHUJKH &KULVWLQH9HUHOOHQ'XPRXOLQ7HUH]D8KURYD-DQ:DKOVWU|P-DFHN=DUHPED

Language coordinators:9HUHQD%DDNHIRUPHUO\5|GLJ.DWULQ%DUWK0RQLFD%DVFXxDQD*DUGH7RPiã %HUQDUG 6DEULQD %HW] 5HLQHNH %RV $GULHQ &RPH /HRQRU &RUUHLD *XHGHV -HQQ\ &DOODJKDQ 6HOHQH &DSRGDUFD 6pEDVWLHQ &KDUSHQWLHU :LOGVRQ 9LHLUD GD 6LOYD 0DUWLQD 'L 5HQ]R 'DQLHO (FNHU $QD 0DULD )LQLVWHUUD 5XWK )XOODP &DPLOOH *HQRYHV 0HWWH *LOOLQJ 2OLYLD - +DQGOH\ &DULQD+YDOVWHGW&KULVWLQH+HOG.HUVWLQ.RSSHUV&ODXGLD/DPDQQD0DWLOGH/DXUj$VXQFLyQ 0DUWtQH] 'HVFDOV 6DXO 0DUWLQH]+RUWD 7LDJR 0HVWUH 6DUD 0LQVWHU 'DQLHOD 0RQ]D .ULVWLQD 0QNHO/LVDQQH0W]H0DUWLQ2HKPHQ+HOHQH3DGLHX/DXUHQW3DWHUVNL1DGLD3HSSD6XVDQD 3UR.RLYLVWR%HDWH5LQGDO'DZQ5RJHUV1LLQL5¡UHQIRUPHUO\+HLQRQHQ$QD6DOJXHLUR3DYOD âDãLQNRYi &DWKHULQH 7D\ORU (ULND 7LPHZHOO -HQQ\ 7RZQKLOO 3DWULFLD 7ULJR &XELOOR 0DUOHHQ 5YDQ:DOVHP0DULH1RHOOH:LWMHV$Qp*U]HJRU]:LWNRZVNL$ELJDLO:ULJKW'DQLHO=LHORQND Eugeniusz Zielonka, Paola Zinzi

AUSTRIA

Graz (Medizinische Universitäts Graz, Psychiatrie): 5DSKDHO 0 %RQHOOL .DUHQ +HFKW %ULJLWWH +HUUDQKRI  $QQD +ROO IRUPHUO\ +|GO +DQV3HWHU .DSIKDPPHU 0LFKDHO .RSSLW] 6DELQH /LOHN0DUNXV0DJQHW1LFROH0OOHU'DQLHOD2WWL$QQDPDULD3DLQROG.DULQ5HLVLQJHU0RQLND 6FKHLEO+HOPXW6FK|JJO-DVPLQ8OODK

Innsbruck (Universitätsklinik Innsbruck, Neurologie):(YD0DULD%UDXQZDUWK)ORULDQ%UXJJHU /LVD %XUDWWL (YD0DULD +DPHWQHU &DUROLQH +HSSHUJHU &KULVWLDQH +RODV $QQD +RWWHU $QQD +XVVO%DUEDUD/DUFKHU3KLOLSS0DKONQHFKW&KULVWRSK0OOHU%HUQDGHWWH3LQWHU:HUQHU3RHZH (YD0DJGDOHQD5HLWHU.ODXV6HSSL)DELHQQH6SUHQJHU*UHJRU:HQQLQJ

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BELGIUM

&KDUOHURL,QVWLWXW GH 3DWKRORJLHHW GH *pQpWLTXH,3*0LFKHO'XSXLV&pFLOH0LQHW3DVFDOH Ribaï, Dominique Van Paemel, Christine Verellen-Dumoulin

CZECH REPUBLIC

Prague (Extrapyramidové centrum, Neurologická klinika, 1. LF UK a VFN): -LĜt .OHPStĜ 9HURQLND0DMHURYi-DQ5RWK

FINLAND

Kuopio: Paivi Hartikainen, Mari Ollokainen

Tampere (Terveystalo Healthcare Service Centre): Maire Santala

Turku-Suvituuli (Rehabilitation Centre Suvituuli): 3LD(NOXQG+HOL+LLYROD+DQQHOH+\SS|QHQ .LUVWL0DUWLNDLQHQ.DWUL7XXKD

FRANCE

$QJHUV &HQWUH GH UpIpUHQFH GHV PDODGLHV QHXURJpQpWLTXH &+8 G¶$QJHUV3KLOLSSH $OODLQ 'RPLQLTXH %RQQHDX 0DULH %RVW %pQpGLFWH *RKLHU 0DULH$QQH *XpULG $XGUH\ 2OLYLHU -XOLH 3URX]HW$GULDQD3UXQGHDQ&ODULVVH6FKHUHU*DJRX&KULVWRSKH9HUQ\

