المؤلفون: Onderwater, Gerrit L. J., van Dongen, Robin M., Harms, Amy C., Zielman, Ronald, van Oosterhout, Willebrordus P. J., van Klinken, Jan B., Goeman, Jelle J., Terwindt, Gisela M., van den Maagdenberg, Arn M. J. M., Hankemeier, Thomas, Ferrari, Michel D.

المصدر: Annals of Neurology; Apr2023, Vol. 93 Issue 4, p715-728, 14p

مصطلحات موضوعية: LIQUID chromatography-mass spectrometry, CEREBROSPINAL fluid, MIGRAINE aura, MIGRAINE, MEDICAL ethics committees

مستخلص: Objective: Impaired amine metabolism has been associated with the etiology of migraine, that is, why patients continue to get migraine attacks. However, evidence from cerebrospinal fluid (CSF) is lacking. Here, we evaluated individual amine levels, global amine profiles, and amine pathways in CSF and plasma of interictal migraine patients and healthy controls. Methods: CSF and plasma were sampled between 8:30 am and 1:00 pm, randomly and interchangeably over the time span to avoid any diurnal and seasonal influences, from healthy volunteers and interictal migraine patients, matched for age, sex, and sampling time. The study was approved by the local medical ethics committee. Individual amines (n = 31), global amine profiles, and specific amine pathways were analyzed using a validated ultraperformance liquid chromatography mass spectrometry platform. Results: We analyzed n = 99 participants with migraine with aura, n = 98 with migraine without aura, and n = 96 healthy volunteers. Univariate analysis with Bonferroni correction indicated that CSF L‐arginine was reduced in migraine with aura (10.4%, p < 0.001) and without aura (5.0%, p = 0.03). False discovery rate‐corrected CSF L‐phenylalanine was also lower in migraine with aura (6.9%, p = 0.011) and without aura (8.1%, p = 0.001), p = 0.088 after Bonferroni correction. Multivariate analysis revealed that CSF global amine profiles were similar for both types of migraine (p = 0.64), but distinct from controls (p = 0.009). Global profile analyses were similar in plasma. The strongest associated pathways with migraine were related to L‐arginine metabolism. Interpretation: L‐Arginine was decreased in the CSF (but not in plasma) of interictal patients with migraine with or without aura, and associated pathways were altered. This suggests that dysfunction of nitric oxide signaling is involved in susceptibility to getting migraine attacks. ANN NEUROL 2023;93:715–728 [ABSTRACT FROM AUTHOR]

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المؤلفون: Harder, Aster V.E., Winsvold, Bendik S., Noordam, Raymond, Vijfhuizen, Lisanne S., Børte, Sigrid, Kogelman, Lisette J.A., de Boer, Irene, Tronvik, Erling, Rosendaal, Frits R., Willems van Dijk, Ko, O'Connor, Emer, Fourier, Carmen, Thomas, Laurent F., Kristoffersen, Espen S., Fronczek, Rolf, Pozo‐Rosich, Patricia, Jensen, Rigmor H., Ferrari, Michel D., Hansen, Thomas F., Zwart, John‐Anker

المصدر: Annals of Neurology; Aug2021, Vol. 90 Issue 2, p203-216, 14p

مصطلحات موضوعية: CLUSTER headache, GENETIC variation, GENETIC disorders, LINKAGE disequilibrium, RNA sequencing

مصطلحات جغرافية: TRONDHEIM (Norway)

مستخلص: Objective: Identifying common genetic variants that confer genetic risk for cluster headache.Methods: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses.Results: An association was found with cluster headache for 4 independent loci (r2  < 0.1) with genomewide significance (p < 5 × 10-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2  = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients.Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216. [ABSTRACT FROM AUTHOR]

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المؤلفون: Mulder, Inge A., Li, Mei, Vries, Tessa, Qin, Tao, Yanagisawa, Takeshi, Sugimoto, Kazutaka, Bogaerdt, Antoon, Danser, A. H. Jan, Wermer, Marieke J. H., Maagdenberg, Arn M. J. M., MaassenVanDenBrink, Antoinette, Ferrari, Michel D., Ayata, Cenk, de Vries, Tessa, van den Bogaerdt, Antoon, van den Maagdenberg, Arn M J M

