Serotonin Deficiency in Medulla Implicated in Sudden Infant Death Syndrome
Serotonin Deficiency in Medulla Implicated in Sudden Infant Death Syndrome
Duncan JR, Paterson DS, Hoffman JM, et al
JAMA. 2010;303:430-437
Sudden infant death syndrome (SIDS) may result from developmental abnormalities in brainstem control of autonomic function and breathing, as evidenced by abnormalities in SIDS patients of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata implicated in this control. The goal of this autopsy study was to evaluate the association of 5-HT receptor abnormalities in infants dying from SIDS with decreased tissue levels of 5-HT and/or with levels of tryptophan hydroxylase (TPH2), its key biosynthetic enzyme.
Between 2004 and 2008, brains of 41 infants dying from SIDS (cases) were compared with brains of 7 infants who died acutely from known causes (controls), as well as with brains of 5 hospitalized infants with chronic hypoxia-ischemia. Compared with age-adjusted controls, SIDS cases had 26% lower serotonin levels in 2 brainstem regions: the raphé obscurus (P = .05) and paragigantocellularis lateralis (PGCL; P = .04), but there was no evidence of excessive 5-HT degradation reflected in 5-hydroxyindoleacetic acid (5-HIAA) levels, 5-HIAA:5-HT ratio, or both.
Compared with controls, SIDS cases had 22% lower TPH2 levels (P = .03), and 29% to 55% lower 5-HT1A receptor binding in 3 medullary nuclei that receive 5-HT projections. In SIDS cases, but not in the controls, there was a decrease with age in 5-HT1A receptor binding in 4 nuclei, 3 of which contain 5-HT neurons. The SIDS and hospitalized groups differed significantly in regard to the profile of 5-HT and TPH2 abnormalities.
Study limitations include possibly compromised high-performance liquid chromatography neurotransmitter measurements because of prolonged postmortem intervals; inability to measure synaptic neurotransmitter levels in postmortem tissues; and small control group.
Compared with controls, SIDS was associated with lower brainstem levels of 5-HT and TPH2, suggesting medullary 5-HT deficiency underlying the pathogenesis of this disorder. Reduced 5-HT synthesis, rather than significant breakdown of 5-HT, is supported by the lack of changes in 5-HIAA levels or neurotransmitter turnover (5-HIAA:5-HT ratio). Correlation of 5-HT1A binding alterations among components of the medullary 5-HT system in the SIDS cases (and controls) offers further proof that the medullary 5-HT system is an interrelated network regulating respiratory and autonomic functions.
Based on these findings, the investigators suggest that SIDS may be caused by a defect in at least 1 component of the medullary 5-HT system, but that simultaneous defects in all 5-HT markers are not required in every case. Reduced 5-HT1A receptor binding in older SIDS cases may reflect a progressive decrease with age in infants having the "SIDS abnormality," or it may suggest that infants with a more pronounced abnormality take longer to outgrow the risk period for SIDS and continue to die at older ages.
Differences in the pattern of abnormalities between the SIDS group and the hypoxia-ischemia group suggest that chronic hypoxia-ischemia is not the primary mechanism explaining 5-HT abnormalities in SIDS. 5-HT1A receptor binding was significantly lower in SIDS infants without known extrinsic risk factors, suggesting that with less involvement of the medullary 5-HT system, additional risk factors are needed for death to occur.
The investigators suggest that insufficient 5-HT levels early in fetal development result in a compensatory increase in immature 5-HT neurons with decreased 5-HT1A binding and 5-HT transporter levels. With a partial defect in this system, medullary 5-HT-mediated pathways may function reasonably well during the awake state but less well when exposed to homeostatic stressors during sleep.
Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome
Duncan JR, Paterson DS, Hoffman JM, et al
JAMA. 2010;303:430-437
Summary
Sudden infant death syndrome (SIDS) may result from developmental abnormalities in brainstem control of autonomic function and breathing, as evidenced by abnormalities in SIDS patients of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata implicated in this control. The goal of this autopsy study was to evaluate the association of 5-HT receptor abnormalities in infants dying from SIDS with decreased tissue levels of 5-HT and/or with levels of tryptophan hydroxylase (TPH2), its key biosynthetic enzyme.
Between 2004 and 2008, brains of 41 infants dying from SIDS (cases) were compared with brains of 7 infants who died acutely from known causes (controls), as well as with brains of 5 hospitalized infants with chronic hypoxia-ischemia. Compared with age-adjusted controls, SIDS cases had 26% lower serotonin levels in 2 brainstem regions: the raphé obscurus (P = .05) and paragigantocellularis lateralis (PGCL; P = .04), but there was no evidence of excessive 5-HT degradation reflected in 5-hydroxyindoleacetic acid (5-HIAA) levels, 5-HIAA:5-HT ratio, or both.
Compared with controls, SIDS cases had 22% lower TPH2 levels (P = .03), and 29% to 55% lower 5-HT1A receptor binding in 3 medullary nuclei that receive 5-HT projections. In SIDS cases, but not in the controls, there was a decrease with age in 5-HT1A receptor binding in 4 nuclei, 3 of which contain 5-HT neurons. The SIDS and hospitalized groups differed significantly in regard to the profile of 5-HT and TPH2 abnormalities.
Viewpoint
Study limitations include possibly compromised high-performance liquid chromatography neurotransmitter measurements because of prolonged postmortem intervals; inability to measure synaptic neurotransmitter levels in postmortem tissues; and small control group.
Compared with controls, SIDS was associated with lower brainstem levels of 5-HT and TPH2, suggesting medullary 5-HT deficiency underlying the pathogenesis of this disorder. Reduced 5-HT synthesis, rather than significant breakdown of 5-HT, is supported by the lack of changes in 5-HIAA levels or neurotransmitter turnover (5-HIAA:5-HT ratio). Correlation of 5-HT1A binding alterations among components of the medullary 5-HT system in the SIDS cases (and controls) offers further proof that the medullary 5-HT system is an interrelated network regulating respiratory and autonomic functions.
Based on these findings, the investigators suggest that SIDS may be caused by a defect in at least 1 component of the medullary 5-HT system, but that simultaneous defects in all 5-HT markers are not required in every case. Reduced 5-HT1A receptor binding in older SIDS cases may reflect a progressive decrease with age in infants having the "SIDS abnormality," or it may suggest that infants with a more pronounced abnormality take longer to outgrow the risk period for SIDS and continue to die at older ages.
Differences in the pattern of abnormalities between the SIDS group and the hypoxia-ischemia group suggest that chronic hypoxia-ischemia is not the primary mechanism explaining 5-HT abnormalities in SIDS. 5-HT1A receptor binding was significantly lower in SIDS infants without known extrinsic risk factors, suggesting that with less involvement of the medullary 5-HT system, additional risk factors are needed for death to occur.
The investigators suggest that insufficient 5-HT levels early in fetal development result in a compensatory increase in immature 5-HT neurons with decreased 5-HT1A binding and 5-HT transporter levels. With a partial defect in this system, medullary 5-HT-mediated pathways may function reasonably well during the awake state but less well when exposed to homeostatic stressors during sleep.