The correlation between ubiquitin in the brainstem and sleep apnea in SIDS victims

Background: The sudden infant death syndrome (SIDS) is still the main cause of postneonatal infant death and its etiology has stimulated many competing theories, among which is the role of hypoxia and brainstem abnormalities. One report claims an increased in ubiquitin in the liver of SIDS victims, ubiquitin being one of the heat-shock proteins. The correlation between ubiquitin in the brainstem and sleep apnea in SIDS was investigated here. Materials and methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age, including 26 cases of SIDS. All the infants had been recorded during one night in a pediatric sleep laboratory some 3–12 weeks before death. The frequency and duration of sleep apnea were analyzed. Brainstem material was collected at autopsy and examined immunohistochemically for ubiquitin. The density of ubiquitin-positive elements was measured semiquantitatively. Correlation analyses were carried out between the density of ubiquitin-positive elements and the data on sleep apnea. Results: In the victims of SIDS, a statistically significant positive correlation was found between the density of ubiquitin-positive neuronal factors in the pons and the frequency of obstructive apnea (P=0.001) and statistically significant negative correlations were seen between the density of ubiquitin-positive cells in the ependyma in the pons and the duration of obstructive apnea (P=0.044) and between the density of ubiquitin-positive cells in the subependyma in the medulla and the frequency of central apnea (P=0.024). Conclusions: It was found that three significant associations existed between the pathological data referring to ubiquitin and physiological data in SIDS victims. These facts are in agreements with he association of sleep apnea in SIDS.     

The correlation between serotonergic neurons in the brainstem and sleep apnea in SIDS victims

Background: In the sudden infant death syndrome (SIDS), a medullary serotonergic network deficiency theory has been proposed, amongst many other hypotheses. The correlation between serotonergic neurons or dendritic spines in the brainstem of SIDS and sleep apnea was investigated here. Materials and methods: Twenty-seven thousand infants were studied prospectively to characterize their sleep-wake behavior. Of these, 38 infants died under 6 months of age, including 26 cases of SIDS. The frequency and duration of sleep apnea were analyzed. Brainstem material was collected and immunohistochemistry for tryptophan hydroxylase (TrypH) carried out. The density of TrypH-positive neurons was measured quantitatively. Correlation analyses were carried out between the TrypH-associated pathological data and the physiological data of sleep apnea. Results: One significant positive correlation between the density of TrypH-positive neurons in the dorsal raphe nucleus of the midbrain and the duration of central apnea (P=0.027) was found in SIDS victims. Conclusions: Some of serotonergic facts could be involved in the pathophysiology of SIDS.     

Substance P in the midbrains of SIDS victims and its correlation with sleep apnea

Background: Substance P (SP) is a neuropeptide transmitter found in sensory neurons of the central nervous system and related to pain sensation and respiratory regulation. Some reports claim an increase in SP in the brains of SIDS victims, so the correlation between SP and sleep apnea was investigated here. Materials and methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age, which included 26 cases of sudden infant death syndrome (SIDS). All the infants had been recorded during one night in a pediatric sleep laboratory some 3–12 weeks before death. The frequency and duration of sleep apnea were analyzed. Brainstem material was collected and immunohistochemistry for SP was carried out. The density of SP positive fibers was measured in the nucleus spinal and mesencephalic nervi trigemini and nucleus parabranchialis in the brainstem of abovementioned cases. Correlation analyses were carried out between the density of SP and the data of sleep apnea. Results: There was no SIDS specific correlation of SP through the above-listed parts of the midbrain with frequency and duration of sleep apnea. Conclusions: There was no significant association between the SP findings and apnea data in SIDS; this is not in agreement with the association of apnea in pathophysiology of SIDS.     