Bordeaux (Hôpital Pellegrin): %ODQGLQH%DELORQL6DEULQD'HEUX[HOOHV&KDUORWWH'XFKp&\ULO*RL]HW /DHWLWLD-DPHDX'DQLHOOH/DIRXFULqUH8PEHUWR6SDPSLQDWR

Clermont-Ferrand (Hôpital Gabriel Montpied): -XOLHQ &RXWWLHU %pUHQJqUH 'HELOO\ &KULVWLQH 'HODLJXH)UDQFN'XULI3HUULQH/HJHQGUH6\OYLH/RLVHDX0LJXHO8OOD7LSKDLQH9LGDO

Creteil (Hôpital Henri Mondor): $QQH&DWKHULQH %DFKRXG/pYL )DULGHK %DGHL 0DULH)UDQoRLVH %RLVVp/RW¿%RXGDOL/DXUHQW&OHUHWGH/DQJDYDQW/DXULH/HPRLQH*UDFD0RUJDGR.DWLD<RXVVRY Lille-Amiens:

Lille (CHRU Roger Salengro): $JQqV $QQLF 5HFND %DUWKpOpP\ &KULVWHOOH 'H %UX\FNHU 0DU\OLQH &DEDUHW  $QQH6RSKLH &DUHWWH 1LFRODV &DUULqUH (ULF 'HFRUWH /XF 'HIHEYUH 0DULH 'HOOLDX[ $UQDXG 'HOYDO $OL]p 'HSHOFKLQ $ODLQ 'HVWHH 1HOO\ 'HZXOI3DV]  7KLEDXW 'RQGDLQH )ORUHQFH 'XJDXTXLHU .DWK\ 'XMDUGLQ /XFLH +RSHV 3LHUUH .U\VWNRZLDN 0DULH+pOqQH /HPDLUH 6\OYLH 0DQRXYULHU (XJpQLH 0XWH] 0LUHLOOH 3HWHU /XFLH 3ORPKDXVH %HUQDUG 6DEORQQLqUH &OpPHQFH 6LPRQLQ&pOLQH7DUG6WpSKDQLH7KLEDXOW7DQFKRX,VDEHOOH9XLOODXPH

Amiens (CHU Sud): 0DUFHOOLQ%HOORQHW$OH[DQGUD%HQRLW+DVVDQ%HUULVRXO6WpSKDQLH%OLQ)UDQoRLVH &RXUWLQ&pFLOH'XUX9pURQLTXH)DVTXHO0pODQLH)ODPHQW2OLYLHU*RGHIUR\3LHUUH.U\VWNRZLDN %pDWULFH 0DQWDX[ $OLFLD 3OD\H 0DUWLQH 5RXVVHO 0pOLVVD 7LU %pDWULFH 6FKOHU 6DQGULQH Wannepain

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Paris (Hôpital de la Pitié Salpêtrière): 6DQGUD%HQDLFK $OH[LV%ULFH6DUDK%RVWHU3HUULQH&KDUOHV $OH[DQGUD'XUU&ODLUH(ZHQF]\N+pOqQH)UDQFLVTXH&pOLQH-DXɣUHW'DPLDQ-XVWR$EGXOUDKPDQ .DVVDU 6WHSKDQ .OHEH )DELHQ /HVQH 3DROR 0LODQL 0DULH/RUUDLQH 0RQLQ (PPDQXHO 5R]H $OLQD7DWDUX0D\D7FKLNYLODG]p

Rouen (Hôpital Charles Nicolle): 6DQGULQH%LRX[(YDQJHOLQH%OLDX[&DUROH*LUDUG/XFLH*X\DQW 0DUpFKDO 'LGLHU +DQQHTXLQ 9pURQLTXH +DQQLHU 6pYHULQH -RXUGDLQ 'DYLG 0DOWrWH 'RURWKpH Pouliquen

Strasbourg (Hôpital Civil): 0DWKLHX$QKHLP1DGLD%DUXQ 2XKDLG/DJKD%RXNEL]D1DGLQH/RQJDWR Christophe Marcel, &OpOLH 3KLOOLSSV *DEULHOOH 5XGROI *LVqOH 6WHLQPHW] &KULVWLQH 7UDQFKDQW &DUROLQH:DJQHU0DULH$JDWKH=LPPHUPDQQ

Toulouse (Hôpital Purpan): /HLO\%ORQGHDX)DELHQQH&DOYDV6DPLD&KHULHW+HOqQH'HODEDHUH -HDQ )UDQoRLV'HPRQHW-pUpPLH3DULHQWH0LFKqOH3LHUUH6DQGULQH5ROODQG

GERMANY

Aachen (Universitätsklinikum Aachen, Neurologische Klinik): &KULVWRSK0LFKDHO.RVLQVNL(YD 0LONHUHLW'DQLHOD3UREVW.DWKULQ5HHW]&KULVWLDQ6DVV-RKDQQHV6FKLHIHU&KULVWLDQH6FKODQJHQ &RUQHOLXV-:HUQHU

