**4. CR disorders in patients with DVB and development of cognitive disorders**

All patients received drug therapy according to the standards of specialized medical care; positional therapy, exercise therapy, mechanotherapy, psychotherapy. Patients of the main group (25 people, mean age 59.5 ± 4.8 years), along with the treatment described above, received melatonin 3 mg per day for 30–40 minutes before sleep for 3 months and used intraoral repositioning applicators. Patients in the control group (24 patients, mean age 62.3 ± 4.2 years) were prescribed only standard therapy. Already a month after the start of therapy, the patients of the main group had a positive dynamic: decrease in daytime sleepiness, snoring, and an expression of morning fatigue. After 3 months, the sleep characteristics of the patients in the main group were statistically significant (p < 0.05), differed from the control group by a shorter sleep time (8.8 ± 3.2 vs. 20.9 ± 16.7 minutes), an extended total sleep duration (431, 0 ± 34.7 vs. 386.9 ± 90.4 minutes), greater representation of the 4th stage of slow sleep (12.6 ± 3.5% vs. 8.1 ± 6.7%) and a lower total waking time (8, 0 ± 4.2 vs. 37.5 ± 12.8 minutes). After 6 months of therapy, positive changes in the polysomnography index remained, a reduction in the frequency of obstructive events in the patients of the main group as com-

Simultaneously with the normalization of sleep, the positive dynamic of clinical and neurological indicators was demonstrated. By the 3rd month. Therapy, the cumulative cognitive parameters of the MoCA test, the psychoemotional functions and the quality of life of the patients in the main group were statistically significantly improved, in contrast to the controls. Detailed study of night sleep in patients with stroke is not only of scientific interest, but also has serious practical significance in matters of prognosis, secondary prevention, as well as

The use of a standardized criterion for assessing the dynamics of the CR of the heart rate extends the diagnostic capabilities, reveals new pathogenetic links of the CVD, optimizes the treatment regimen for patients with CVP. Identification of CR abnormalities in the management of BP and heart rhythm in combination with sleep disturbances allows to include mela-

Thus, the detection of sleep disorders and desynchronosis in patients with CVD requires that

**1.** Change of daily regime according to a chronotype of the patient and reduction of a mode

**3.** Optimization of the motor activity regime with the recommendation of walking outdoors

**6.** Melatonin administration at a dose of 3 mg per day. For 30–40 minutes before bedtime.

medical, psychological and social aspects is included in complex therapy.

**4.** Inclusion of photo- and color therapy in the complex of rehabilitation;

**5.** The Chronopharmacological approach in Drug Administration.

It is advisable to use the following chronotherapeutic approaches:

of work and rest in conformity with natural photoperiods;

pared with the control.

tonin drugs in therapy.

medical and rehabilitation measures.

94 Circadian Rhythm - Cellular and Molecular Mechanisms

**2.** Use of physiologically appropriate diet;

and moderate insolation;

At present, there is enough evidence on the association of early and progressive CR disorders, changes in quality and sleep architecture with an increased risk of developing cognitive impairment (CI) [67–70, 103–112].

When analyzing 12,926 documents from the PubMed, EMBase, ISI WebofScience and PsycINFO databases published before October 28, 2016, among 246,786 patients in 25,847, an average of 9.49 years was observed in dementia. The prognostic role of sleep disturbances, their subtypes (insomnia, OSAS, excessive sleepiness during the day, sleep disorders, and nonspecific sleeping problems) in the development of dementia were evaluated. Compared to those without sleep disorders, patients with sleep disorders had a higher risk of developing dementia. Subgroup analysis showed that insomnia increases the risk of developing AD, but not vascular dementia (VD). In contrast, OSAS was associated with a higher risk of early onset of SI, incl. AD and VD [105].

The relationship between the sleep architecture and the potential risk of developing CI in the community is considered on the basis of Framingham Heart Study (FHS). For 19 years' study (the average follow-up period was 12 ± 5 years), there were 321 patients participating in Sleep Heart Health Study between 1995 and 1998, over the age of 60 at the time of sleep assessment. 32 cases of dementia were traced; 24 cases were due to AD. After adjusting for age and sex, a low percentage of FSP and greater latency of REM sleep were associated with a higher risk of dementia. Each percentage reduction in FSP was associated with an increasing the risk of dementia by approximately 9% (p < 0.05). The relationship between the percentage of FSP and dementia was similar for the following adjustments for multiple covariates, including vascular risk factors, depressive symptoms, and drug use. The stages of slow wave sleep were not associated with the risk of dementia [106].