Serotonergic receptors in the midbrain correlated with physiological data on sleep apnea in SIDS victims

Background: Recently it has been reported that serotonin and related matters are associated with the sudden infant death syndrome (SIDS), which is still the main cause of postneonatal infant death. To further explore this claim, the correlation between serotonin receptors in the brainstem and sleep apnea in SIDS victims was investigated. Materials and methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age including 26 cases of SIDS. All the infants had been recorded during one night in a pediatric sleep laboratory some 3–12 weeks before death. The frequency and duration of sleep apnea were analyzed. Brainstem material was collected and immunohistochemistry on 5-hydroxy tryptamine 1A (5HT1A) receptor was carried out. The density of 5HT1A receptor-positive neurons was measured quantitatively. Nonparametric analysis of the density of 5HT1A receptor-positive neurons was carried out between SIDS and non-SIDS cases. Correlation analyses were performed between the density of 5HT1A receptor-positive neurons and the data on sleep apnea. Results: There was no correlation between the pathological data on 5HT1A receptors and the physiological data on sleep apnea in SIDS victims. Conclusions: No correlation between pathological findings of serotonin and physiological findings of sleep apnea were not in agreement with the association of sleep apnea in pathophysiology of SIDS.     

Correlation between the Ki-67 antigen in the brainstem and physiological data on sleep apnea in SIDS victims

Background: The Ki-67 antigen appears in all human proliferating cells during late G1, S, M and G2 phases of the cell cycle, but is consistently absent in the G_o phase (noncycling) cells. The correlation between Ki-67 in the brainstem and sleep apnea in victims of the sudden infant death syndrome (SIDS) was investigated to elucidate cell kinetics in the brainstem of this condition, which is still the main cause of postneonatal infant death. Materials and methods: Twenty-six cases of SIDS occurred among 38 infants dying under 6 months of age in a cohort of 27,000 infants studied prospectively to characterize their sleep–wake behavior. All the infants had been recorded during one night in a pediatric sleep laboratory some 3–12 weeks before death. The frequency and duration of sleep apnea were analyzed. At autopsy, brainstem material was collected and immunohistochemistry for Ki-67 was carried out. The density of Ki-67-positive neurons was measured semiquantitatively. Correlation analyses were carried out between the density of Ki-67-positive neurons and the data on sleep apnea. Results: Except in two cases in SIDS victims and in one control, the detection of Ki-67 was negative. No correlation analysis between the Ki-67 and of sleep apnea was found. Conclusions: There were no abnormal cell kinetics detected by the demonstration of Ki-67 antigen in the brainstems of SIDS victims.     

The relationship between neuronal plasticity and serotonergic neurons in the brainstem of SIDS victims

Background: The sudden infant death syndrome (SIDS) is still the main cause of postneonatal infant death and its cause is still unknown. Recently, the medullary serotonergic network deficiency theory has been proposed and an association between SIDS and neuronal plasticity has also been suggested. The growth-associated phosphoprotein 43 (GAP43) is a marker of synaptic plasticity and is critical for normal development of the serotonergic innervation. Therefore, the characteristics of GAP43-positive elements and their association with serotonergic neurons were here investigated in the brainstem of SIDS victims. Materials and methods: The materials of this study included 26 cases of SIDS and 12 control cases. The brainstem material was collected and the immunohistochemistry of GAP43 and tryptophan hydroxylase (TrypH) carried out. The density of GAP43-positive neurons and dendrites and of TrypH-positive neurons were measured quantitatively. Non-parametric analyses of GAP43 between SIDS and non-SIDS and correlation analyses between GAP43 and TrypH were performed. Results: No significant difference in GAP43-associated findings was found between SIDS and non-SIDS nor any significant correlation between GAP43-associated findings and TrypH-positive neurons. Conclusions: The results of this study were not in agreement with the association of GAP43 with SIDS and with serotonergic innervation in SIDS.     