Berlin (Universitätsmedizin Berlin, Klinik und Poliklinik für Neurologie): 0DUNXV %HXWK +DUDOG*HOGHUEORP-RVHI3ULOOHU+DUDOG3U‰(LNH6SUXWK6LOYLD7KLHO

Bochum (Huntington-Zentrum (NRW) Bochum im St. Josef-Hospital): -UJHQ$QGULFK*LVD (OOULFKPDQQ /HQQDUG +HUUPDQQ 5DLQHU +RɣPDQQ %DUEDUD .DPLQVNL 3HWHU .UDXV &DUVWHQ Saft, Christiane Stamm

Dinslaken (Reha Zentrum in Dinslaken im Gesundheitszentrums Lang):+HUZLJ/DQJH5REHUW Maiwald

Dresden (Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Klinik und Poliklinik für Neurologie): &HFLOH %RVUHGRQ 8OULNH +XQJHU 0DWWKLDV /|KOH $QWRQLD0DDVV&KULVWLDQD2VVLJ6LPRQH6FKPLGW$OH[DQGHU6WRUFK$QQHWW:RO]0DUWLQ:RO] Erlangen (Universitätsklinikum Erlangen, Molekulare Neurologie und Klinik für

Neurologie):=DFKDULDV.RKO&KULVWLQD.R]D\-DVPLQ8OODK-UJHQ:LQNOHU

Freiburg (Universitätsklinik Freiburg, Neurologie): 8OULNH %HUJPDQQ 5HJLQD %|ULQJHU 3KLOLSS &DSHWLDQ*HULW.DPPHO-RKDQQ/DPEHFN0LULDP0lFKWHO6LPRQH0HLHU0LFKHO5LMQWMHV%LUJLW Zucker

Hamburg (Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurologie): .DL%RHOPDQV&KULVWRV*DQRV,QHV*RHUHQGW:DOEXUJLV+HLQLFNH8WH+LGGLQJ -DQ/HZHUHQ]$OH[DQGHU0QFKDX0LFKDHO2UWK-HQQ\6FKPDOIHOG/DUV6WXEEH6LPRQH=LWWHO Hannover (Neurologische Klinik mit Klinischer Neurophysiologie, Medizinische Hochschule

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Itzehoe (Schwerpunktpraxis Huntington, Neurologie und Psychiatrie): 0LFKDHO5LEEDW Marburg KPP (Klinik für Psychiatrie und Psychotherapie Marburg-Süd): %HUQKDUG/RQJLQXV Marburg UNI (Universitätsklinik Marburg, Sprechstunde für choreatiforme

Bewegungsstörungen):&DUVWHQ0|OOHU.DWULQ%UN

München (Huntington-Ambulanz im Neuro-Kopfzentrum - Klinikum rechts der Isar der Neurologischen Klinik und Poliklinik der Technischen Universität München): $QWMH/VHEULQN0DUN0KODX$OH[DQGHU3HLQHPDQQ0LFKDHO6WlGWOHU$GROI:HLQGO-XOLDQH Winkelmann, Cornelia Ziegler

Münster (Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie): Natalie %HFKWHO +HLNH %HFNPDQQ 6WHIDQ %RKOHQ 1LFROH *|SIHUW (YD +|O]QHU +HUZLJ /DQJH 5DOI Reilmann, Stefanie Rohm, Silke Rumpf, Christian Sass, Sigrun Schepers, Nathalia Weber Taufkirchen (Isar-Amper-Klinikum - Klinik Taufkirchen (Vils)):0LFKDHO%DFKPHLHU0DWWKLDV

'RVH1LQD+RIVWHWWHU5DOI0DUTXDUG$O]EHWD0KOElFN

Ulm (Universitätsklinikum Ulm, Neurologie): .DWULQ%DUWK$QGUHD%XFN-XOLD&RQQHPDQQ'DQLHO (FNHU &DUROLQ *HLWQHU &KULVWLQH +HOG $QGUHD .HVVH %HUQKDUG /DQGZHKUPH\HU )UDQ]LVND /H]LXV -DQ /HZHUHQ] 6ROYHLJ 1HSSHU $QNH 1LHVV 0LFKDHO 2UWK $ULDQH 6FKQHLGHU 'DQLHOD Schwenk, Sigurd Süssmuth, Sonja Trautmann, Melanie Vogel, Patrick Weydt

ITALY

Bari (Neurophysiopathology of Pain Unit, Basic Medical, Neuroscience and Sensory System Department, University of Bari): &ODXGLD &RUPLR 2OLPSLD 'LIUXVFROR *LRYDQQL )UDQFR Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso

Bologna (DIBINEM - Alma Mater Studiorum - Università di Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna): *LRYDQQD&DODQGUD%XRQDXUD6DELQD&DSHOODUL3LHWUR Cortelli, Roberto Gallassi, Roberto Poda, Cesa Scaglione