Among 96 patients in the acute period of IS, 79% of patients had heterogeneous post-stroke CI. In 21% of patients they had a dysmnestic character. The concentration of 6-SOMT was lower in patients with IS compared with the control. In the study of chronotypes, it was found that the majority of patients had an early variant, while the social jetlag value was 40 minutes. This indicator decreased with increasing age of patients. In most patients, IS developed in the morning, these patients had the lowest content of 6-SOMT in daily urine and the lowest values for MMSE. Potentially this is associated with a decrease in the protective activity of the melatonin. There was a correlation between chronobiological parameters and cognitive status. Thus, the expression of the "social jetlag" was associated with the semantic coding of memory, reflecting the function of the hippocampus. Patients with a late version of the chronotype were characterized by higher rates of delayed reproduction and semantic verbal fluency. With an increase in the social jostlag, the concentration of 6-SOMT in urine, probably compensatory, increased. The use of melaxen accelerated the recovery of CR, which had a positive effect on the rehabilitation of patients. It has been suggested that in elderly and senile patients, a high concentration of 6-SOMT in the acute period of IS was a marker of dysregulatory cognitive impairment, whereas its low content in the presence of a cognitive deficit may indicate a mixed, hippocampal type of CI [86].

Possible prospects for the use of melatonin in elderly patients with CI are due to its antioxidant, neuroprotective and nootropic effects. The positive effect of exogenous forms of melatonin on sleep in elderly patients is confirmed by the results of two placebo-controlled studies in which more than 500 patients over the age of 55, with primary insomnia [1107].

The use of the personalized chronotherapeutics approaches allows to neutralize the negative

Features of Circadian Rhythms in Patients with Cerebrovascular Diseases

http://dx.doi.org/10.5772/intechopen.75963

97

We thank Dmitry Petrov for his assistance in translation of the text. We wish to acknowledge the patients who participated in our studies. The content of the chapter is solely the respon-

The authors declare no conflicts of interest regarding the content of the manuscript.

2 Restorative and Sports Medicine of Moscow Healthcare Department, Moscow Centre for

[1] Rapoporta SI, Frolova VA, Khetagurova LG. Khronobiologiya i khronomeditsina: Rukovodstvo/Pod red. M.: OOO "Meditsinskoe informatsionnoe agentstvo", 2012. 480 p.

[2] Agadzhanyan NA, Gubin DG. Desinkhronoz: mekhanizmy razvitiya ot molekulyarno-geneticheskogo do organizmennogo urovnya. Uspekhi fiziologicheskikh nauk.

[3] Sergey MC, Rapoport SI, Agarval RK, et al. Potential chronobiological triggering factors of acute heart attack~!2009-12-29~!2010-01-11~!2010-04-22~!. The Open Nutraceuticals

[4] Feng W, Hendry RM, Adams RJ. Risk of recurrent stroke, myocardial infarction, or death

[5] Morris CJ, Yang JN, Scheer FA. The impact of the circadian timing system on cardiovascular and metabolic function. Progress in Brain Research. 2012;**199**:337-358. DOI:

Journal [Internet]. May 20, 2010;**3**(3):166-173. DOI: 10.2174/1876396001003030166

in hospitalized stroke patients. Neurology. 2010;**74**(7):588-593

impact of desynchronosis.

**Acknowledgements**

sibility of the authors.

**Conflicts of interest**

Elena Kostenko1,2\* and Liudmila Petrova<sup>2</sup>

\*Address all correspondence to: ekostenko58@mail.ru

1 Pirogov Russian National Research Medical University, Russia

Research and Practice in Medical Rehabilitation, Moscow, Russia

**Author details**

**References**

(in Russian)

2004;**35**(2):57-72 (in Russian)

10.1016/B978-0-444-59427-3.00019

Using 6 mg of melatonin once a day before bedtime for 10 days in patients with moderate CI (MCI) led to significant improvement in memory and regression of depressive symptoms simultaneously with normalization of the sleep-wake cycle [103]. H. Jean-Louis et al. [108], Peck et al. [109], observed 26 patients with MCI syndrome received similar results. While 1 mg melatonin administration just before sleep for 4 weeks, there was a significant decrease in forgetfulness in the auditory memory modality and improvement in night sleep compared with placebo. By Cardinali et al. there was made the retrospective analysis of the effect of melatonin therapy on cognitive functions, night sleep and wakefulness in 96 patients with MCI (61 patients received melatonin in doses of 3–9 mg once daily for 9–18 months). It has been proven that melatonin therapy contributes to significant cognitive improvement and regression of depressive symptoms [110].

The high efficiency of the combination of memantine and melatonin in the correction of MCI was shown in the experiment [111].

There is a discussion about the importance of light therapy in correcting of CI. Most of the studies demonstrate the stabilization of CR sleep-wakefulness and a reduction in the time of sleep in dementia with melatonin and light therapy [112].

The prevalence and correction of sleep disorders in patients with CVD need further study in randomized clinical trials in large groups of patients for understanding their impact and establishing cause-effect relationships in the development of CI. These investigations results will help to develop a treatment strategy.
