In this article we report the presence of lower levels of medullary 5-HT and TPH2 in infants dying from SIDS, pointing to a deficiency, as opposed to an excess, of 5-HT in the pathogenesis of the disorder. The absence of changes in 5-HIAA levels or neurotransmitter turnover (5-HIAA:5-HT ratio) excludes the possibility of substantial 5-HT degradation and supports reduced 5-HT synthesis. In this data set, we also confirmed 5-HT1A
receptor binding alterations, although not in the arcuate nucleus, raphé obscurus, or medial accessory olive.9
There were no differences in SIDS risk factors between the 200611
and current data sets that explained this difference, nor were there any obvious differences in the controls to explain the variation in control levels between data sets. While these inconsistencies warrant further analysis, binding differences are remarkably similar in all other nuclei across our data sets and are associated with abnormalities in different parameters of 5-HT function, ie, 5-HT cell density11
and 5-HT and TPH2 levels.
We also report that 5-HT1A
binding alterations correlate among components of the medullary 5-HT system in the SIDS cases (and controls), substantiating our concept that the medullary 5-HT system is an interrelated network that modulates respiratory and autonomic functions3
—a concept likewise increasingly supported by animal data.3,23–25
We now postulate that SIDS can be viewed as a disorder caused by a defect in 1 or more components of the medullary 5-HT system and that any single case need not express defects in all 5-HT markers simultaneously.
With regard to 5-HT1A receptor binding, the consistent finding over 4 data sets of several significant interactions between age and diagnosis warrants mention. Although interpretation is impossible without longitudinal study, the reduced binding in older SIDS cases may reflect a progressive decrease with age in those infants with the “SIDS abnormality.” Alternatively, it may reflect the possibility that infants with a stronger abnormality take longer to outgrow the risk period for SIDS and continue to die at older ages.
In this study, we also asked whether 5-HT abnormalities in infants with SIDS could be explained by hypoxia-ischemia. We did not observe, however, a similar pattern of abnormalities between the SIDS and hospitalized (hypoxia-ischemia) group, suggesting that the primary mechanisms underlying 5-HT abnormalities in SIDS are not mediated by chronic hypoxia-ischemia. A striking difference between the SIDS and hospitalized groups was the association of reduced TPH2 levels with reduced 5-HT levels in the SIDS group compared with unaltered 5-HT levels in the hospitalized group. These findings indicate that the SIDS cases demonstrate a different TPH2: 5-HT ratio and that the SIDS profile does not mimic that of the hospitalized group; the basis of this discrepancy is currently unknown.
Catecholaminergic abnormalities in the brainstems of infants with SIDS are controversial, with reports of positive and negative findings using immunocytochemistry and tissue autoradiography.26–29
Our study does not support a major abnormality in SIDS cases in medullary 5-HT nuclei that receive projections from rostral catecholaminergic cell bodies in the pons and midbrain.
The finding of at least 1 risk factor in 95% of SIDS cases underscores the importance of risk factors in the pathogenesis of SIDS, even in the era of the recommendation for supine sleep position. The finding of 2 or more risk factors in 88% of SIDS cases further underscores that SIDS results from the simultaneous occurrence of multiple events.3
Infants with SIDS but without known extrinsic risk factors had significantly lower 5-HT1A
receptor binding, suggesting that additional risk factors are necessary to precipitate death when the medullary 5-HT system is less compromised.
Three concerns in this study warrant consideration. The first is the possibility of compromised neurotransmitter measurements using HPLC, attributable to prolonged postmortem intervals. Animal models, however, suggest that 5-HT degradation is not significant, at least over a 27-hour postmortem delay, in cerebral cortical sites that receive 5-HT projections.30
In addition, we made adjustments in this study for postmortem interval in all statistical analyses as warranted. Furthermore, we analyzed brainstem tissues only in infants with relatively short postmortem intervals (<30 hours) and avoided any freeze-thaw procedures. Second, we were unable to measure neurotransmitter levels at the synapse in postmortem tissues. Our data therefore represent combined intracellular and extracellular stores without precise cellular localization. The final concern is the small sample size of the control group, which is an unavoidable reflection of the extraordinary rareness of death as well as autopsies in infants without SIDS who die unexpectedly. Our response was to study all cases in greater depth with different modalities, to compare data from different data sets, and to combine these data when possible.9–11
Independent investigators have now also reported 5-HT1A
receptor deficits confirmed in SIDS cases using a different technique, ie, immunocytochemistry, thereby confirming our receptor results.31,32
These findings raise the question as to how reduced 5-HT and TPH2 levels are related to the increased 5-HT cell density,11
morphologic 5-HT neuronal immaturity,11
reduced 5-HT transporter binding relative to 5-HT cell number,11
and altered 5-HT receptor binding9–11
in the SIDS cases. We hypothesize that TPH2 levels are reduced in the medullary 5-HT system for as-yet unknown developmental, genetic, and/or environmental reasons, with a secondary reduction in 5-HT levels and impaired 5-HT neurotransmission.33
We further propose that insufficient 5-HT levels early in development, potentially as early as the first or second trimester, result in a compensatory increase in immature 5-HT neurons with immature (decreased) 5-HT1A
binding and 5-HT transporter levels.34
That the defect is partial rather than total could explain why medullary 5-HT-mediated pathways function reasonably well at baseline or during waking but are unable to respond to homeostatic stressors during sleep when the partial deficit is potentially unmasked, thereby resulting in sudden death. Our data suggest that future animal models mimicking the 5-HT abnormalities of SIDS should focus on underproduction, rather than overproduction, of 5-HT and TPH2.