المصدر: Annals of Neurology; Oct2020, Vol. 88 Issue 4, p771-784, 14p

مصطلحات موضوعية: CALCITONIN gene-related peptide, PEPTIDE receptors, TRANSIENT ischemic attack, CEREBRAL ischemia, MICE

مستخلص: Objective: Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.Methods: Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro.Results: Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta.Interpretation: Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020;88:771-784. [ABSTRACT FROM AUTHOR]

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المؤلفون: Eikermann-Haerter, Katharina, Arbel-Ornath, Michal, Yalcin, Nilufer, Yu, Esther S, Kuchibhotla, Kishore V, Yuzawa, Izumi, Hudry, Eloise, Willard, Carli R, Climov, Mihail, Keles, Fatmagul, Belcher, Arianna M, Sengul, Buse, Negro, Andrea, Rosen, Isaac A, Arreguin, Andrea, Ferrari, Michel D, van den Maagdenberg, Arn M J M, Bacskai, Brian J, Ayata, Cenk

المصدر: Annals of Neurology; Aug2015, Vol. 78 Issue 2, p193-210, 18p

مستخلص: Objective: Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV 2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear.Methods: We employed in vivo multiphoton microscopy of the genetically encoded Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo.Results: FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains.Interpretation: Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs. [ABSTRACT FROM AUTHOR]

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المؤلفون: Eikermann‐Haerter, Katharina, Arbel‐Ornath, Michal, Yalcin, Nilufer, Yu, Esther S., Kuchibhotla, Kishore V., Yuzawa, Izumi, Hudry, Eloise, Willard, Carli R., Climov, Mihail, Keles, Fatmagul, Belcher, Arianna M., Sengul, Buse, Negro, Andrea, Rosen, Isaac A., Arreguin, Andrea, Ferrari, Michel D., Maagdenberg, Arn M. J. M., Bacskai, Brian J., Ayata, Cenk

المصدر: Annals of Neurology; Aug2015, Vol. 78 Issue 2, p193-210, 18p

مستخلص: Objective Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. Methods We employed in vivo multiphoton microscopy of the genetically encoded Ca²⁺-indicator yellow cameleon to investigate synaptic morphology and [Ca²⁺]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. Results FHM1 mutations elevate neuronal [Ca²⁺]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca²⁺]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca²⁺]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. Interpretation Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca²⁺ homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs. Ann Neurol 2015;78:193-210 [ABSTRACT FROM AUTHOR]

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المؤلفون: van den Maagdenberg, Arn M. J. M., Pizzorusso, Tommaso, Kaja, Simon, Terpolilli, Nicole, Shapovalova, Maryna, Hoebeek, Freek E., Barrett, Curtis F., Gherardini, Lisa, van de Ven, Rob C. G., Todorov, Boyan, Broos, Ludo A. M., Tottene, Angelita, Gao, Zhenyu, Fodor, Mariann, De Zeeuw, Chris I., Frants, Rune R., Plesnila, Nikolaus, Plomp, Jaap J., Pietrobon, Daniela, Ferrari, Michel D.

المصدر: Annals of Neurology; Jan2010, Vol. 67 Issue 1, p85-98, 14p

مستخلص: Objective The CACNA1A gene encodes the pore-forming subunit of neuronal CaV2.1 Ca²⁺ channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma. Methods We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences. Results Cacna1a^S218L mice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage-dependent negative shift in voltage dependence of CaV2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1a^S218L mice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus. Interpretation The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema. ANN NEUROL 2010;67:85-98 [ABSTRACT FROM AUTHOR]

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المؤلفون: Eikermann-Haerter, Katharina, Baum, Michael J., Ferrari, Michel D., van den Maagdenberg, Arn M.J.M., Moskowitz, Michael A., Ayata, Cenk