Florence (Department of Neuroscience, University of Florence & Careggi University Hospital): (OLVDEHWWD %HUWLQL &DWHULQD %DUWROL )HUQDQGD )RUWXQDWR (OHQD *KHOOL $QGUHD *LQHVWURQL&ODXGLD0HFKL0DUFR3DJDQLQL6LOYLD3LDFHQWLQL6LOYLD3UDGHOOD$QQD0DULD5RPROL Sandro Sorbi

Genoa (Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova): *LRYDQQL $EEUX]]HVH 0RQLFD %DQGHWWLQL GL 3RJJLR*LRYDQQD)HUUDQGHV3DROD0DQGLFK5REHUWD0DUFKHVH(PLOLR'L0DULD

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Naples (Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University of Naples): *LXVHSSH 'H 0LFKHOH /XLJL 'L 0DLR &DUOR 5LQDOGL0DUFR0DVVDUHOOL6LOYLR3HOXVR$OHVVDQGUR5RFD&LQ]LD9DOHULD5XVVR(OHQD6DOYDWRUH Pierpaolo Sorrentino, Tecla Tucci

Pozzilli (IS) (IRCCS Neuromed): 0LOHQD &DQQHOOD 9DOHQWLQD &RGHOOD )UDQFHVFD 'H *UHJRULR $QQXQ]LDWD 'H 1LFROD )UDQFHVFD (OLIDQL 7L]LDQD 0DUWLQR )UDQFHVFD /RYR ,UHQH 0D]]DQWH 0DUWLQD3HWUROOLQL0DULD6LPRQHOOL)HUGLQDQGR6TXLWLHUL0DXUL]LR9H]]D

Rome (LIRH Foundation):%DUEDUD'¶$OHVVLR&KLDUD(VSRVLWR,UHQH0D]]DQWH)HUGLQDQGR6TXLWLHUL 5RPH 'HSDUWPHQW RI 1HXURORJ\ 8QLYHUVLWj &DWWROLFD GHO 6DFUR &XRUH ,QVWLWXWH RI

Translational Pharmacology & Institute of Cognitive Sciences and Technologies, National Research Council of Italy): $QQD 5LWD %HQWLYRJOLR )UDQFHVFR %RYH  &ODXGLR &DWDOOL 5DɣDHOOD 'L *LDFRSR $OIRQVR )DVDQR 0DULQD )URQWDOL $ULDQQD *XLGXEDOGL 7DPDUD ,DORQJR*LRLD-DFRSLQL*LRYDQQD/RULD$QQD0RGRQL0DUWLQD3HWUDFFD&DUOD3LDQR3LFFLQLQQL &KLDUD'DYLGH4XDUDQWD6LOYLD5RPDQR)UDQFHVFR6ROHWL0DUFHOOD6ROLWR0DULD6SDGDUR)ODYLD Torlizzi, Paola Zinzi

5RPH $]LHQGD 2VSHGDOLHUD 6DQW¶$QGUHD 'HSDUWPHQW RI 1HXURVFLHQFH 0HQWDO +HDOWK and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza 8QLYHUVLW\RI5RPH,QVWLWXWHRI7UDQVODWLRQDO3KDUPDFRORJ\ ,QVWLWXWHRI&RJQLWLYH Sciences and Technologies, National Research Council of Italy): Giulia Coarelli, Michela )HUUDOGHVFKL0DULQD)URQWDOL*LRLD-DFRSLQL*LRYDQQL5LVWRUL6LOYLD5RPDQR3DROD=LQ]L

NETHERLANDS

Enschede (Medisch Spectrum Twente):0RQLTXH6(YDQ+RXW-HURHQ33YDQ9XJW$0DULWGH Weert, Marloes Verhoeven

Groningen (Polikliniek Neurologie): 0HLNH 'HNNHU 1LFR /HHQGHUV -RRVW YDQ 2RVWURP -HVSHU .ORRVWHU%HUU\.UHPHU

Leiden (Leiden University Medical Centre (LUMC)):9HUHQD%DDNH6LPRQ-$YDQGHQ%RJDDUG 5HLQHNH %RV (YH 0 'XPDV (OOHQ 3 µW +DUW $QQH .DPSVWUD 5D\PXQG $& 5RRV $QQH Schoonderbeek

Maastricht: $QQHOLHQ'XLWV0D\NH2RVWHUORR0LUHOOD:DEHU

NORWAY

Bergen (Haukeland University Hospital, Dept of Medical Genetics and Olaviken Psychiatric Hospital): (OOHQ‘NODQG%OLQNHQEHUJ1.62ODYLNHQCV+'FOLQLF(ULN+DXJH+LOGH7\YROO Oslo University Hospital (Dept. of Medical Genetics, Dept. of Neurology, Dept.of

