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World J Psychiatr. Sep 22, 2013; 3(3): 62-64
Published online Sep 22, 2013. doi: 10.5498/wjp.v3.i3.62
Acetylcholinesterase inhibitors in cognitive impairment in Huntington’s disease: A brief review
Joe John Vattakatuchery, Renjith Kurien, 5 Boroughs Partnership NHS Foundation Trust, Warrington WA28WA, United Kingdom
Author contributions: Both authors contributed equally to this article.
Correspondence to: Joe John Vattakatuchery, MBBS, MRCPsych, Consultant Psychiatrist, 5 Boroughs Partnership NHS Foundation Trust, Hollins Park House, Hollins Lane, Warrington WA28WA, United Kingdom. joejohn@doctors.net.uk
Telephone: +44-19-25666647 Fax: +44-19-25666645
Received: June 29, 2013
Revised: August 24, 2013
Accepted: September 3, 2013
Published online: September 22, 2013

Abstract

Huntington’s disease (HD) is a neurodegenerative disease associated with cognitive deficits. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms. The cognitive dysfunction includes executive dysfunction, psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss and difficulty learning new skills. Acetylcholinesterase inhibitors have shown good effect in the treatment of other types of dementia and it is postulated that it might delay cognitive decline in HD. We reviewed the evidence for Acetylcholinesterase inhibitors in the treatment of cognitive decline and dementia associated with Huntington’s disease. We identified 6 articles that investigated the role of Acetylcholinesterase inhibitors for treatment of cognitive deficits in Huntington’s disease. Following the review, the authors concluded that there is limited evidence for the use of Acetylcholinesterase inhibitors for cognitive impairment in HD.

Key Words: Huntington’s disease, Huntington’s dementia, Cognitive deficits, Acetylcholinesterase inhibitors, Donepezil, Rivastigmine, Galantamine

Core tip: The evidence for Acetylcholinesterase inhibitors in the treatment of cognitive decline and dementia associated with Huntington’s disease is reviewed in this article. Six articles were identified that investigated the role of Acetylcholinesterase inhibitors for treatment of cognitive deficits in Huntington’s disease (HD). We concluded that there is limited evidence for the use of Acetylcholinesterase inhibitors for cognitive impairment in HD.



INTRODUCTION

The clinical description of Huntington’s disease (HD) was reported by George Huntington in 1872 and led to increased recognition of the condition[1]. The prevalence of the illness is about 5.70 per 100000 births[2]. HD is characterised by movement disorder, cognitive deficits and psychiatric symptoms. HD is a progressive neurodegenerative autosomal dominant disorder caused by a single defective gene on chromosome 4. In HD, mutation of HTT gene leads to abnormal CAG trinucleotide repeat[3]. A larger number of repeat is associated with earlier onset of the illness[4].

The clinical features of HD frequently include cognitive dysfunction[5]. Cognitive dysfunction may be present in the early stages of the disease, even before the onset of motor symptoms[6]. Cognitive dysfunction includes executive dysfunction, psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss and difficulty learning new skills. Cognitive dysfunction lead to frontal and subcortical dementia[7]. There are structural and functional brain changes in HD that correlate to cognitive deficits[8]. Decreased Acetyl Choline levels have been noted in HD patients[9,10].

REVIEW OF LITERATURE
Search strategy

We used Medline, EMBASE and PsychINFO databases and used key terms such as Acetylcholinesterase inhibitors, HD, Huntington’s dementia, Donepezil, Galantamine and Rivastigmine. The bibliographies of all identified articles and previously published reviews were scanned for additional studies.

Description of identified studies

Six studies were identified that investigated the effect of acetylcholine esterase inhibitors in HD.

Fernandez et al[11] conducted an open label trial of 8 patients with HD and prescribed Donepezil. Two patients had slight improvement in memory and concentration at 5 mg/d. There was no statistically significant improvement at 6 wk from baseline scores on all neuropsychological tests. Due to 4 patients dropping out, analysis at 12 wk was not done due to lack of statistical power.

