Dodick, David W.

Background Women with endometriosis are more likely to have migraine. The mechanisms underlying this co-morbidity are unknown. Prolactin, a neurohormone secreted and released into circulation from the anterior pituitary, can sensitize sensory neurons from female, but not male, rodents, monkeys and human donors. Methods We used a syngeneic model of endometriosis to determine whether elevated prolactin levels can sensitize trigeminal ganglion neurons and increase vulnerability to migraine pain. Results Mice with endometriotic lesions showed increased serum prolactin levels and developed persistent abdominal, but not cephalic, allodynia. However, inhalation of a transient receptor potential ankyrin 1 agonist, umbellulone, a known environmental trigger of headache in some patients, elicited cephalic allodynia in mice with endometriosis but not sham controls, suggesting that endometriosis can promote sensitization of trigeminal neurons and migraine attacks. Endometriosis dysregulated the expression of prolactin receptor isoforms in trigeminal neurons and increased their excitability measured by in vitro patch clamp electrophysiology. Inhibition of pituitary prolactin following a 2-week treatment with a dopamine receptor agonist, cabergoline, prevented cephalic allodynia elicited by activation of trigeminal afferents with umbellulone. Cabergoline treatment also normalized the expression of prolactin receptor isoforms in trigeminal ganglia and the hyperexcitability of trigeminal neurons. Conclusions These data demonstrate that circulating prolactin in endometriosis promotes vulnerability to migraine through sensitization of trigeminal afferents. Clinically available dopamine receptor agonists or novel monoclonal antibodies targeting prolactin signaling may be effective for migraine prevention in women with endometriosis.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of the neurodegenerative disease chronic traumatic encephalopathy (CTE). As part of the 2021 TES NINDS consensus diagnostic criteria, certainty levels of underlying CTE neuropathology can be determined (i.e., suggestive, possible, probable) partially based on the presence/absence of supportive psychiatric features including but not limited to depression, anxiety, and apathy. These are ‘supportive’ because of their non‐specificity and unclear biological correlates in this setting. We examined the association between CSF biomarkers of amyloid, tau, neurodegeneration, microglial activation and neuroinflammation and supportive psychiatric features of TES in former American football players.MethodThe sample included 180 male former football players (120 professional, 60 college) from the DIAGNOSE CTE Research Project. Participants completed a lumbar puncture, and CSF assays were conducted for biomarkers of amyloid (Aβ40, Aβ42), p‐tau (p‐tau181, p‐tau231, p‐tau217), neurodegeneration (total tau), axonal degeneration (NfL), microglial activation (strem2) and neuroinflammation (GFAP, IL‐6). Biomarkers were log‐transformed. The Apathy Evaluation Scale (AES), Beck Depression Inventory‐II (BDI‐II) and the Beck Anxiety Inventory (BAI) self‐report questionnaires were completed by participants. Multivariable regression models tested the association between each CSF biomarker and each scale, controlling for age, race, body mass index, revised Framingham stroke risk profile and Alcohol Use Disorders Identification Test. P‐values were adjusted for multiple comparisons using false discovery rate methods.Result140 participants had successful LPs and available CSF for assays. 33(22%) reported moderate/severe anxiety, 34(22%) reported moderate/severe depression, and 51(33%) had an elevated AES score. Higher CSF concentrations of IL‐6 were associated with higher scores on the BAI (unstandardized‐β=0.016, 95%CI [0.017, 0.026], padj=0.004), BDI‐II (unstandardized‐β=0.013, 95%CI [0.004, 0.021], padj=0.008) and AES (unstandardized‐β=0.014, 95%CI [0.006,0.022], padj=0.002). There were no significant relationships between other biomarkers with the BDI‐II, BAI or AES.ConclusionIn this sample of former American football players, there were significant associations between IL‐6 (a proinflammatory cytokine) and reported symptoms of depression, anxiety, and apathy. CSF biomarkers of amyloid, tau and neurodegeneration had no associations, highlighting the role of neuroinflammatory processes in the manifestation of psychiatric symptoms of TES. Continued research on the biological correlates of TES features will inform future iterations of the criteria.