The correlation between τ protein in the brainstem and sleep apnea in SIDS victims

Background: Recently, it has been reported that neuronal plasticity in the brainstem arousal pathway is related to the sudden infant death syndrome (SIDS). τ protein may contribute to axonal development and neural plasticity; therefore, the correlation between τ protein in the brainstem and sleep apnea in SIDS was investigated here. Materials and methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age, including 26 cases of SIDS. The frequency and duration of sleep apnea were analyzed on all the infants, having been recorded during one night in a pediatric sleep laboratory some 3–12 weeks before death. The brainstem material was collected and immunohistochemistry of τ was carried out. The density of τ-positive elements was measured semiquantitatively. Correlation analyses were carried out between the density of τ-positive elements and the data of sleep apnea. Results: In the 26 SIDS cases, τ-positive findings were observed in the sub-pia mater in two cases, in the colloid plexus in one case, in the ependyma and subependyma in five cases, in neurons in two cases and as a general diffusion in one case. In 12 control cases, τ-positive findings were observed in the sub-pia mater in one case and in neuronal elements in three cases. No correlation was found on analysis. Conclusions: There was no correlation between the finding of τ in the brainstem of SIDS victims and the incidence of sleep apnea.     

The correlation between microtubule-associated protein 2 in the brainstem of SIDS victims and physiological data on sleep apnea

Background: Microtubule-associated protein 2 (MAP2), a cytoskeletal protein of the neuron, is a marker of early ischemic neuronal damage. As a chronic hypoxic situation exists in the brains of victims of the sudden infant death syndrome (SIDS), the correlation between MAP2-positive neurons or dendritic spines in the brainstem and sleep apnea was investigated in SIDS, which is still the main cause of postneonatal infant death. Materials and methods: Twenty-seven thousand infants were studied prospectively to characterize their sleep–wake behavior and amongst these, 38 infants died under 6 months of age. They included 26 cases of SIDS. The frequency and duration of sleep apneae were analyzed. The brainstem material was collected and immunohistochemistry of MAP2 was carried out. The density of MAP2-positive neurons, dendrites, and dendritic spines were measured quantitatively. Correlation analyses were carried out between the MAP2-associated pathological data and the physiological data of sleep apnea. Results: One negative correlation between the density of MAP2-positive endrites in the pars compacta of pedunculo-pontine tegmentum nucleus (PPTNc) and the duration of obstructive apnea (P=0.017) and two SIDS-specific positive correlations between the density of MAP2-positive dendrites in the pars dissipata of pedunculo-pontine tegmentum nucleus (PPTNd) and the duration of central apnea (P=0.005) and between the dorsal raphe and the frequency of obstructive apnea were found in SIDS victims. The density of MAP2-positive dendritic spines in PPTNc was significantly higher in SIDS than in control (P=0.034). Conclusions: The significant correlations with the MAP2-positive findings in the midbrain arousal pathway and the characteristics of sleep apnea in SIDS victims were in agreement with the association with apnea and arousal-deficiency in SIDS.     

Pathological data on apoptosis in the brainstem and physiological data on sleep apnea in SIDS victims

The sudden infant death syndrome (SIDS) is still the main cause of postneonatal infant death and its cause is still unknown. A chronic hypoxic situation has been shown to exist in the brains of SIDS victims and apoptosis has been demonstrated in hypoxic situations. In this study, the correlation between apoptotic neurons or glias and sleep apnea in SIDS was investigated in the brainstem of SIDS victims. Materials and methods: In a cohort of 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age. They included 26 cases of SIDS. The frequency and duration of sleep apnea were analyzed. The brainstem material was collected and terminal-deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method was carried out. The density of TUNEL-positive neurons or glias was measured quantitatively. Correlation analyses were carried out between the apoptosis-associated pathological data and the physiological data of sleep apnea. Results: No significant negative or positive correlation between the density of TUNEL-positive neurons or glias and the characteristics of sleep apnea was observed in SIDS victims. No statistically significant differences associated with apoptotic neurons and glias were observed between SIDS and non-SIDS. Conclusions: The pathological findings of apoptosis were not in agreement with the hypothesis refer to apnea and arousal phenomenon in pathophysiology of SIDS.     

