Cytokines in primary headache disorders: a systematic review and meta-analysis

Musubire, Abdu K; Cheema, Sanjay; Ray, Jason C; Hutton, Elspeth; Matharu, Manjit

doi:10.1186/s10194-023-01572-7

Cited by 27 publications

(15 citation statements)

References 75 publications

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“…This proinflammatory cytokine has been involved in pathological processes underlying chronic pain conditions such as new daily persistent headache 45 and migraines. 46 Noteworthy, we previously showed that ΤΝFα is positively correlated with sTREM2 in CSF. 15 It remains to be further determined whether increased TNFα in chronic pain induces microglial activation or whether TNFα is produced by chronic painactivated microglia.…”

Section: Discussionmentioning

confidence: 92%

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

Sadlon,

Takousis,

Ankli

et al. 2023

Annals of Neurology

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ObjectiveDebate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative.MethodsParticipants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid β1–42, phosphorylated tau 181 (ptau181), total tau (t‐tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes.ResultsThe study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non‐Alzheimer pathophysiology and chronic pain showed increased CSF levels of t‐tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid‐positive and neurodegeneration‐negative chronic pain patients showed higher memory function cross‐sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group.InterpretationOur study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2023

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Section: Discussionmentioning

confidence: 92%

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

Sadlon,

Takousis,

Ankli

et al. 2023

Annals of Neurology

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“…Even though MOH is commonly seen in migraine patients and various studies have focused on proinflammatory cytokines in migraine, a link between inflammation and leaky gut has not been investigated in MOH patients. In a recent meta-analysis, IL-6, IL-8, IL-1β, and tumor necrosis factor α were the proinflammatory cytokines implicated in migraine patients [ 22 ]. The role of the gut-brain axis in migraine headache has already been suggested in several papers [ 23 ] and different gut microbiome profiles were reported in episodic and chronic migraine patients, and healthy controls [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

Vuralli,

Ceren Akgor,

Gok Dagidir

et al. 2024

J Headache Pain

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Objective Medication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation. Materials and methods The study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels. Results Serum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores. Conclusion We have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH. Graphical Abstract

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“…NDPH can be characterized by migraine-like headaches, and sometimes it is difficult to distinguish between the two disorders. Elevated levels of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α are commonly observed in patients with migraine [ 26 ]. Although the etiology of NDPH is not fully understood, previous clinical evidence suggested that infection and inflammation may be important predisposing factors for NDPH [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Brain structure and cortical activity changes of new daily persistent headache: multimodal evidence from MEG/sMRI

et al. 2023

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Background New daily persistent headache (NDPH) is a rare but debilitating primary headache disorder that poses a significant burden on individuals and society. Despite its clinical importance, the underlying pathophysiological mechanisms of NDPH remain unclear. In this study, we aimed to investigate the brain structural changes and neural activity patterns in patients with NDPH using multimodal brain imaging analysis of structural magnetic resonance imaging (sMRI) combined with magnetoencephalography (MEG). Methods Twenty-eight patients with NDPH and 37 healthy controls (HCs) were recruited for this study, and their structural and resting-state data were collected by 3.0 Tesla MRI and MEG. We analyzed the brain morphology using voxel-based morphometry and source-based morphometry. In each brain region, MEG sensor signals from 1 to 200 Hz were analyzed using an adapted version of Welch's method. MEG source localization was conducted using the dynamic statistical parametric mapping, and the difference of source distribution between patients with NDPH and HCs was examined. Results Our results revealed significant differences in the regional grey matter volume, cortical thickness, and cortical surface area between the two groups. Specifically, compared with HCs, patients with NDPH showed a significant decrease in cortical thickness of the left rostral cortex in the middle frontal gyrus, decreased cortical surface area of the left fusiform gyrus, decreased grey matter volume of the left superior frontal gyrus and the left middle frontal gyrus, and increased grey matter volume of the left calcarine. Furthermore, the power of the whole brain, bilateral frontal lobes, and right temporal lobe in the NDPH group were higher than that in HCs in the ripple frequency band (80-200 Hz). Functional and structural analysis suggested that there were structural changes and abnormal high frequency cortical activity in both frontal and temporal lobes in patients with NDPH. Conclusion Our findings indicated that patients with NDPH have abnormalities in brain morphology, such as cortical area, cortical thickness, and grey matter volume, accompanied by abnormal cortical neural activity. Brain structural changes in the frontotemporal cortex and abnormalities in cortical ripple activity may be involved in the pathogenesis of NDPH.

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Cytokines in primary headache disorders: a systematic review and meta-analysis

Cited by 27 publications

References 75 publications

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

Brain structure and cortical activity changes of new daily persistent headache: multimodal evidence from MEG/sMRI

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