AbstractBackgroundClinically meaningful cognitive impairment has typically been defined as a single impaired test score, but this approach is prone to false‐positive errors. Examining two test scores at a lower threshold (i.e., using neuropsychological criteria) can improve diagnostic reliability and has shown stronger associations with biomarkers of Alzheimer’s disease. Cognitive impairment in episodic memory and/or executive functioning is a core feature of traumatic encephalopathy syndrome (TES). However, there remains a need to improve the specificity of TES criteria. We applied 1‐ vs. 2‐test criteria for cognitive impairment in former American football players to examine whether 2‐test criteria showed stronger associations with biomarkers of tau, axonal injury, and neurodegeneration.Method169 male former American football players from the DIAGNOSE CTE Research Project completed neuropsychological assessment, lumbar puncture, and MRI (see Table). Episodic memory measures were delayed recall from Craft Story, Brief Visuospatial Memory Test, and NAB List Learning. Executive functioning measures were FAS, Stroop Interference, NAB Mazes, and Trails B. Cerebrospinal fluid (CSF) was measured using Lumipulse technology (p‐tau, t‐tau) and an in‐house ELISA (neurofilament light [NfL]). Hippocampal volumes were extracted from structural MRI using Freesurfer 7.1. Cognitive impairment was identified by 1‐test criteria (≥1.5 SD below norms on one test in either domain) and 2‐test criteria (>1 SD below norms on two tests within a domain). Regressions adjusting for age, race, education, and APOE ε4 status assessed whether meeting 1‐ or 2‐test criteria, separately, predicted log‐transformed CSF p‐tau181, p‐tau231, t‐tau, and NfL, and hippocampal volumes.Result37 of the 99 football players that were impaired by 1‐test criteria did not meet 2‐test criteria, and four uniquely met 2‐test but not 1‐test criteria (see Figure). Cognitive impairment by 2‐test but not 1‐test criteria predicted higher log‐CSF NfL (2‐test: B = 0.24, p = .007; 1‐test: B = 0.06, p = .53), smaller left hippocampal volume (2‐test: B = ‐195.84, p = .01; 1‐test: B = ‐131.52, p = .08), and smaller right hippocampal volume (2‐test: B = ‐161.19, p = .045; 1‐test: B = ‐134.88, p = .08). Neither criterion predicted p‐tau181, p‐tau231, or t‐tau.Conclusion2‐test criteria demonstrated stronger associations between cognitive impairment and markers of axonal injury and neurodegeneration. Incorporating multiple test scores to identify cognitive impairment could improve diagnostic specificity in TES.

AbstractBackgroundTraumatic encephalopathy syndrome (TES) is the proposed clinical syndrome of chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impacts in contact/collision sports. A core clinical feature of TES is cognitive impairment, particularly in memory and executive functions. Cognitive intraindividual variability (IIV) is the extent of variability in neuropsychological test performance (i.e., dispersion of test scores) and is believed to be an indicator of disruption in executive control, linked to altered fronto‐subcortical circuits. Here, we examined cognitive IIV as a method to detect subtle executive dysfunction in TES that may not be captured by traditional neuropsychological measures.MethodThe sample included former American football players (120 professional, 60 college); participants were males, aged 45‐74. Participants completed a baseline neuropsychological test battery (n = 8 excluded for suboptimal performance validity). A multidisciplinary diagnostic consensus conference classified participants using the 2021 NINDS Consensus Diagnostic Criteria for TES (see Table‐1): (1) No‐TES (n = 62); (2) TES‐CTE Suggestive (n = 35); (3) TES‐CTE Possible (n = 21); (4) TES‐CTE Probable (n = 54). TES‐CTE Possible and Probable were combined. The coefficient of variation (CoV) was used to measure cognitive IIV (CoV = iSD/iOTBM, iOTBM = average T‐score across neuropsychological tests; iSD = standard deviation of iOTBM). A higher CoV indicates greater score dispersion. To avoid circularity, memory and executive tests used for classifying TES groups were intentionally excluded from the CoV calculation. Analysis of covariance compared the TES groups on CoV, controlling for age, education, and race.ResultResults showed a significant difference in CoV between TES groups, F(2, 165) = 8.20 p<.001, partial η2 = .09. The TES‐CTE Possible/Probable group had the highest CoV (M = .226, SE = .007), compared with the TES‐no (M = .192, SE = .008, p<.001) and TES‐CTE Suggestive groups (M = .178, SE = .011, p<.001). CoV did not significantly differ between the TES‐no and TES‐CTE suggestive groups (Mdiff = 0.014, SE = .013, p = .293).ConclusionThe TES‐CTE possible/probable group had the highest cognitive IIV with ∼23% dispersion (vs. ∼18‐19% in TES‐no and TES‐CTE suggestive groups), suggesting greater cognitive variability in those with the greatest likelihood for having underlying CTE (based on TES criteria). This finding emphasizes the potential utility of exploring cognitive IIV as a method for detecting nuanced executive dysfunction in TES.