Investigation into the correlation in SIDS victims between Alzheimer precursor protein A4 in the brainstem and sleep apnea

Background: Recently, the appearance of beta-amyloid precursor protein (APP) has been demonstrated in the neonatal brain following hypoxic–ischaemic injury. As chronic hypoxia is one of the favoured theories of causation in the sudden infant death syndrome (SIDS), the correlation between APP in the brainstem and sleep apnea in SIDS was investigated. Materials and methods: Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age, which included 26 cases of SIDS. All the infants had been recorded during one night in a pediatric sleep laboratory, some 3–12 weeks before death. The frequency and duration of sleep apnea were analyzed. The brainstem material was collected and immunohistochemistry with anti-Alzheimer precursor protein A4 (APP) was carried out. The density of APP-positive elements was measured semi-quantitatively. Correlation analyses were carried out between the density of APP-positive elements and the data on sleep apnea. Results: No correlation was found. Conclusion: No correlation between pathological data of APP and physiological data of sleep apnea was not in agreement with the association of sleep apnea in pathophysiology of SIDS.     

Sleep apnea in mice: a useful animal model for study of SIDS?

Although the incidence of sudden infant death syndrome (SIDS) has been decreased by education programs to avoid sleeping in prone position, the pathological mechanisms of SIDS have not fully been understood. Basic research on sleep apnea using experimental animals may help further understanding and prevention of SIDS because the syndrome is thought as inability to wake up from respiratory arrest (apnea) during sleep. Although several animal models of sleep apnea have been described previously, mice would be useful experimental animals in that these animals are frequently used in genetic engineering. Those considerations prompted us to establish a method for measuring ventilation of mice concomitantly with electroencephalography and electromyography for assessing sleep–wake states. Normal wild-type mice developed two types of central sleep apneas (CSA), that is, post-sigh and spontaneous apneas, as normal humans do. Moreover, post-sigh apneas in mice were observed exclusively during slow-wave sleep (SWS) while spontaneous apneas were seen in both SWS and rapid eye movement (REM) sleep. These characteristics are very similar to those of sleep apneas in healthy human infants and children. Therefore, mice seem to be a promising experimental animal model for studying the genetic and molecular basis of respiratory regulation and dysregulation during sleep in humans, especially infants and children. However, we should keep in mind limitations in studying mice as an animal model of SIDS, since they are nocturnal rodents and they sleep in the prone position.     

Partial arousal deficiency in SIDS victims and noradrenergic neuronal plasticity

Sudden infant death syndrome (SIDS) victims had exhibited during sleep a reduction in cortical arousals despite an increase in subcortical activation. Arousal deficiency in SIDS victims was partial. We could suggest the latent existence of inadequate noradrenergic neuronal plasticity as the background of this partial arousal deficiency of SIDS victims.     

Sudden infant deaths: stress, arousal and SIDS

The prevalence of the sudden infant death syndrome (SIDS) has dropped in most countries following the development of education campaigns on the avoidance of preventable risk factors for SIDS. These include factors in the infant’s microenvironment, such as prenatal passive smoking, administration of sedative drugs, prone sleep, high ambient temperature or sleeping with the face covered. Sleep laboratory studies have shown that these risk conditions contribute to the development of respiratory and autonomic disorders and reduce the child’s arousability. The opposite effects were seen when studying factors protective from SIDS, such as breastfeeding or the use of a pacifier. In victims of SIDS, similar breathing, autonomic and arousal characteristics were recorded days or weeks before their death. It is concluded that in some infants, already immature control mechanisms can be aggravated by environmental factors.     