Rot et al[12] investigated the effect of Rivastigmine on four symptomatic HD patients (3 females, 1 male). Unified Huntington’s Disease Rating Scale (UHDRS), Mini Mental State Examination (MMSE) and Trail making test were used to assess change in cognitive function. They were evaluated at baseline and 26 wk of therapy. The results showed an improvement in cognitive and behavioral parts of UHDRS, MMSE and Trail making test. There was no improvement in motor and functional subscales of UHDRS. As the study had only four subjects (only 3 completed the trial) and did not have a control group, it is difficult to make any worthwhile conclusions about the efficacy of Acetylcholinesterase inhibitors from this study.

Petrikis et al[13] report a case of a 35-year-old male patient with HD who presented with symptoms of an acute psychotic episode. He was evaluated using Positive and Negative Syndrome Scale, Extrapyramidal Symptom Rating Scale and MMSE. He was initially treated with Haloperidol Decanoate and after a month this was changed to Galantamine. The authors report good improvement of psychotic symptoms and chorea on Galantamine but there was no improvement in his cognitive functioning (Table 1).

Table 1 Trials and reports of Acetylcholinesterase use in Huntington’s disease.
Ref.DesignMedication usedOutcome measuresResult
Fernandes et al[11]Open labelled studyDonepezilUHDRS, MMSE, Wechsler memory scale-III, Symbol Digit, Odd Man Out test, Hopkins Verbal Learning testNo statistical significance between mean scores at baseline and 6 wk on all neuropsychological tests.
Rot et al[12]Longitudinal studyRivastigmineUHDRS, MMSE, Trail making testImprovement on cognitive tests and behavioural part of UHDRS
Petrikis et al[13]Case reportGalantaminePANSS ESRS MMSEImprovement on PANSS and ESRS but no improvement on MMSE
de Tommaso et al[14]Prospective, open labelled randomized controlled trialRivastigmineMMSE, Marsden and Quinn Chorea Severity Scale, Total Functional Capacity score, Abnormal Involuntary Movement scaleImprovement on MMSE compared to baseline
Cubo et al[15]Randomized controlled trialDonepezilUHDRS, Alzheimers Disease Assessment Scale, Sickness Impact ProfileNo significant improvement except for improvement on UHRDS-FAS (Verbal Fluency test)
de Tommaso et al[16]Randomized, blinded, controlled, open labelled prospectiveRivastigmineMMSE, Marsden and Quinn Chorea Severity scale, Total Functional Capacity score, Abnormal Involuntary Movement scaleSlight increase in MMSE but not statistically significant

de Tommaso et al[14] conducted a single centre; short term randomised open labelled controlled study in twenty one patients affected by HD. Patients received Rivastigmine as an add-on therapy for 8 mo. Fourteen patients were allocated to Rivastigmine group and 7 to control group. Patients were evaluated using MMSE, Marsden and Quinn Chorea Severity Scale and Abnormal Involuntary Movements Scale. Patients on Rivastigmine approached statistically significant improvement (P = 0.06) in MMSE score compared to their basal score. Statistical significance was not achieved when intervention group was compared to control group during repeated measures of other clinical features in the 8 mo of the study. Rivastigmine did not appear to reduce hyperkinesia in the intervention group. This study has several drawbacks. The study had only 21 patients and the lack of statistically significant results may be due to the lack of power. Secondly, MMSE was used to assess cognitive function. This may not be an appropriate tool because MMSE fails to capture frontal lobe dysfunction, which is typically impaired in HD.

Cubo et al[15] investigated the effect of donepezil on motor and cognitive function in HD. Thirty patients were randomly allocated to active or placebo groups. Drug and placebo were administered for 6 wk (Donepezil 5 mg) and Donepezil was increased to 10 mg at 6 wk for further 6 wk. Patients were evaluated at baseline, 6 and 12 wk. Unified Huntington’s disease rating scale (UHRDS) was used to evaluate motor performance. Cognitive function was assessed using cognitive section of Alzheimer’s Disease Assessment Scale and UHDRS. Chorea change was used as primary outcome measure and cognitive function change was used as a secondary outcome measure. There was no significant improvement in chorea measure between the two groups. There was no significant improvement in any measure of cognition except of a trend towards improvement on UHRDS-FAS (Verbal Fluency test). The study was not designed to evaluate change in cognitive function on Donepezil as chorea change was used as primary outcome measure. One of the exclusion criteria was dementia with HD.

de Thommaso et al[16] reported the results of two-year follow up of HD patients on Rivastigmine therapy previously evaluated in a short-term study. This was a long term, open-label, blinded, controlled study. The evaluation was carried out in a final group of 11 treated patients and 6 non-treated patients. The results showed a slight increase in MMSE scores in patients Rivastigmine compared to non-treated group who exhibited a mild decline in MMSE scores. However, these differences were not statistically significant. This study has similar drawbacks as those raised about their original study.

