Pathophysiology of the migraine aura

Lauritzen, Martin

doi:10.1093/brain/117.1.199

Cited by 1,009 publications

(204 citation statements)

References 55 publications

(78 reference statements)

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…than in the depolarized state (the conditions of the present study with porous membranes). The change in K ϩ handling is thus a likely explanation for the altered cortical spreading depression in migraine associated with aura as hypothesized by Lauritzen (25). We suggest that the decreased removal of extracellular K ϩ during the recovery phase of nerve impulse transmission is probably the critical manifestation of altered pump function that leads to disease.…”

Section: Fig 2 Nasupporting

confidence: 57%

Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase α2 Subunit Cause Familial Hemiplegic Migraine Type 2

Segall

Scanzano

Kaunisto

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

A number of missense mutations in the ATP1A2 gene, which encodes the Na,K-ATPase ␣2 subunit, have been identified in familial hemiplegic migraine with aura. Loss of function and haploinsufficiency have been the suggested mechanisms in mutants for which functional analysis has been reported. This paper describes a kinetic analysis of mutant T345A, recently identified in a detailed genetic analysis of a large Finnish family (Kaunisto, M. A., Harno, H., Vanmolkot, K. R., Gargus, J. J., Sun, G., Hamalainen, E., Liukkonen, E., Kallela, M., van den Maagdenberg, A. M., Frants, R. R., Farkkila, M., Palotie, A., and Wessman, M. (2004) Neurogenetics 5, 141-146). Introducing T345A into the conserved rat ␣2 enzyme does not alter cell growth or catalytic turnover but causes a substantial decrease in apparent K ؉ affinity (2-fold increase in K 0.5(K ؉ ) ). In view of the location of Thr-345 in the cytoplasmic stalk domain adjacent to transmembrane segment 4, the 2-fold increase in K 0.5(K ؉ ) is probably due to T345A replacement altering K ؉ occlusion/deocclusion. Faster K ؉ deocclusion of the mutant via the E 2 (K) ؉ ATP 3 E 1 ⅐ATP ؉ K ؉ partial reaction is evidenced in (i) a marked increase (300%) in K ؉ stimulation of Na-ATPase at micromolar ATP, (ii) a 4-fold decrease in K ATP , and (iii) only a modest increase (ϳ3-fold) in I 50 for vanadate, which was used as a probe of the steady state E 1 /E 2 conformational equilibrium. We suggest that the decreased apparent K ؉ affinity is the basis for a reduced rate of extracellular K ؉ removal, which delays the recovery phase of nerve impulse transmission in the central nervous system and, thereby, the clinical picture of migraine with aura. This is the first demonstration of a mutation that leads to a disease associated with a kinetically altered but fully functional Na,K-ATPase, refining the molecular mechanism of pathogenesis in familial hemiplegic migraine.Familial hemiplegic migraine (FHM) 1 is a rare autosomal dominant form of migraine with aura. This disorder is usually associated with hemiparesis and can be accompanied with clinical features ranging from ataxia to epileptic seizures. This genetically heterogeneous disease has been traced to at least two loci, FHM1 and FHM2. FHM1, which accounts for over 50% of all FHM families, has been traced to chromosome 19p13 and associated with missense mutations in the CACNA1A gene encoding the ␣1 subunit of the voltage-dependent neuronal (P/Q type) calcium channel. A recent breakthrough in migraine genetics is the discovery of missense mutations in the ATP1A2 gene on chromosome 1q23 that encodes the ␣2 isoform of the Na,K-ATPase. This finding gives strong support to the notion that FHM is caused by disruption of normal cation transport. The Na,K-ATPase is an integral membrane protein complex that comprises a large catalytic ␣ subunit of ϳ110 kDa as well as a smaller, highly glycosylated ␤ subunit that ensures the proper folding and mooring of ␣ in the plasma membrane. This P-type ion pump catalyzes the ATP-driven exchange of intrace...

show abstract

Section: Fig 2 Nasupporting

confidence: 57%

Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase α2 Subunit Cause Familial Hemiplegic Migraine Type 2

Segall

Scanzano

Kaunisto

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…2C). The hyperemia is then followed by a mild hypoperfusion (6,18,19,(45)(46)(47)(48)(49)(50)(51)) lasting 1-2 h-not unlike what was described many minutes after the aura in human occipital cortex (7,10,15,20,21).…”

Section: Discussionmentioning

confidence: 91%

Mechanisms of migraine aura revealed by functional MRI in human visual cortex

Hadjikhani

Río

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,320

999

View full text Add to dashboard Cite

Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept͞onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 ؎ 1.1 mm͞min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.

show abstract

“…None of our patients had clinically apparent focal seizure activity at the time of scanning. Spreading depression may occur in migrainous aura [44, 45]; however, patients scanned during aura do not have increased signal intensity on DWI [46]. Finally, DWI characteristics of acute infarction may occasionally be observed in the subacute phase due to T 2 shine-through.…”

Section: Discussionmentioning

confidence: 99%

‘Footprints’ of Transient Ischemic Attacks: A Diffusion-Weighted MRI Study

Ay¹,

Oliveira‐Filho²,

Buonanno³

et al. 2002

Cerebrovasc Dis

114

View full text Add to dashboard Cite

Objective: Diffusion-weighted imaging (DWI) conveys temporal as well as anatomic information about brain infarction, and is therefore well suited to identify ischemic injury that has occurred simultaneously, or closely linked in time, with a transient ischemic attack (TIA). We aimed to determine the proportion and clinical characteristics of patients with TIA who harbor infarction(s) on DWI. Methods: Using T₂-weighted imaging (T₂-WI), fast fluid attenuated inversion recovery (FLAIR), and DWI, we studied 57 consecutive patients presenting with acute focal neurologic symptoms lasting less than 24 h. Results: A hyperintense DWI lesion was identified in a vascular territory appropriate to the symptoms in 27 patients (47%). Lesions judged to be clinically appropriate on T₂-WI and FLAIR overlapped with a DWI lesion in 41 and 48% of patients, respectively. Independent predictors of infarction on DWI were previous nonstereotypic TIAs, presentation with motor symptoms, and identified stroke mechanism. Conclusion: DWI establishes that recent infarction occurs in almost half of patients with the clinical syndrome of TIA and this subgroup is more likely to harbor an underlying cardiac or cerebrovascular abnormality.

show abstract

Pathophysiology of the migraine aura

Cited by 1,009 publications

References 55 publications

Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase α2 Subunit Cause Familial Hemiplegic Migraine Type 2

Kinetic Alterations due to a Missense Mutation in the Na,K-ATPase α2 Subunit Cause Familial Hemiplegic Migraine Type 2

Mechanisms of migraine aura revealed by functional MRI in human visual cortex

‘Footprints’ of Transient Ischemic Attacks: A Diffusion-Weighted MRI Study

Contact Info

Product

Resources

About