Abstract Former American football players are at risk for developing traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The objective of this study was to determine whether hyposmia is present in traumatic encephalopathy syndrome. The study included 119 former professional American football players, 60 former college football players, and 58 same-age asymptomatic unexposed men from the DIAGNOSE CTE Research Project. All subjects included in the analysis had completed the Brief Smell Identification Test (B-SIT). Traumatic encephalopathy syndrome and the level of CTE certainty were diagnosed using the 2021 NINDS consensus diagnostic criteria. TES is categorized antemortem by provisional levels of increasing CTE certainty: Suggestive, Possible, and Probable. Former players who had traumatic encephalopathy syndrome and Probable CTE had lower B-SIT scores than those with TES and Suggestive CTE. Hyposmia was more likely in the former players with TES who were either CTE Possible or Probable than in those who did not have TES or had TES but were less likely to have CTE, or CTE Suggestive. There was no difference in B-SIT scores between all former players versus unexposed men nor overall between the football players with and without TES. We conclude that lower B-SIT scores may be a clinical biomarker for underlying CTE in former American football players.

Background Migraine is associated with obesity. These analyses evaluated weight change with atogepant used as a preventive migraine treatment. Methods Five atogepant clinical trials in adults with migraine (one phase 2b/3; four phase 3) were included: Three 12-week, randomized, placebo-controlled trials (episodic migraine: two; chronic migraine: one); one 40-week, open-label extension trial and one 52-week, standard care, randomized, long-term safety trial in episodic migraine. Change from baseline in body weight was measured. Results Mean baseline body mass indexes were 30.0–30.7 kg/m 2 (pooled episodic migraine [United States only]) and 25.0–25.5 kg/m 2 (chronic migraine [East Asia, Europe, and North America]). More participants treated with atogepant 60 mg once-daily compared to placebo experienced ≥7% weight loss at any time in the pooled episodic migraine placebo-controlled trials (4.9% vs. 2.8%), chronic migraine placebo-controlled trial (5.8% vs. 2.0%), and pooled open-label extension and long-term safety trials (24.0% vs.14.7% in standard care [long-term safety only]). In the placebo-controlled trials, weight loss with atogepant 60 mg once-daily was observed at week 2 (pooled episodic migraine: −0.32%; chronic migraine: −0.39%), increasing at week 12 (pooled episodic migraine: −1.02%; chronic migraine: −1.50%); compared to weight gain with placebo at week 12 (pooled episodic migraine: +0.49%; chronic migraine: +0.10%). In the long-term episodic migraine studies, weight loss with atogepant 60 mg once-daily was observed at week 4 (long-term safety: −0.42%; open-label extension: −0.76%), increasing at week 40 (long-term safety: −2.38%; open-label extension: −2.09%). Conclusion Atogepant was associated with modest dose- and duration-dependent weight loss. Trial registration ClinicalTrials.gov identifiers: NCT02848326 (CGP-MD-01); NCT03777059 (3101-301-002); NCT03700320 (long-term safety trial); NCT03939312 (open-label extension trial); NCT03855137 (3101-303-002).