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+DJJDJ-RKDQQHVVHQ$UYLG+HLEHUJ/DUV5HWWHUVW¡O2GGYHLJ5¡VE\-XWWD5XPPHO$OPD6LNLULF %RGLO6WRNNH0DUOHHQYDQ:DOVHP5DJQKLOG:HKXV

Trondheim (St. Olavs Hospital): ,QJD %M¡UQHYROO 6LJULG %RWQH 6DQGR 0DUWH *M¡O +DXJ +DQQD +DXJDQ6W¡UVHWK9LEHNH$UQWVHQ

32/$1'

Gdansk (St. Adalbert Hospital, Gdansk, Medical University of Gdansk, Neurological and Psychiatric Nursing Dpt.): $UWXU']LDGNLHZLF]$JQLHV]ND.RQNHO(ZD1DURĪDĔVND0DOJRU]DWD 1RZDN3LRWU5RERZVNL(PLOLD6LWHN-DURVODZ6ODZHN:LWROG6ROWDQ0LFKDO6]LQZHOVNL Katowice (Medical University of Silesia, Katowice): 0LFKDá $UNXV]HZVNL 0DJGDOHQD %áDV]F]\N

0DJGDOHQD %RF]DUVND-HG\QDN Ewelina Ciach-Wysocka, $JQLHV]ND *RU]NRZVND %DUEDUD -DVLĔVND0\JD$OHNVDQGUD.DF]PDUF]\N*DEULHOD.áRGRZVND±'XGD*U]HJRU]2SDOD0RQLND 5XG]LĔVND Daniel Stompel

Krakow (Krakowska Akademia Neurologii): .U]\V]WRI %DQDV]NLHZLF] 'RURWD %RüZLĔVND .DPLOD %RMDNRZVND-DUHPHN0DáJRU]DWD'HF1DWDOLD*UDEVND0DOJRU]DWD.UDZF]\N(ZHOLQD.XERZLF] 0LFKDOLQD 0DOHF/LWZLQRZLF] 0RQLND 5XG]LĔVND $JDWD 6WHQZDN $QGU]HM 6]F]XGOLN (OĪELHWD 6]F]\JLHá0DJGDOHQD:yMFLN$QQD:DVLHOHZVND

Poznan (Poznan University of Medical Sciences, Poland): -DFHN$QLRáD$QQD%U\O$QQD&LHVLHOVND $QHWD .OLPEHUJ -HU]\ 0DUFLQNRZVNL +XVDP 6DPDUD -XVW\QD 6HPSRáRZLF] %DUWáRPLHM :LĞQLHZVNL'DQLHO=LHORQND

Warsaw-MU (Medical University of Warsaw, Neurology): $QQD *RJRO IRUPHUO\ .DOEDUF]\N 3LRWU-DQLN=\JPXQW-DPUR]LN$QQD.DPLQVND+XEHUW.ZLHFLQVNL1DWDOLD6]HMNR

Warsaw-IPiN (Institute of Psychiatry and Neurology Dep. of Genetics, First Dep. of Neurology): -DNXE$QWF]DN.DWDU]\QD-DFKLQVND:LROHWWD.U\VD0DU\OD5DNRZLF]3U]HP\VODZ Richter, Rafal Rola, Danuta Ryglewicz, +DOLQD6LHQNLHZLF]-DURV], ,ZRQD6WĊSQLDN$QQD6XáHN *U]HJRU]:LWNRZVNL-DFHN=DUHPED(O]ELHWD=G]LHQLFND.DUROLQD=LRUD-DNXWRZLF]

PORTUGAL

Coimbra – (Hospital Universitário de Coimbra):&ULVWLQD-DQXiULR)LOLSD-~OLR

Lisbon-HSM (Hospital de Santa Maria, Clinical Pharmacology Unit, Instituto de Medicina Molecular):/HRQRU&RUUHLD*XHGHV0LJXHO&RHOKR-RDTXLP-)HUUHLUD7LDJR0HVWUH7LDJR 0HQGHV$QDEHOD9DODGDV

Porto-HGSA (Hospital Santo António- Centro Hospitalar do Porto): *RQoDOR&DomR6DUD&DYDFR -RDQD'DPiVLR-RDQD)HUQDQGHV5XL/RXUHLUR,QrV0RUHLUD0DULQD0DJDOKmHV

Porto- HSJ (Hospital de São João):&DUORV$QGUDGH$QGUHLD&RVWD&DUROLQD*DUUHWW0LJXHO*DJR -RDQD*XLPDUmHV-RmR0DVVDQR-RDQD0HLUHOHV$QD0RQWHLUR

SPAIN

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Barcelona-Bellvitge (Hospital Universitari de Bellvitge): -RUGL %DV 1~ULD %XVTXHWV 0DWLOGH &DORSD6HUJH-DXPj&ODVVHQ1DGLD5RGUtJXH]'HGLFKi

Barcelona- Clínic i Provincial (Hospital Clínic i Provincial): 0DUtD7HUHVD%XRQJLRUQR$QGUpVGH OD&HUGD6DQWD0DUtD(VWHEDQ0XxR]3LODU6DQWDFUX]

