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Is Period3 genotype associated with sleep and recovery in patients with disorder of consciousness?

Gloria Bedini (PhD)¹, Anna Bersano (MD, PhD)², Davide Rossi Sebastiano (MD, PhD)³, Davide Sattin (PsyD)⁴, Francesca Ciaraffa (MD, PhD)², Valentina Tosetti (PhD)¹, Greta Brenna (MSC)⁵, Silvana Franceschetti (MD, PhD)³, Emilio Ciusani (PhD)⁶, Matilde Leonardi (MD)⁴, Jesus Vela-Gomez (NR)², Giorgio B. Boncoraglio (MD)², and Eugenio A. Parati (MD)^1-2 

¹Laboratory of Cellular Neurobiology, Neurology Unit, UCV; ²Neurology Unit, UCV; ³Neurophysiology and Diagnostic Epileptology Unit; ⁴Neurology, Public Health, Disability Unit, Coma Research Centre coordinator, Scientific Department; ⁵Biostatistician, Service Clinical Research – Scientific Department; ⁶Laboratory of Clinical Pathology and Medical Genetics; Neurological Institute “Carlo Besta” I.R.C.C.S. Foundation, Via Celoria 11, Milan 20133 (Italy).

 

Abstract

Background. Sleep evaluation is increasingly being used as prognostic tool in patients with disorders of consciousness, but, surprisingly, the role of Period3 (Per3) gene polymorphism has never been evaluated. Objective. The aim of this study was to investigate the contribution of Per3 genotype on sleep quantity and consciousness recovery level in patients with disorders of consciousness (DOC).

Methods. In this observational study, we evaluated 71 patients with DOC classified as vegetative state/unresponsive wakefulness syndrome or minimally conscious state. Demographic and clinical data were collected and a standardised diagnostic workup, including a polysomnographic record, was applied. After informed consent provided by proxy, genomic DNA was obtained and Per3 polymorphism was analysed by polymerase chain reaction to identify 5/5, 4/5, or 4/4 genotype.

Results. Per3^5/5 genotype was found in 12.7% of our DOC patients. The median total Coma Recovery Scale–revised score in Per3^5/5 carriers was significantly higher than 4/4 genotype (10, range 5-16 vs 7, range 4-11; post hoc P = .036). Moreover, total sleep time seemed to be higher in 5/5 genotype (5/5, 221 minutes, range 88-515 minutes; 4/4, 151.5 minutes, range 36-477 minutes; and 4/5, 188 minutes, range 44-422 minutes).

Conclusion. For the first time we have shown a possible association between Per3 polymorphism and consciousness recovery level in DOC patients. Even though the exact molecular mechanism has not been defined, we speculate that its effect is mediated by higher total sleep time and slow wave sleep, which would improve the preservation of main cerebral connections.

Keywords: Disorders of consciousness, vegetative state/unresponsive wakefulness syndrome, minimally conscious state, Period3 gene, sleep, outcome research.

 

 

Supplement.

Clinical practice and research have shown how difficult it is to establish the diagnosis and prognosis of disorders of consciousness (DOC) patients. Nowadays, the only reliable methods for the evaluation of the residual brain function of these particular patients is the Coma Recovery Scale-Revised (CRS-R), a neurobehavioral scale specifically used to differentiate patients in Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) from Minimally Conscious State (MCS). Also some specific neurophysiological measurements, and among them sleep recording^[1-3], seem promising tool for the evaluation of the integrity of DOC brain function.

A number of genes has been shown to be associated with different sleep traits and homeostasis, such as diurnal preference or electroencephalogram characteristics^[4,5]. In particular, the human Period3 (Per3) gene has been recognized to have a role in circadian rhythmicity generation^[6], and it has also been associated with total sleep deprivation in both physiological and pathological conditions^{[7, 8, 4, 9]}. However, the role of this gene in DOC patients has never been investigated.

Assuming that particular genotypes may affect the performance and residual functions of DOC patients, the aim of this paper was to explore the role of Per3 gene in conditioning sleep patterns and to understand/analyze behavioral responses in a population of DOC patients in the Coma Research Centre (CRC) of the Neurological Institute “C. Besta” of Milan (Italy).