Catecholaminergic and dopamine-containing neurons in the spinal cord of pigeons: an immunohistochemical study

Within the different species belonging to the vertebrate radiation, catecholaminergic elements of the spinal cord present a partly conservative, partly variable pattern. Unfortunately, the overall picture is far from clear since the situation for birds is largely obscure. Therefore, we examined the distribution of dopamine (DA)- and tyrosine hydroxylase (TH)-positive cells and fibers in the spinal cord of the adult pigeon by immunohistochemistry. TH-immunoreactive cells were located within two restricted areas. One group of cells with multipolar shape was located in laminae VI and VII, close to the white-gray border. These cells were more frequently found at rostral and caudal levels while being scarce at cervical-thoracic levels. The second group of cells was located in lamina VIII surrounding the central canal. These cells were bipolar in shape and were found ventrally and laterally to the central canal, with most of them contacting the lumen of the canal through a separate process. The TH-immunoreactive fibers were distributed in both the gray and the white matter. In the gray matter, they were mainly distributed around the central canal (lamina VIII), in the ventral horn close to the border of laminae VII-IX and in the lateral part of the dorsal horn in laminae II-VI. In the white matter the fibers were present in the lateral columns running longitudinal to the main axis. DA-immunoreactive cells were also located within two restricted areas, closely matching the distribution of TH-immunopositive ones. Additionally, the DA-immunoreactive cells had the same shape as the TH-immunoreactive cells, as bipolar neurons contacted the central canal and multipolar ones were located in the laminae VI and VII. Also the distribution of DA- and TH-immunoreactive fibers roughly matched. Both, DA-immunoreactive cells and fibers were scarcer than TH-immunoreactive ones. This finding suggests that the catecholaminergic system in the spinal cord consists of DA-immunoreactive cells as well as other catecholaminergic cells.     

The dorsal motor nucleus of the vagus (DMNV) in sudden infant death syndrome (SIDS): Pathways leading to apoptosis

Sudden infant death syndrome (SIDS) remains the commonest cause of death in the post-neonatal period in the developed world. A leading hypothesis is that an abnormality in the brainstem of infants who succumb to SIDS, either causes or predisposes to failure to respond appropriately to an exogenous stressor. Neuronal apoptosis can lead to loss of cardiorespiratory reflexes, compromise of the infant's ability to respond to stressors such as hypoxia, and ultimately a sleep-related death. The dorsal motor nucleus of the vagus (DMNV) is a medullary autonomic nucleus where abnormalities have regularly been identified in SIDS research. This review collates neurochemical findings documented over the last 30 years, including data from our laboratory focusing on neuronal apoptosis and the DMNV, and provides potential therapeutic interventions targeting neurotransmitters, growth factors and/or genes.     

Questionnaire study to Japanese SIDS families

Objectives: To clarify the situation of the incidence of the sudden infant death syndrome (SIDS) in Japan to provide the basis for health administration training. Method: The questionnaire study about the circumstances and responses in discovering the death of a SIDS infant was carried out by the SIDS Family Association, Japan. The bereaved parents were asked to reply as to whether or not the SIDS was the cause of their children’s death, carried out a cross-tabulation and a χ²-test of significance. Result: We found differences between SIDS and non-SIDS infants in respect to the place of death, the health condition up to death, the sleeping position at the time of death and room sharing. With regards to the responses on the death of a child, we found differences between the SIDS and non-SIDS infants in respect to whom the infant was in contact with at the time of death and especially with the responses of the paramedics. Other differences found were in respect to whether or not considerations were given to the family in informing them about procedures and treatment, in informing them of the procedures and medical information or to the family’s feelings in advising an autopsy and whether or not a sufficient explanation was provided before the autopsy. Conclusion: To lighten the trauma suffered by a SIDS family, it is necessary that we pay adequate attention to giving consideration to the family through general informed consent including giving thoughtful consideration in advising an autopsy.     

