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Relationship Among Key Neuroendocrine Hormones
Page 6 of 13Goracke‑Postle et al. BMC Neurol (2021) 21:384
BDNF, CNTF, FSH, GH, LH, PRL, and TSH; inflammatory cytokines/chemokines: IL-1α, IL-1ra, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, TNFα, IFN-α2, IP-10, MCP-1, MIP1β, and RANTES; and neurotransmitters/ neuropeptides: Dynorphin A, neuropeptide Y, somatostatin, β endorphin, cortisol, neurotensin, orexin A, substance P, melatonin, oxytocin, melanocyte-stimulating hormone (α-MSH). Figure 1 illustrates the correlations among analytes (at p ≤ 0.001); a full list of analytes that demonstrated correlations (p ≤ 0.05) among the participants with CP is included in the Supplemental Information (Supplemental Table 1).
Considering this initial complete cohort, there were 35 analyte pairings with positive correlations as per our criteria from 21 distinct analytes (all p ≤ 0.001; Table 2). These 35 correlations represent combinations of endo- crine, inflammatory, and excitatory neuropeptides. The specific correlation pattern represents a novel approach to considering analytes that may shed light on the mech- anistic underpinnings of secondary processes that may be ongoing in CP and result in clinical signs and their manifestation.
To assess the potential of such protein signatures in CSF to distinguish differences relating to biological variables underlying various subpopulations of CP patients, we assessed analyte correlations between various sub- groups. This analysis provided novel information, with analyte signature correlations becoming apparent for specific subsets of participant groups. This report focuses on birth term as a defining characteristic; how- ever, the Supplemental Information provides full analy- ses of various subgroups based on additional clinical characteristics.
Gestational age subgroup analyses Term birth No significant correlations between analytes were detected at the pre-determined significance level (p ≤ 0.001) used to report the rest of the subgroup findings. There were, however, two correlations at p ≤ 0.05 specific to Term Birth participants (correlations which were not present for Preterm Birth or Extremely Preterm Birth participants) specifically between IL-1ra and orexin A and between orexin A and substance P (identical data for both correla- tions: Correlation (Corr) = 0.99; 95% Confidence Interval (CI) = [0.89, 1]; Adjusted P (Adj P) = 0.041) (Fig. 2).
Preterm birth Preterm Birth status resulted in clusters of analytes that were highly correlated to one another (Fig. 3). There were 14 discrete correlations not found in the other ges- tational subgroup (bolded in Table 3); these correlations
represent unique correlations in this sample specific to individuals born preterm.
Extremely preterm birth Extremely Preterm Birth status also resulted in distinct analyte correlations different from both Term Birth and Preterm Birth participants (Fig. 4). There were 24 dis- crete analyte correlations unique in this sample of par- ticipants in the extremely preterm birth status (bold in Table 4).
Table 2 Significant Pearson’s correlations (p ≤ 0.001) between analyte pairs, representing 21 distinct analyte correlations (bold font)
Analyte 1 Analyte 2 Correlation 95% CI Adj. p
Dynorphin A AGRP 0.71 [0.34, 0.85] < .001 Dynorphin A ACTH 0.79 [0.60, 0.90] < .001 Dynorphin A IL-12p70 0.68 [0.41, 0.84] 0.001 Dynorphin A TNFα 0.80 [0.60, 0.90] < .001 Dynorphin A substance P 0.78 [0.57, 0.89] < .001 AGRP IL-6 0.73 [0.49, 0.87] < .001 AGRP IL-8 0.71 [0.46, 0.86] < .001 AGRP IL-10 0.91 [0.81, 0.96] < .001 AGRP IL-12p40 0.73 [0.50, 0.87] < .001 AGRP MIP-1β 0.94 [0.87, 0.97] < .001 AGRP TNFα 0.67 [0.40, 0.84] 0.001
FSH LH 0.89 [0.78, 0.95] < .001 TSH ACTH 0.69 [0.42, 0.84] 0.001 ACTH IL‑12p70 0.82 [0.65, 0.92] < .001
ACTH TNFα 0.92 [0.83, 0.96] < .001
ACTH β endorphin 0.67 [0.40, 0.83] 0.001 ACTH substance P 0.91 [0.81, 0.96] < .001
IFNα2 IL‑12p70 0.73 [0.49, 0.87] < .001 IL-1α IL‑12p40 0.78 [0.57, 0.89] < .001 IL‑1α IP-10 0.79 [0.60, 0.90] < .001 IL-1RA orexin A 0.75 [0.52, 0.88] < .001 IL‑6 IL‑10 0.87 [0.74, 0.94] < .001
IL‑6 IL‑12p40 0.68 [0.41, 0.84] 0.001
IL‑8 MIP‑1β 0.73 [0.49, 0.87] < .001
IL‑10 IL‑12p40 0.74 [0.51, 0.87] < .001
IL‑10 MIP‑1β 0.81 [0.63, 0.91] < .001
IL‑12p40 IP‑10 0.81 [0.63, 0.91] < .001
IL‑12p70 TNFα 0.91 [0.81, 0.96] < .001
IL‑12p70 substance P 0.82 [0.64, 0.91] < .001
TNFα substance P 0.93 [0.86, 0.97] < .001
β endorphin orexin A 0.81 [0.63, 0.91] < .001
β endorphin substance P 0.81 [0.62, 0.91] < .001
β endorphin αMSH 0.70 [0.44, 0.85] 0.001
orexin A substance P 0.70 [0.44, 0.85] 0.001
orexin A αMSH 0.79 [0.58, 0.90] < .001
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Between subgroup analyses Differences in correlations between subgroups were also directly tested. As noted above, to be included in between-group analysis, each correlation first had to be statistically significant within the subgroups. Thirty- two pairs of correlations were statistically significant across all subgroups. Then the identified correlations were tested against one another to check whether they were significantly different by birth status. Based on this approach, there was a significant difference between the Preterm and Extremely Preterm Birth subgroups for the correlation between TNFα and substance P (Extremely Preterm r to z = 0.99, Preterm r to z = 0.82, Z Differ- ence = 1.49, p < 0.05).