Barcelona-Hospital Mútua de Terrassa: 0LTXHO$JXLODU%DUEHUD$QD5RMR6HEDVWLiQ6RQLD$UULEDV 3DUGR 'RORUV %DGHQHV *XLD 1RHPL &DO]DGR /DXUD &DVDV +HUQDQ] -XDQ 3DEOR 7DUWDUL 'tD] =RULWD-XGLW/ySH]&DWHQD3LODU4XLOp])HUUHU*HPPD7RPH&DUUXHVFR

Barcelona-Merced (Hospital Mare de Deu de La Merced): 0LVHULFRUGLD )ORULDFK 5REHUW &qOLD 0DUHFD9LODGULFK(OYLUD5RFD-HV~V0LJXHO5XL],GLDJR$QWRQLR9LOOD5LEDOOR

Barcelona-Santa Cruz y San Pablo (Hospital de la Santa Creu i Sant Pau): $QWRQLD&DPSRORQJR 5DPRQ )HUQDQGH] GH %REDGLOOD -DLPH .XOLVHYVN\ %RMDUVN\ 6DXO 0DUWLQH]+RUWD -DYLHU 3DJRQDEDUUDJD-HVXV3HUH]3HUH]5RVHU5LERVD&DUROLQD9LOOD

Burgos (Servicio de Neurología Hospital General Yagüe): Esther Cubo, Cecilia Gil Polo, Natividad Mariscal

Canarias (Hospital Insular de Gran Canaria): Sandra Gutierrez Romero, -RVp0DWtDV$UEHOR5RFtR 0DORGH0ROLQD,GDLUD0DUWtQ-XDQ0DQXHO3HULDxH]%HDWUL]8GDHWD

Fuenlabrada (Hospital Universitario): )HUQDQGR$ORQVR)UHFK0DUtDGHO9DOOH/RDUWH Granada (Hospital Universitario San Cecilio, Neurología):)UDQFLVFR%DUUHUR%ODV0RUDOHV Madrid-BTCIEN (Fundación CIEN): %HOpQ )UDGHV 0DULQD ÈYLOD 9LOODQXHYD 0DULD $VFHQVLRQ =HD

Sevilla

Madrid-Clinico (Hospital Clínico Universitario San Carlos):)HUQDQGR$ORQVR)UHFK0DUtDGHO 0DU)HQROODU5RFtR*DUFtD5DPRV*DUFtD&ODUD9LOODQXHYD

Madrid RYC (Hospital Ramón y Cajal, Neurología):0yQLFD%DVFXxDQD0DUWD)DWiV9HQWXUD-XDQ *DUFtD &DOGHQWH\ *XLOOHUPR *DUFtD 5LEDV -XVWR *DUFtD GH <pEHQHV -RVp /XLV /ySH]±6HQGyQ 0RUHQR9HUyQLFD0DxDQHV%DUUDO3DWULFLD7ULJR&XELOOR

Madrid FJD (Madrid-Fundación Jiménez Díaz):&LFL)HOL])HOL]3HGUR-RVp*DUFtD5Xt]$QD*DUFtD -XDQ *DUFtD &DOGHQWH\ 5RVD *XHUUHUR /ySH] $QWRQLR +HUUDQ] %iUFHQDV $VXQFLyQ 0DUWtQH] 'HVFDOV9HURQLFD3XHUWDV0DUWLQ1RHOLD5RGUtJXH]0DUWtQH]0DUtD-RVp6DLQ]$UWLJD9LFHQWD 6iQFKH]$QJHO0DUWtQH]3XH\R-DYLHUGHO9DO)HUQDQGH]

Murcia (Hospital Universitario Virgen de la Arrixaca):0RUHDX0DUtD'RORUHV$ODUFyQ&DUPHQ $QW~QH]$OPDJUR(VWKHU'LpJXH]/RUHQ]D)RUWXQD6DOYDGRUD0DQ]DQDUHV-XDQ0DUtQ0XxR] 0DUtD0DUWLULR$QWHTXHUD7RUUHV)XHQVDQWD1RJXHUD3HUHD/DXUD9LYDQFRV

Oviedo (Hospital Central de Asturias):6RQLD*RQ]iOH]/XLV0HQpQGH]*XLVDVROD0DUWD3DUD3ULHWR 5HQp5LEDFRED&DUORV6DOYDGRU3DEOR6iQFKH]/R]DQR

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Pamplona (Complejo Hospitalario de Navarra): ,W]LDU *DVWRQ )HUPLQ *DUFLD$PLJRW 0DULD 'RORUHV0DUWLQH]-DXUULHWD0DULD$QWRQLD5DPRV$UUR\R