المصدر: Annals of Neurology; Oct2009, Vol. 66 Issue 4, p564-568, 5p

مستخلص: Familial hemiplegic migraine type 1 (FHM1), a severe migraine with aura variant, is caused by mutations in the CACNA1A gene. Mutant mice carrying the FHM1 R192Q mutation exhibit increased propensity for cortical spreading depression (CSD), a propagating wave of neuroglial depolarization implicated in migraine aura. The CSD phenotype is stronger in female R192Q mutants and diminishes after ovariectomy. Here, we show that orchiectomy reciprocally increases CSD susceptibility in R192Q mutant mice. Chronic testosterone replacement restores CSD susceptibility by an androgen receptor-dependent mechanism. Hence, androgens modulate genetically-enhanced CSD susceptibility and may provide a novel prophylactic target for migraine. Ann Neurol 2009;66:564-568 [ABSTRACT FROM AUTHOR]

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المؤلفون: van Oosterhout, Floor, Michel, Stephan, Deboer, Tom, Houben, Thijs, van de Ven, Rob C. G., Albus, Henk, Westerhout, Joost, Vansteensel, Mariska J., Ferrari, Michel D., van den Maagdenberg, Arn M. J. M., Meijer, Johanna H.

المصدر: Annals of Neurology; Sep2008, Vol. 64 Issue 3, p315-324, 10p

مستخلص: Objective Mammalian circadian rhythms are driven by the circadian pacemaker of the suprachiasmatic nucleus (SCN) and are synchronized to the external 24-hour light/dark cycle. After advance time zone transitions (eastbound jet lag), overt circadian rhythms require several days to adjust. The retarded adaptation may protect against acute imbalance of different brain systems. Abrupt circadian rhythm changes may trigger migraine attacks, possibly because migraineurs have an inadequate adaptation mechanism. The novel R192Q knock-in migraine mouse model carries mutated Cav2.1 calcium channels, causing increased presynaptic calcium influx and neurotransmitter release. We investigated whether these mice have an abnormal adjustment to phase advance shifts. Methods We examined phase resetting to 6-hour advance shifts of the light/dark cycle with behavioral and electroencephalographic recordings in R192Q and wild-type mice. We recorded excitatory postsynaptic currents in the SCN, and electrical impulse frequency in vitro and in vivo. Results R192Q mice showed a more than twofold enhanced adjustment of behavioral wheel-running activity and electroencephalographic patterns, as well as enhanced shifts of electrical activity of SCN neurons in vivo. No differences were found for in vitro recordings of the electrical impulse frequency in SCN slices. Interpretation R192Q migraine mice lack the physiological retardation in circadian adaptation to phase advance shifts. The opposite findings in vivo and in vitro exclude involvement of the retinal input pathway or the phase-shifting capacity of the SCN. Thus, the physiological inhibitory process appears to be mediated by Cav2.1 channel-dependent afferent signaling from extra-SCN brain areas to the SCN. Ann Neurol 2008;64:315-324 [ABSTRACT FROM AUTHOR]

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المؤلفون: Badrising, Umesh A., Maat-Schieman, Marion L.C., Ferrari, Michel D., Zwinderman, Aeilko H., Wessels, Judith A.M., Breedveld, Ferdinand C., van Doorn, Pieter A., van Engelen, Baziel G.M., Hoogendijk, Jessica E., Höweler, Chris J., de Jager, Aeiko E., Jennekens, Frans G.I., Koehler, Peter J., de Visser, Marianne, Viddeleer, Alain, Verschuuren, Jan J., Wintzen, Axel R., Höweler, Chris J

المصدر: Annals of Neurology; 2002, Vol. 51 Issue 3, p369-372, 4p

المؤلفون: Kors, Esther E., Terwindt, Gisela M., Vermeulen, Frans L.M.G., Fitzsimons, Robin B., Jardine, Philip E., Heywood, Peter, Love, Seth, Van Den Maagdenberg, Arn M.J.M., Haan, Joost, Frants, Rune R., Ferrari, Michel D., Kors, E E, Terwindt, G M, Vermeulen, F L, Fitzsimons, R B, Jardine, P E, Heywood, P, Love, S, van den Maagdenberg, A M, Haan, J

المصدر: Annals of Neurology; 2001, Vol. 49 Issue 6, p753-760, 8p