CGRP receptors:A headache to study, but will antagonists prove therapeutic in migraine?

The 4th International Symposium on CGRP was expertly organized, at a difficult time, by Inger Jansen-Olesen and Lars Edvinsson and held on 28-30 September 2001 at the Royal Danish School of Pharmacy, Copenhagen, Denmark.

Spatial correlations between beta-amyloid (A beta) deposits and blood vessels in familial Alzheimer's disease

In sporadic Alzheimer’s disease (SAD), the classic (‘dense-cored’) ß-amyloid (Aß) deposits are aggregated around the larger blood vessels in the upper laminae of the cerebral cortex. To determine whether a similar relationship exists in familial AD (FAD), the spatial correlations between the diffuse, primitive, and classic ß-amyloid (Aß deposits and blood vessels were studied in ten FAD cases including cases linked to amyloid precursor protein (APP) and presenilin (PSEN) gene mutations and expressing apolipoprotein E (apo E) allele E4. Sections of frontal cortex were immunolabelled with antibodies against Aß and with collagen IV to reveal the Aß deposits and blood vessel profiles. In the FAD cases as a whole, Aßdeposits were distributed in clusters. There was a positive spatial correlation between the clusters of the diffuse Aßdeposits and the larger (>10 µm) and smaller diameter (<10 µm) blood vessels in one and three cases respectively. The primitive Aß deposits were spatially correlated with larger and smaller blood vessels each in four cases and the classic deposits in three and four cases respectively. Apo E genotype of the patient did not influence spatial correlation with blood vessels. Hence, spatial correlations between the classic deposits and larger diameter blood vessels were significantly less frequent in FAD compared with SAD. It was concluded that both Aß deposit morphology and AD subtype determine spatial correlations with blood vessels in AD.

Spatio-temporal imaging of corticaldesynchronization in migraine visual aura:a magnetoencephalography case study

Objective.-To determine cortical oscillatory changes involved in migraine visual aura using magnetoencephalography (MEG). Background.-Visual aura in the form of scintillating scotoma precedes migraine in many cases. The involvement of cortical spreading depression within striate and extra-striate cortical areas is implicated in the generation of the disturbance, but the details of its progression, the effects on cortical oscillations, and the mechanisms of aura generation are unclear. Methods.-We used MEG to directly image changes in cortical oscillatory power during an episode of scintillating scotoma in a patient who experiences aura without subsequent migraine headache. Using the synthetic aperture magnetometry method of MEG source imaging, focal changes in cortical oscillatory power were observed over a 20-minute period and visualized in coregistration with the patient's magnetic resonance image. Results.-Alpha band desynchronization in both the left extra-striate and temporal cortex persisted for the duration of reported visual disturbance, terminating abruptly upon disappearance of scintillations. Gamma frequency desynchronization in the left temporal lobe continued for 8 to 10 minutes following the reported end of aura. Conclusions.-Observations implicate the extra-striate and temporal cortex in migraine visual aura and suggest involvement of alpha desynchronization in generation of phosphenes and gamma desynchronization in sustained inhibition of visual function.

Spatial patterns of β-amyloid (Aβ) deposits in familial and sporadic Alzheimer's disease

The spatial patterns of the diffuse, primitive, and classic β-amyloid (Aβ) deposits were compared in cortical regions in early-onset familial Alzheimer's disease (EO-FAD) linked to mutations of the amyloid precursor protein APP) or presenilin 1 (PSEN1) genes, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The objective was to determine whether genetic factors influenced the spatial patterns of the Aβ deposits. Aβ deposits were distributed either in clusters which were regularly distributed parallel to the pia mater or in larger, non-regularly distributed clusters. There were no significant differences in spatial pattern of the diffuse deposits between patient groups but mean cluster size of the diffuse deposits was larger in FAD compared with SAD. Primitive Aβ deposits were more frequently distributed in regular clusters and less frequently distributed in large clusters in FAD compared with SAD. Classic Aβ deposits were more frequently distributed in regularly spaced clusters and less frequently distributed in large clusters in LO-FAD compared with EO-FAD. There were no significant differences in the spatial patterns or cluster sizes of Aβ deposits in cases classified according to apolipoprotein E (APOE) genotype. These results suggest (1) greater deposition of Aβ in the form of clusters of diffuse deposits in FAD, (2) a greater proportion of diffuse deposits may be converted to primitive deposits in SAD, (3) classic deposits are more widely distributed in EO-FAD, and (4) the presence of APOE allele ε4 has little effect on the spatial patterns of Aβ deposits.