Abstract Protease activated receptor 2 (PAR2) is a G-protein coupled receptor expressed in meningeal neurons, fibroblasts and mast cells that may be targeted to treat migraine. MEDI0618, a fully humanized PAR2 monoclonal antibody, engineered to enhance FcRn-dependent recycling and currently in clinical development, was evaluated in human and rodent in vitro assays, in multiple murine in vivo migraine models and in a model of post-traumatic headache. MEDI0618 bound specifically and with high affinity to cells expressing human PAR2 (hPAR2) and prevented matriptase-induced increase in cytosolic calcium. Similarly, MEDI0618 prevented matriptase-induced calcium in primary fibroblasts and microvascular endothelial cells from human dura mater. MEDI0618 had no effect on hPAR1 receptors. Single-cell calcium imaging of acutely dissociated mouse trigeminal ganglion neurons confirmed expression and functionality of mouse PAR2. Studies in vivo used evoked cutaneous allodynia as a surrogate of headache-like pain and, in some experiments, rearing as a measure of non-evoked headache pain. MEDI0618 was administered subcutaneously to C57BL6/J female mice prior to induction of migraine-like pain with (i) systemic nitroglycerin or compound 48/80 (mast cell degranulator); or (ii) with supradural compound 48/80 or an inflammatory mediator (IM) cocktail. To assess possible efficacy against CGRP receptor (CGRP-R)-independent pain, MEDI0618 was also evaluated in the IM model in animals pretreated with systemic olcegepant (CGRP-R antagonist). Migraine-like pain was also induced by inhalational umbellulone, a TRPA1 agonist, in animals primed with restraint stress in the presence or absence of MEDI0618 as well as in a model of post-traumatic headache pain induced by a mild traumatic brain injury. MEDI0618 prevented cutaneous allodynia elicited by systemic nitroglycerin, compound 48/80 and from supradural compound 48/80 and IM. Systemic olcegepant completely blocked periorbital cutaneous allodynia induced by supradural CGRP but failed to reduce IM-induced cutaneous allodynia. In contrast, MEDI0618 fully prevented IM-induced cutaneous allodynia, regardless of pretreatment with olcegepant. Umbellulone elicited cutaneous allodynia only in restraint stress-primed animals, which was prevented by MEDI0618. MEDI0618 prevented the decrease in rearing behaviour elicited by compound 48/80. However, MEDI0618 did not prevent mild traumatic brain injury-related post-traumatic headache measures. These data indicate that MEDI0618 is a potent and selective inhibitor of PAR2 that is effective in human and rodent in vitro cell systems. Further, blockade of PAR2 with MEDI0618 was effective in all preclinical migraine models studied but not in a model of post-traumatic headache. MEDI0618 may represent a novel therapy for migraine prevention with activity against CGRP-dependent and independent attacks.

AbstractINTRODUCTIONBlood‐based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players.METHODSThe sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45–74). Plasma assays were conducted for beta‐amyloid (Aβ) 40, Aβ42, hyper‐phosphorylated tau (p‐tau) 181+231, total tau (t‐tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin‐6 (IL‐6), Aβ42/p‐tau181 and Aβ42/Aβ40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES).RESULTSP‐tau181 and p‐tau231(padj = 0.016) were higher and Aβ42/p‐tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p‐tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD‐related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES‐chronic traumatic encephalopathy (TES‐CTE) Possible/Probable (padj = 0.008).DISCUSSIONPlasma p‐tau181 and p‐tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI‐related neuropathologies.Highlights Former football players had higher plasma p‐tau181 and p‐tau231 and lower Aβ42/ptau‐181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES‐CTE possible/probable compared to TES‐CTE no/suggestive.

ImportancePatients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH.ObjectiveTo assess erenumab efficacy and safety in patients with nonopioid CM-MOH.Design, Settings, and ParticipantsThis randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort)InterventionsErenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks.Main Outcomes and MeasuresThe primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs.ResultsThe primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P &amp;lt; .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was –9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, –2.7; 95% CI, –3.9 to –1.6; P &amp;lt; .001) and –7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, –1.2; 95% CI, –2.4 to –0.1; P = .03), vs –6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common.Conclusions and RelevanceIn this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months.Trial RegistrationClinicalTrials.gov Identifier: NCT03971071

Background We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. Methods Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. Results Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. Conclusions Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.