CONCLUSION

Cognitive deficits due to Huntington’s disease are common and cause significant morbidity. Cubo et al[15] postulates that the role of cholinergic system in cognitive deficits may be less relevant than previously thought and cholinergic stimulation may not be beneficial. There are no adequately powered well-designed trials to support the use of ACE inhibitors in treating cognitive impairment in HD[17]. Review of existing studies suggests that there is limited evidence for the use of Acetylcholinesterase inhibitors in the treatment of cognitive deficits associated with HD. Large randomised controlled trials with adequate follow up are needed to investigate the efficacy of ACE inhibitors in HD.

Footnotes

P- Reviewer: Orlacchio A S- Editor: Song XX L- Editor: A E- Editor: Wang CH

References
1.  Lanska DJ. George Huntington (1850-1916) and hereditary chorea. J Hist Neurosci. 2000;9:76-89.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord. 2012;27:1083-1091.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 333]  [Cited by in F6Publishing: 334]  [Article Influence: 27.8]  [Reference Citation Analysis (0)]
3.  Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10:83-98.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1048]  [Cited by in F6Publishing: 1083]  [Article Influence: 83.3]  [Reference Citation Analysis (0)]
4.  Snell RG, MacMillan JC, Cheadle JP, Fenton I, Lazarou LP, Davies P, MacDonald ME, Gusella JF, Harper PS, Shaw DJ. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet. 1993;4:393-397.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 483]  [Cited by in F6Publishing: 486]  [Article Influence: 15.7]  [Reference Citation Analysis (0)]
5.  Rosenblatt A, Leroi I. Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics. 2000;41:24-30.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 111]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
6.  Phillips W, Shannon KM, Barker RA. The current clinical management of Huntington’s disease. Mov Disord. 2008;23:1491-1504.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 88]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
7.  Novak MJ, Tabrizi SJ. Huntington’s disease: clinical presentation and treatment. Int Rev Neurobiol. 2011;98:297-323.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 83]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
8.  Montoya A, Price BH, Menear M, Lepage M. Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci. 2006;31:21-29.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Spokes EG. Neurochemical alterations in Huntington’s chorea: a study of post-mortem brain tissue. Brain. 1980;103:179-210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 234]  [Cited by in F6Publishing: 242]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
10.  Lange KW, Javoy-Agid F, Agid Y, Jenner P, Marsden CD. Brain muscarinic cholinergic receptors in Huntington’s disease. J Neurol. 1992;239:103-104.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 26]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
11.  Fernandez HH, Friedman JH, Grace J, Beason-Hazen S. Donepezil for Huntington’s disease. Mov Disord. 2000;15:173-176.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Rot U, Kobal J, Sever A, Pirtosek Z, Mesec A. Rivastigmine in the treatment of Huntington’s disease. Eur J Neurol. 2002;9:689-690.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 26]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
13.  Petrikis P, Andreou C, Piachas A, Bozikas VP, Karavatos A. Treatment of Huntington’s disease with galantamine. Int Clin Psychopharmacol. 2004;19:49-50.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  de Tommaso M, Specchio N, Sciruicchio V, Difruscolo O, Specchio LM. Effects of rivastigmine on motor and cognitive impairment in Huntington’s disease. Mov Disord. 2004;19:1516-1518.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 37]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
15.  Cubo E, Shannon KM, Tracy D, Jaglin JA, Bernard BA, Wuu J, Leurgans SE. Effect of donepezil on motor and cognitive function in Huntington disease. Neurology. 2006;67:1268-1271.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 68]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
16.  de Tommaso M, Difruscolo O, Sciruicchio V, Specchio N, Livrea P. Two years’ follow-up of rivastigmine treatment in Huntington disease. Clin Neuropharmacol. 2007;30:43-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 31]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
17.  Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for symptomatic treatment in Huntington’s disease. Cochrane Database Syst Rev. 2009;CD006456.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]