During the study period, January 2011 – May 2013, 153 DOC adult patients were admitted to the CRC of our Neurological Institute. Since DNA collection started only after 6 months from the CRC onset, 110 patients were included in the present study. From this pool of patients, 17 subjects were further excluded due to diagnosis of severe disability, 14 for lack of DNA collection informed consent forms from a legal representative/next-of-kin, and 8 for inadequate DNA quality. Out of the 71 DOC patients, 26 were traumatic and 45 had vascular origin. The patients mean age at injury was 45 years, and 58% were male. The mean GCS score derived by past clinical data was 4, and 44 of our DOC patients were diagnosed as VS/UWS, whereas 27 as MCS. The overall CRS-r mean value was 8 and, based on their diagnosis, the VS/UWS patients had a mean value of 7, whereas MCS patients 10. Twenty-two of our patients was Per3^4/4, 40 Per3^4/5 and 9 Per3^5/5, and this last one genotype tend to be more represented in the MCS patients’ group. The mean value of CRS-r scale was different in the three subgroups; in particular, a higher score (10) was found in Per3^5/5 in comparison to Per3^4/4 carriers (7) patients (Figure 1). This finding was confirmed both in MCS patients and VS/UWS suggesting that, regardless of the coma severity, DOC patients carried the Per3^5/5 genotype could be associated with a better outcome. In addition, Per3^5/5 DOC patients seem to have a longer time of sleep than the others, indicating a possible role of Per3 gene on the sleep regulation (Figure 2).

With the result of this work we have demonstrated for the first time a possible association between Per3 gene and the functional status of DOC patients. We have also verified that Per3^5/5 DOC patients are more subject to an increased susceptibility to sleep deprivation.

The identification of new therapeutic targets and the personalization of rehabilitation programs remain milestones in DOC patients’ diagnosis. Based on the findings of this study, it is possible to presume that a greater regularization of the sleep/wake cycles in DOC patients could allow the preservation of their residual cognitive function. Therefore, these data could permit the introduction of specific clinical practice measures in the daily management of such patients. For example, exposure to natural light during the day, turning off the light in the hospital room during night and the regularization, in terms of time, of the execution of clinical examinations, could improve their therapeutic course of treatment.

References.

[1] Cologan V, Drouot X, Parapatics S, et al. Sleep in the unresponsive wakefulness syndrome and minimally conscious state. 2013; J Neurotrauma 30:339-346.

[2] de Biase S, Gigli GL, Lorenzut S, et al. The importance of polysomnography in the evaluation of prolonged disorders of consciousness: sleep recordings more adequately correlate than stimulus-related evoked potentials with patients’ clinical status. Sleep Med. 2014; 15:393-400.

[3] Cologan V, Schabus M, Ledoux D, et al. Sleep in disorders of consciousness. Sleep Med Rev. 2010; 14:97-105.

[4] Sehgal A, Mignot E. Genetics of sleep and sleep disorders. 2011; Cell. 146:194-207.

[5] Landolt HP. Genetic determination of sleep EEG profiles in healthy humans. Prog Brain Res. 2011; 193:51-61.

[6] Dijk, DJ, Archer SN. PERIOD3, circadian phenotypes, and sleep homeostasis. Sleep Med Rev. 2010; 14:151-160.

[7] Viola AU, Archer SN, James LM, et al. PER3 polymorphism predicts sleep structure and waking performance. Curr Biol. 2007; 17:613-618.

[8] Ebisawa T, Uchiyama M, Kajimura N, et al. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep. 2001; 2:342-346.

[9] Benedetti F, Dallaspezia S, Colombo C, et al. A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neurosci Lett. 2008; 445:184-187.

 

Acknowledgements. The authors would like to thank:

(1)   all the patients’ families for their kind cooperation in this study;

(2)    the other following members of the Coma Research Centre (CRC) multidisciplinary team: Dr. A. Andronache, Dr. R. Benti, Dr. D. Caldiroli, Dr. P. Fazio, Dr. G. Marotta, Dr. F. Molteni, Dr. M. Pagani, Dr. F. Panzica, Dr. B. Reggiori, Dr. C. Rosazza, Dr. G. Varotto, Dr. E. Visani, Dr. D. Duran, Dr. AM. Giovannetti, Dr. V. Covelli, Dr. MG Bruzzone, Dr. S. Ferraro, Dr. A. Nigri, Ms. E. Gioffredi.

The project CRC was supported by Grant No. IX/000407 – 05/08/2010 awarded by Regione Lombardia. The study was conducted in collaboration with European Federation of Biomedical Research FERB.