Parent-infant cosleeping: The appropriate context for the study of infant sleep and implications for sudden infant death syndrome (SIDS) research

Nearly all laboratory research on human infant sleep assumes that solitary sleeping is the normal and desirable environment. Yet solitary sleeping in infancy is a very recent custom limited to Western industrialized societies, and most of the world's peoples still practice parent-infant cosleeping. A hypothesis is presented that cosleeping provides a sensory-rich environment which is the more appropriate environment in which to study normal infant sleep. In addition, two preliminary, in-laboratory, polygraphic investigations of mother-infant cosleeping are reported in normal infants within the peak age range for sudden infant death syndrome (SIDS). Five mother-infant pairs coslept for 1 night in the first study; in the second, three additional pairs slept separately for 2 nights and coslept the third consecutive night. The results suggest that cosleeping is associated with enhanced infant arousals and striking temporal overlap in infant and maternal arousals. Infant sleep also showed subtle alterations with cosleeping, as manifested in increased overlap with corresponding maternal sleep stages and decreased amount of Stage 3–4. These are the first in-laboratory investigations of parent-infant cosleeping. The implications of the hypothesis and preliminary results for research on the normal development of infant sleep and on SIDS are discussed.     

Quantitative and immunohistochemical analysis of neuronal types in the mouse caudal nucleus tractus solitarius: focus on GABAergic neurons

γ-Aminobutyric acid-ergic (GABAergic) neurons are major inhibitory interneurons that are widely distributed in the central nervous system. The caudal nucleus tractus solitarius (cNTS), which plays a key role in respiratory, cardiovascular, and gastrointestinal function, contains GABAergic neurons for regulation of neuronal firing. In the present study, GABAergic neuronal organization was analyzed in relation to the location of subnuclei in the mouse cNTS. According to the differential expression of glutamate decarboxylase 67 (GAD67), vesicular glutamate transporter 2 (VGLUT2), calbindin, and tyrosine hydroxylase (TH) mRNAs, the cNTS was divided into four subnuclei: the subpostrema, dorsomedial, commissural, and medial subnuclei. The numerical density and size of soma in the four subnuclei were then quantified by an unbiased disector analysis. Calbindin-positive cells constituted subpopulations of small non-GABAergic neurons preferentially localized in the subpostrema subnucleus. TH-positive cells constituted large neurons preferentially localized in the medial subnucleus. GABAergic neurons constituted a subpopulation of small neurons, preferentially localized in the commissural and medial subnuclei, which represented ≥50% of small cells in these subnuclei. Thus, the GABAergic small neurons were located around TH-positive large cells in the ventrolateral portion of the cNTS. This finding, in combination with results of previous studies in the rat cNTS showing that large cells originate efferents from the cNTS, suggests that GABAergic small neurons in the commissural and medial subnuclei might regulate output from the cNTS.     

Is Tourette syndrome a cause of sudden infant death syndrome and childhood obstructive sleep apnea?

The cause of sudden infant death syndrome (SIDS) is unknown. Sleep-related impairment of respiratory control and arousal are postulated; hyperdopaminergic and hyposerotonergic dysfunction may contribute to events leading to infant apnea and SIDS. Psychosocial adversity and impulsive and compulsive behaviours characterize some families of SIDS victims. Tourette syndrome (TS) is a common hereditary neurobehavioral disorder characterized by the frequent presence of impulsive and compulsive behaviors. Sleep disorders are common and include sleep apnea and abnormal arousal. Hyperdopaminergic and hyposerotonergic abnormalities are postulated to contribute to the pathophyusiology of the disorder. The following is a report of the presence of incidents of infant apnea and SIDS in families in which TS was present. In an additional TS family, a child had obstructive sleep apnea syndrome (OSAS). Results of a preliminary survey suggest that TS gene carriers are at increased risk of life-threatening apneas of infancy and that the prevalence of SIDS in such families may be 2 to 5 times the prevalence in the general population. The presence in some pedigrees of sleep apnea in children and adults suggest that in some instances disorders of sleep-related ventilatory control and arousal occurring throughout the life-span share common pathophysiological mechanisms. © 1993 Wiley-Liss, Inc.