Sevilla (Hospital Virgen Macarena): )iWLPD'DPDV+HUPRVR-RVp0DQXHO*DUFtD0RUHQR&DUROLQD 0HQGH]/XFHQD(YD0DUtD3DFKHFR&RUWHJDQD-RVp&KDFyQ3HxD/XLV5HGRQGR9LROHWD6iQFKH] 6iQFKH]

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Medication and cognition

Dundee (Scottish Huntington’s Association, Ninewells Hospital): 'DYLG *RXGLH /LQGVD\ %XFKDQDQ3DXOD0F)DG\HQ$OLVRQ7RQQHU$QQH0DULH7D\ORU

Edinburgh (SE Scotland Genetic Service, Western General Hospital): Maureen Edwards, Carrie +R6FRWWLVK+XQWLQJWRQV$VVRFLDWLRQ0DULH0F*LOO0DU\3RUWHRXV3DXOLQH3HDUVRQ

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Glasgow (Glasgow HD Management Clinic, Southern General Hospital)&DWKHULQH'HLWK-DQH Ireland, Stuart Ritchie

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Leeds (Chapel Allerton Hospital, Department of Clinical Genetics): -HUHP\ &RVJURYH 'HHQD *DOODQWUHH6WHSKDQLH+DPHU(PPD+REVRQ6WXDUW-DPLHVRQ$OLVRQ.UDXV0DQG\/RQJWKRUSH ,YDQD0DUNRYD+DQQDK0XVJUDYH&DUROLQH3HDF\$VKRN5DPDQ/L]5RZHWW-HDQ7RVFDQR6XH Wild, Pam Yardumian

Leicester (Leicestershire Partnership Trust, Mill Lodge): Carole Clayton, Heather Dipple, Dawn )UHLUH3DWLQR&DUROLQH+DOODP-XOLD0LGGOHWRQ

London (St. Georges-Hospital):8UXM$QMXP-DQ&RHEHUJK&KDUORWWH(GG\1D\DQD/DKLUL0HULHO McEntagart, Michael Patton, Maria Peterson, Sarah Rose

London (Guy’s Hospital): 7KRPDVLQ$QGUHZV$QGUHZ'RXJKHUW\&KDUORWWH*ROGLQJ)UHG.DYDOLHU +DQD/DLQJ$OLVRQ/DVKZRRG'HQH5REHUWVRQ'HERUDK5XGG\$ODVWDLU6DQWKRXVH$QQD:KDLWH London (The National Hospital for Neurology and Neurosurgery):7KRPDVLQ$QGUHZV6WHIDQLH

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Northampton (St Andrew’s Healthcare):(OYLQD&KX&DUROLQH.QLJKW0DUL2¶1HLOO'HEDVLVK'DV Purkayastha

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Preston (Neurology Department, Preston Royal Hospital): Marianne Hare, Tahir Majeed, Nicola Verstraelen (Ritchie)

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EHDN’s associate site in Singapore:

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References

 $ QRYHO JHQH FRQWDLQLQJ D WULQXFOHRWLGH UHSHDW WKDW LV H[SDQGHG DQG XQVWDEOH RQ +XQWLQJWRQ¶V disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 1993;72:971-983.

 5RRV5$+XQWLQJWRQ¶VGLVHDVHDFOLQLFDOUHYLHZ2USKDQHW-5DUH'LV

 1HKO&3DXOVHQ-6+XQWLQJWRQ6WXG\*&RJQLWLYHDQGSV\FKLDWULFDVSHFWVRI+XQWLQJWRQGLVHDVH FRQWULEXWHWRIXQFWLRQDOFDSDFLW\-1HUY0HQW'LV

 5HDG\5(0DWKHZV0/HVHUPDQ$3DXOVHQ-63DWLHQWDQGFDUHJLYHUTXDOLW\RIOLIHLQ+XQWLQJWRQ¶V GLVHDVH 0RYHPHQW GLVRUGHUV  RɤFLDO MRXUQDO RI WKH 0RYHPHQW 'LVRUGHU 6RFLHW\  726.

 'Xɣ.3DXOVHQ-0LOOV-HWDO0LOGFRJQLWLYHLPSDLUPHQWLQSUHGLDJQRVHG+XQWLQJWRQGLVHDVH Neurology 2010;75:500-507.

 .LUNZRRG 6& 6LHPHUV ( +RGHV 0( &RQQHDOO\ 30 &KULVWLDQ -& )RURXG 7 6XEWOH FKDQJHV DPRQJSUHV\PSWRPDWLFFDUULHUVRIWKH+XQWLQJWRQ¶VGLVHDVHJHQH-1HXURO1HXURVXUJ3V\FKLDWU\ 2000;69:773-779.

