Bassetti, Claudio

Baumann, Christian

Hersberger, Martin

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Christian R. BaumannMartin HersbergerClaudio L. BassettiHypocretin-1 (orexin A)levels are normalin Huntington’s diseaseReceived: 24 August 2005Received in revised form: 9 January 2006Accepted: 24 January 2006Published online: 5 April 2006Sirs: Sleep-wake disturbances arecommon in Huntington’s disease(HD), and include disturbances ofthe sleep-wake cycle, insomnia/disturbed night sleep with noc-turnal awakenings, and morerarely excessive daytime sleepi-ness, and disturbed REM sleep [1–3]. Furthermore, alteration ofnutrition status and energy bal-ance (including weight loss andaltered plasma concentrations ofghrelin and leptin) are common inHD [4, 5].At the present time, there areno biochemical markers for thediagnosis of HD.Hypocretins (orexins) arehypothalamic neuropeptideswhich are involved in the regula-tion of arousal, feeding behaviorand energy expenditure (i.a. viainteractions with ghrelin andleptin). In the sleep-wake disor-der narcolepsy-cataplexy, which isassociated with altered energyexpenditure, cerebrospinal fluid(CSF) hypocretin-1 levels are de-creased due to a loss of hypotha-lamic hypocretin neurons [6, 7].Petersen et al. recently reported asignificant loss of hypocretinneurons and dramaticallydecreased CSF hypocretin-1 levelsin the best studied rodent modelof HD [8]. Furthermore, the au-thors observed a decrease of hyp-ocretin-immunopositive neuronsin the hypothalamus of five humanHD patients. In our preliminarystudy, therefore, we intended totest whether CSF hypocretin-1levels are decreased in human HDpatients.In seven genetically confirmedHD patients (mean age 51 years,range 35–74 five men), we as-sessed duration of disease (de-fined as time from onset of firstsymptom to lumbar puncture),body mass indices and sleep-wakedisturbances by standardizedsleep questionnaires (includingEpworth Sleepiness Scale=ESS;available in six patients). CSFhypocretin-1 levels were deter-mined in all patients in a singleradioimmunoassay as previouslydescribed [9]. Levels were com-pared with those of controlswithout neurological or othersleep-wake disorders (n=20), andwith patients with other neuro-degenerative disorders (Parkin-son’s disease, n=6, mean age 71years; dementia with Lewy bodies,n=9, mean age 73 years; Alzhei-mer’s disease, n=7, mean age 72years).In the HD patients, meanduration of disease was 4.1 years(range 1–10). Mean BMI was 26.3(range 22–33). Four patients re-ported unintentional weight loss.Sleep-wake disorders were com-mon complaints, and includedinsomnia (n=4), fragmentednight sleep without daytimetiredness (n=1), and REM sleepbehavior disorder (n=1). Exces-sive daytime sleepiness (definedas ESS score>10) was not re-ported (mean ESS score 6.3,range 4–8).CSF hypocretin-1 levels werenormal in all HD patients (mean441 pg/ml, range 326–583) (Fig.1). Levels did not differ signifi-cantly from those of patients withParkinson’s disease (487 pg/ml,range 307–654 pg/ml), dementiawith Lewy bodies (504 pg/ml,range 382–667), and Alzheimer’sdisease (474 pg/ml, range 333–564). There were no associationsbetween the presence of sleep-wake disorders, Epworth Sleepi-ness Scale, duration of the dis-ease, body mass index,unintentional weight loss, andCSF hypocretin-1 levels.We could not find a hypocretinneurotransmission deficiency – asassessed by determination of CSFhypocretin-1 levels – in humanHD. However, Petersen et al. re-ported an approximate 27 % loss ofhypocretin neurons in human HD[8]. We think that this discrepancymay be due to quantitative effects:Gerashchenko and colleagues [10]found that