Discussion There are many different ways that white matter and upper motor neurons can be damaged. It is gener- ally agreed that enough damage will interfere with and
ultimately impair motor control and increase risk for the clinical condition of CP (importantly there are, of course, other associated impairments including cognitive and sensory function). Of the many putative causal agents and pathways to CP, the role of neuroinflammation in perinatal brain damage has received considerable empiri- cal attention. There has also been considerable concep- tual emphasis challenging conventional wisdom about the nature of the threat in relation to inflammation and the developing brain with a distinct shift to a perspective that a core underlying feature may be less about static events (i.e., a one-time insult) and more about sustained states (i.e., an ongoing process). The significance of this shift is in widening the focus of inquiry to include tertiary mechanisms of brain damage, which, in turn, could shed new light on a very old problem – namely treating CP based on its underlying pathophysiology.
There is a working hypothesis that suggests that the relationship among key neuroendocrine hormones,
Fig. 2 Visual representation of the direction and strength of the Pearson’s correlation coefficients between all 33 analytes assayed within the Term Birth subgroup. Positive (blue), negative (red), strong (dark shading), and weak (light shading) correlations are depicted. *In instances where the same value was reported for each variable, no correlation was calculated
Page 8 of 13Goracke‑Postle et al. BMC Neurol (2021) 21:384
excitatory neuropeptides, and neuroinflammatory cytokines as markers may be a critical variable predict- ing outcome. The conceptual basis for this is the past two decades of work supporting the cross-talk among the endocrine, nociceptive, and immune systems. In healthy states there is an optimal balance between stress hormones and proinflammatory cytokines. In children with CP, the white matter damage may be ‘driving’ an immune-mediated inflammatory cascade. There is evi- dence supporting this possibility from three related stud- ies with CP patients, one using umbilical cord serum [1], one using plasma [9], and one using blood [11].
The current analysis expands the previous work and provides further description of the molecular milieu pre- sent in the CNS of CP patients. Such documentation pro- vides a unique opportunity to consider how differences in CNS concentrations of various inflammatory-relevant analytes between differing presentations of CP may be relevant for hypotheses about mechanisms underly- ing the differential outcomes in CP. Specifically, in this
sample, it was observed that Term Birth, Preterm Birth, and Extremely Preterm Birth status was associated with distinct patterns of analyte inter-correlations. If repro- ducibility of these findings could be established, there is an opportunity to better understand the mechanisms underlying various and varying outcomes specific to birth term in CP.
The correlations present in the participants suggest relationships among systems subserving arousal (orexin A), inflammation (TNFα), anti-inflammation (IL-1ra), and neuronal excitation (substance P), with distinctions depending on birth term. Orexin A (hypocretin 1) is an excitatory, hypothalamic neuropeptide that binds to both the orexin 1 and 2 receptors (OX1R and OX2R); the former is thought to act largely through the excitatory Gq protein and both are implicated in wakefulness and sleep cycle stability [14]. Narcoleptic symptoms in dogs and mice are associated with loss-of-function mutations in the gene encoding OX2R, although immunosuppres- sion can delay symptom onset, and deletion of the gene
Fig. 3 Visual representation of the direction and strength of the Pearson’s correlation coefficients between all 33 analytes assayed within the Preterm Birth subgroup. Positive (blue), negative (red), strong (dark shading), and weak (light shading) correlations are depicted
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Relationship Among Key Neuroendocrine Hormones |
Relationship Among Key Neuroendocrine Hormones