 /HPLHUH-'HFUX\HQDHUH0(YHUV.LHERRPV*9DQGHQEXVVFKH('RP5/RQJLWXGLQDOVWXG\ evaluating neuropsychological changes in so-called asymptomatic carriers of the Huntington’s GLVHDVHPXWDWLRQDIWHU\HDU$FWD1HXURO6FDQG

 3DXOVHQ -6 6PLWK 00 /RQJ -' LQYHVWLJDWRUV 3+ &RRUGLQDWRUV RI WKH +XQWLQJWRQ 6WXG\ * &RJQLWLYH GHFOLQH LQ SURGURPDO +XQWLQJWRQ 'LVHDVH LPSOLFDWLRQV IRU FOLQLFDO WULDOV - 1HXURO Neurosurg Psychiatry 2013;84:1233-1239.

 6WRXW -& -RQHV 5 /DEXVFKDJQH , HW DO (YDOXDWLRQ RI ORQJLWXGLQDO  DQG  PRQWK FRJQLWLYH RXWFRPHV LQ SUHPDQLIHVW DQG HDUO\ +XQWLQJWRQ¶V GLVHDVH -1HXURO1HXURVXUJ3V\FKLDWU\ 2012;83:687-694.  'XPDV(0YDQGHQ%RJDDUG6-0LGGHONRRS+$5RRV5$$UHYLHZRIFRJQLWLRQLQ+XQWLQJWRQ¶V GLVHDVH)URQWLHUVLQELRVFLHQFH6FKRODUHGLWLRQ  7KRPSVRQ-&+DUULV-6ROORP$&HWDO/RQJLWXGLQDOHYDOXDWLRQRIQHXURSV\FKLDWULFV\PSWRPV LQ+XQWLQJWRQ¶VGLVHDVH-1HXURSV\FKLDWU\&OLQ1HXURVFL  YDQ'XLMQ(.LQJPD(0YDQGHU0DVW5&3V\FKRSDWKRORJ\LQYHUL¿HG+XQWLQJWRQ¶VGLVHDVHJHQH FDUULHUV-1HXURSV\FKLDWU\&OLQ1HXURVFL  %DDNH95HLMQWMHV5'XPDV(07KRPSVRQ-&1HWZRUN5,RW(+V'5RRV5$&&RJQLWLYHGHFOLQH in Huntington’s disease expansion gene carriers. Cortex 2017;95:51-62.

 8QL¿HG+XQWLQJWRQ¶V'LVHDVH5DWLQJ6FDOHUHOLDELOLW\DQGFRQVLVWHQF\+XQWLQJWRQ6WXG\*URXS Mov Disord 1996;11:136-142.

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 6RORPRQ$&6WRXW-&:HDYHU0HWDO7HQ\HDUUDWHRIORQJLWXGLQDOFKDQJHLQQHXURFRJQLWLYHDQG motor function in prediagnosis Huntington disease. Mov Disord 2008;23:1830-1836.

 .LOORUDQ$%LJODQ.0&XUUHQWWKHUDSHXWLFRSWLRQVIRU+XQWLQJWRQ¶VGLVHDVHJRRGFOLQLFDOSUDFWLFH YHUVXV HYLGHQFHEDVHG DSSURDFKHV" 0RYHPHQW GLVRUGHUV  RɤFLDO MRXUQDO RI WKH 0RYHPHQW Disorder Society 2014;29:1404-1413.

 3ULOOHU-(FNHU'/DQGZHKUPH\HU%&UDXIXUG'$(XURSHZLGHDVVHVVPHQWRIFXUUHQWPHGLFDWLRQ choices in Huntington’s disease. Mov Disord 2008;23:1788.

19. van Duijn E. Treatment of Irritability in Huntington’s Disease. Curr Treat Options Neurol 2010;12:424-433.

20. van Duijn E. Medical treatment of behavioral manifestations of Huntington disease. Handb Clin Neurol 2017;144:129-139.

 &RPR3*5XELQ$-2¶%ULHQ&)HWDO$FRQWUROOHGWULDORIÀXR[HWLQHLQQRQGHSUHVVHGSDWLHQWV with Huntington’s disease. Mov Disord 1997;12:397-401.

 %DUNHU0-*UHHQZRRG.0-DFNVRQ0&URZH6)&RJQLWLYHHɣHFWVRIORQJWHUPEHQ]RGLD]HSLQH use: a meta-analysis. CNS Drugs 2004;18:37-48.

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Supplementary Appendix

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Benzodiazepines: $OSUD]RODP %URPD]HSDP %URWL]RODP &KORUGLD]HSR[LGH &ORED]DP &ORUD]HSDWH 'LD]HSDP (VWD]RODP (WL]RODP )OXUD]HSDP /RSUD]RODP /RUD]HSDP /RUPHWD]HSDP Midazolam, Nitrazepam, Oxazepam, Prazepam, Temazepam, Zolpidem, Zopiclone

SSRI Antidepressants:&LWDORSUDP(VFLWDORSUDP)OXR[HWLQH)OXYR[DPLQH3DUR[HWLQH6HUWUDOLQH Antipsychotics: $PLVXOSULGH &KORUSURWKL[HQH )OXSKHQD]LQH )OXSHQWL[RO )OXVSLULOHQH +DORSHULGRO

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