an average loss of 14 %of rodent hypocretin neurons wasnot followed by a decrease of CSFhypocretin levels. An average lossof 73 %, however, was associatedwith a significant 50 % decline inCSF hypocretin levels. The authorsassumed that surviving hypocretinneurons might compensate forhypocretin neuronal loss by in-creased hypocretin ligand produc-tion. Thus, interpreting Petersen’sfinding together with the observa-tions of Gerashchenko, it is con-ceivable that CSF hypocretin-1levels are normal in HDpatients.C.R. Baumann (&) Æ C.L. BassettiDepartment of NeurologyUniversity HospitalFrauenklinikstrasse 268091 Zurich, SwitzerlandTel.: +41/1 255-55 11Fax: +41/1 255-43 80E-Mail: christian.baumann@usz.chM. HersbergerInstitute of Clinical ChemistryUniversity HospitalZurich, SwitzerlandLETTER TO THE EDITORSJ Neurol (2006) 253: 1232–1233DOI 10.1007/s00415-006-0146-7JON2146In conclusion, we found normalCSF hypocretin-1 levels in patientswith Huntington’s disease, inde-pendent of the presence of sleep-wake disorders, and independentof nutritional status. CSF hypo-cretin-1 determination may not behelpful in the diagnosis of HD.Further studies to evaluate hypo-cretin neuronal loss in HD arerequired.References1. Starr A (1967) A disorder of rapid eyemovements in Huntington’s chorea.Brain 90:545–5642. Brotini S, Gigli GL (2004) Epidemiol-ogy and clinical features of sleep dis-orders in extrapyramidal disease. SleepMed 5:169–793. Wiegand M, Moller AA, Lauer CJ, StolzS, Schreiber W, Dose M, Krieg JC(1991) Nocturnal sleep in Huntington’sdisease. J Neurol 238:203–2084. Trejo A, Tarrats RM, Alonso ME, BollMC, Ochoa A, Velasquez L (2004)Assessment of the nutrition status ofpatients with Huntington’s disease.Nutrition 20:192–65. Popovic V, Svetel M, Djurovic M,Petrovic S, Doknic M, Pekic S, Miljic D,Milic N, Glodic J, Dieguez C, CasanuevaFF, Kostic V (2004) Circulating andcerebrospinal fluid ghrelin and leptin:potential role in altered body weight inHuntington’s disease. Eur J Endocrinol151:451–56. Nishino S, Ripley B, Overeem S, Lam-mers GJ, Mignot E (2000) Hypocretin(orexin) deficiency in human narco-lepsy. Lancet 355:39–407. Peyron C, Faraco J, Rogers W, Ripley B,Overeem S, Charnay Y, Nevsimalova S,Aldrich M, Reynolds D, Albin R, Li R,Hungs M, Pedrazzoli M, Padigaru M,Kucherlapati M, Fan J, Maki R, Lam-mers GJ, Bouras C, Kucherlapati R,Nishino S, Mignot E (2000) A mutationin a case of early onset narcolepsy anda generalized absence of hypocretinpeptides in human narcoleptic brains.Nat Med 6:991–78. Petersen A, Gil J, Maat-Schieman ML,Bjorkqvist M, Tanila H, Araujo IM,Smith R, Popovic N, Wierup N, NorlenP, Li JY, Roos RA, Sundler F, Mulder H,Brundin P (2005) Orexin loss in Hun-tington’s disease. Hum Mol Genet14:39–479. Baumann CR, Dauvilliers Y, Mignot E,Bassetti CL (2004) Normal CSF hypo-cretin-1 (orexin A) levels in dementiawith Lewy bodies associated withexcessive daytime sleepiness. EurNeurol 52:73–610. Gerashchenko D, Murillo-Rodriguez E,Lin L, Xu M, Hallett L, Nishino S,Mignot E, Shiromani PJ (2003) Rela-tionship between CSF hypocretin levelsand hypocretin neuronal loss. ExpNeurol 184:1010–60100200300400500600700CSF hypocretin-1 (pg/ml)HD        PD       DLB       AD        CoFig. 1 CSF hypocretin-1 levels (in pg/ml) inHuntington’s disease (HD, n=7), Parkinson’sdisease (PD, n=6), dementia with Lewy bodies(DLB, n=9), Alzheimer’s disease (AD, n=7), andhealthy controls (Co, n=20)1233

Hypocretin-1 (orexin A) levels are normal in Huntington's disease

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Hypocretin-1 (orexin A) levels are normal in Huntington's disease

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