Despite the clearly recognized progressive functional decline of Huntington’s disease (HD), detailed investigations of factors associated with the rate of functional progression are limited.
Objective:
Understanding factors associated with functional decline through examination of existing HD clinical databases may improve efforts to mitigate it.
Methods:
We analyzed data from 2CARE, a randomized clinical trial with up to 5 years of follow-up, to assess potential risk factors for more rapid functional decline in HD.
Results:
Variables associated with faster functional decline included worse motor performance, worse cognitive test scores, female sex, lower weight and body mass index, and a higher CAG repeat length, especially in younger people.
Conclusion:
While our data are limited to the structured environment and homogeneity of a clinical trial, attention to several of the identified risk factors may be useful towards managing functional decline over time. The observation that women progress faster than men, while potentially confounded by an association between sex and weight, deserves further study.
McGarryA, BiglanK, MarshallF. Huntington’s disease. In: Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease. London: Elsevier; 2015. pp. 861-8.
2.
FeiginA, KieburtzK, BordwellK, ComoP, SteinbergK, SotackJ, et al.Functional decline in Huntington’s disease. Mov Disord. 1995;10(2):211–4.
3.
MarderM, ZhaoH, MyersRH, CudkowiczM, KaysonE, KieburtzK, et al.Rate of functional decline in Huntington’s disease. Neurology. 2000;54(2):452–8.
4.
DorseyER, BeckCA, DarwinK, NicholsP, BrochtAF, BiglanKM, et al.Natural history of Huntington disease. JAMA Neurol. 2013;70(12):1520–30.
5.
McGarryA, McDermottM, KieburtzK, de BlieckEA, BealF, MarderK, et al.A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease. Neurology. 2017;88(2):152–9.
6.
FrankS. Treatment of Huntington’s disease. Neurotherapeutics. 2014;11(1):153–60.
7.
VeenhuizenRB, KootstraB, VinkW, PosthumusJ, van BekkumP, ZijlstraM, et al.Coordinated multidisciplinary care for ambulatory Huntington’s disease patients: Evaluation of 18 months of implementation. Orphanet J Rare Dis. 2011;6:77.
8.
FritzNE, RaoAK, KegelmeyerD, KloosA, BusseM, HartelL, et al.Physical therapy and exercise interventions in Huntington’s disease: A mixed methods systematic review. J Huntingtons Dis. 2017;6(3):217–35.
9.
PiiraA, van WalsemMR, MikalsenG, NilsenKH, KnutsenS, FrichJC. Effects of a one year intensive multidisciplinary rehabilitation program for patients with Huntington’s disease: A prospective intervention study. PLoS Curr. 2013;5: ecurrents.hd.9504af71e0d1f87830c25c394be47027.
10.
KieburtzK, MacDonaldM, ShihC, FeiginA, SteinbergK, BordwellK, et al.Trinucleotide repeat length and progression of illness in Huntington’s disease. J Med Genet. 1994;31(11):872–4.
11.
The Unified Huntington’s Disease Rating Scale: Reliability and consistency. Huntington Study Group. Mov Disord. 1996;11:136–42.
12.
ShoulsonI, KurlanR, RubinAJ, GoldblattD, BehrJ, MillerC, et al. Assessment of functional capacity in neurode-generative movement disorders: Huntington’s disease as a prototype. In: Munsat T, editor. Quantification of Neurological Deficit. Boston: Butterworths; 1989. pp. 271-83.
13.
The Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s Disease. Neurology. 2001;57:397–404.
14.
LandwehrmeyerGB, DuboisB, de YebenesJG, KremerB, GausW, KrausPH, et al.Riluzole in Huntington’s disease: A 3-year, randomized controlled study. Ann Neurol. 2007;62(3):262–72.
15.
HerschSM, SchifittoG, OakesD, BredlauAL, MeyersCM, NahinR, et al.The CREST-E study of creatine for Huntington disease: A randomized controlled trial. Neurology. 2017;89(6):594–601.
16.
BeglingerLJ, O’RourkeJJ, WangC, LangbehnDR, DuffK, PaulsenJS, et al.Earliest functional declines in Huntington disease. Psychiatry Res. 2010;178(2):414–8.
17.
McGarryA, McDermottM, KieburtzK, FungWLA, McCuskerE, PengJ, et al.Risk factors for suicidality in Huntington’s disease: An analysis of the 2CARE Clinical Trial. Neurology. 2019;92(14):e1643–e1651. doi: 10.1212/WNL.0000000000007244
18.
MolenberghsG, KenwardMG. Missing data in clinical studies. Chichester, UK: John Wiley and Sons; 2007.
19.
Bialek, M, ZarembaP, BorowiczKK, CzuczwarSJ. Neuroprotective role of testosterone in the nervous system. Pol J Pharmacol. 2004;56:509–18.
20.
BrannDW1, DhandapaniK, WakadeC, MaheshVB, KhanMM. Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications. Steroids. 2007;72(5):381–405.
21.
SinghM, SuC. Progesterone and neuroprotection. Horm Behav. 2013;63(2):284–90. doi: 10.1016/j.yhbeh.2012.06.003
22.
MarkianosM, PanasM, KalfakisN, VassilopoulosD. Plasma testosterone in male patients with Huntington’s Disease; relations to severity of illness and dementia. Ann Neurol. 2005;57(4):520–5.
23.
PapalexiE, PerssonA, BjorkqvistM, PetersenA, WoodmanB, BatesGP, et al.Reduction of GnRH and infertility in the R6 / 2 mouse model of Huntington’s disease. Eur J Neurosci. 2005;22:1541–6.
24.
HannanAJ, RansomeMI. Deficits in spermatogenesis but not neurogenesis are alleviated by chronic testosterone therapy in R6 / 1 Huntington’s disease mice. J Neuroendocrinol. 2012;24:341–56.
25.
KumarP, KumarP, DeshmukhR, SharmaPL. P2–044: Neuroprotective role of progesterone against 3-nitropropionic acid-induced Huntington’s disease-like symptoms in rats. Alzheimers Dement. 2013;9(4 Suppl):P360.
26.
NuzzoMT, MarinoM. Estrogen/Huntingtin: A novel pathway involved in neuroprotection. Neural Regen Res. 2016;11(3):402–3. doi: 10.4103/1673-5374.179045
27.
NuzzoMT, FiocchettiM, ServadioM, TrezzaV, AscenziP, MarinoM. 17β-Estradiol modulates huntingtin levels in rat tissues and in human neuroblastoma cell line. Neurosci Res. 2016;103:59–63.
28.
ZielonkaD, RenM, De MicheleG, RoosRAC, SquitieriF, BentivoglioAR, et al.The contribution of gender differences in motor, behavioral, and cognitive features to functional capacity independence and quality of life in patients with Huntington’s disease. Parkinsonism Relat Disord. 2018;49:42–7.
29.
FeiginA, KieburtzK, BordwellK, ComoP, SteinbergK, SotackJ, et al.Functional decline in Huntington’s disease. Mov Disord. 1995;10(2):211–4.
30.
BrandtJ, BylsmaFW, GrossR, StineOC, RanenN, RossCA. Trinucleotide repeat length and clinical progression in Huntington’s disease. Neurology. 1996;46(2):527–31.
31.
RavinaB, RomerM, ConstantinescuR, BiglanK, BrochtA, KieburtzK, et al.The relationship between CAG repeat length and clinical progression in Huntington’s disease. Mov Disord. 2008;23(9):1223–7.
32.
RosenblattA, KumarBV, MoA, WelshCS, MargolisRL, RossCA. Age, CAG repeat length, and clinical progression in Huntington’s disease. Mov Disord. 2012;27(2):272–6.
33.
AzizNA, van der BurgJMM, TabriziSJ, LandwehrmeyerGB. Overlap between age-at-onset and disease-progression determinants in Huntington disease. Neurology. 2018;90:e2099–e2106.
34.
ShinB, JungR, OhH, OwensGE, LeeH, KwakS, et al.Novel DNA Aptamers that bind to mutant Huntingtin and modify its activity. Mol Ther Nucleic Acids. 2018;11:416–28.
35.
LeeJM, ChaoMJ, HaroldD, Abu ElneelK, GillisT, HolmansP, et al.A modifier of Huntington’s disease onset at the MLH1 locus. Hum Mol Genet. 2017;26(19):3859–67.
36.
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell. 2015;162:516–26.
37.
MossDJH, PardiñasAF, LangbehnD, LoK, LeavittBR, RoosR, et al.Identification of genetic variants associated with Huntington’s disease progression: A genome-wide association study. Lancet Neurol. 2017;16(9):701–11.