Relationships between beta-amyloid (A beta) deposits and blood vessels in patients with sporadic and familial Alzheimer's disease

The density of diffuse, primitive and classic beta-amyloid (A beta) deposits was studied in relation to the incidence of blood vessels in the superior frontal gyrus of nine cases of sporadic Alzheimer's disease (SAD), two cases of familial Alzheimer's disease (FAD) with amyloid precursor protein (APP) mutations (APP717, Val --> Ile), and eight cases of FAD not linked to chromosomes 21, 14 or 1. Stepwise multiple regression was used to determine for each patient whether variations in the density of A beta deposits along the cortex were significantly correlated with the incidence of blood vessels. In the majority of FAD and SAD cases, the density of the diffuse and primitive type A beta deposits was not related to blood vessels. However, the incidence of the larger diameter (> 10 microns) blood vessels was positively correlated with the density of the classic A beta deposits in eight (89%) SAD and two (20%) FAD cases. The data suggest that the densities of vessels and deposits were not significantly correlated between cases but only within cases, suggesting a strictly local effect. In addition, the spatial association between classic A beta deposits and blood vessels may be more apparent in SAD compared with FAD cases.

A quantitative study of the neuropathology of 32 sporadic and familial cases of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP)

To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP).

DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD):a study of the pathology of nine cases

Frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is a neurodegenerative disease characterized by variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. Histologically, there is neuronal loss, microvacuolation in the superficial cortical laminae, and a reactive astrocytosis. A variety of TDP-43 immunoreactive changes are present in FTLD-TDP including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN) and, oligodendroglial inclusions (GI). Many cases of familial FTLD-TDP are caused by DNA mutations of the progranulin (GRN) gene. Hence, the density, spatial patterns, and laminar distribution of the pathological changes were studied in nine cases of FLTD-TDP with GRN mutation. The densities of NCI and DN were greater in cases caused by GRN mutation compared with sporadic cases. In cortical regions, the commonest spatial pattern exhibited by the TDP-43 immunoreactive lesions was the presence of clusters of inclusions regularly distributed parallel to the pia mater. In approximately 50% of cortical gyri, the NCI exhibited a peak of density in the upper cortical laminae while the GI were commonly distributed across all laminae. The distribution of the NII and DN was variable, the most common pattern being a peak of NII density in the lower cortical laminae and DN in the upper cortical laminae. These results suggest in FTLD-TDP caused by GRN mutation: 1) there are greater densities of NCI and DN than in sporadic cases of the disease, 2) there is degeneration of the cortico-cortical and cortico-hippocampal pathways, and 3) cortical degeneration occurs across the cortical laminae, the various TDP-43 immunoreactive inclusions often being distributed in different cortical laminae.

Relationships between beta-amyloid (Abeta) deposits and blood vessels in familial and sporadic Alzheimer's disease

Introduction: The density of diffuse, primitive and classic beta-amyloid (Abeta) deposits and blood vessels was studied in nine cases of sporadic Alzheimer's disease (SAD) and 10 cases of familial Alzheimer's disease (FAD) including two cases with amyloid precursor protein (APP) mutations (APP717, Val - Ile). Materials and Methods: Sections of frontal cortex stained for Abeta12-28 counterstained with collagen type IV antiserum. Densities measured along the upper cortex in 64-128, 1000 x 200 micron continuous sample fields. Results: The density of diffuse and primitive deposits was not correlated with blood vessels in FAD or SAD. The density of the classic deposits was positively correlated with the larger diameter (> 10 micron) blood vessels in all SAD cases and weakly correlated with blood vessel in three non-APP FAD cases. Conclusions: Blood vessels are less important in the formation of classic Abeta deposits in FAD compared with SAD.

Migraine, A study of environmental and intrapersonal factors

A study was carried out of 45 migrainous patients with visually induced migraine (VIM), and 25 migrainous students, each having an age and sex matched control. The study utilised questionnaires, interviews, electroencephalography (EEG) and visual evoked potentials (VEP). The experimental work and analysis was carried out in the Neuropsychology Unit in collaboration with the Birmingham Migraine Clinic, over a period of five years. The study suggests: 1. The literature on a possible relationship between migraine and epilepsy hitherto published is unreliable (supporting evidence is given). 2. That a much greater precision is needed in defining migraine for research purposes. 3. A revised methodology for the selection of controls is needed and this is proposed. 4. That despite what are now seen to be superficial similarities, there are clear distinctions of a fundamental nature between photo-sensitive epilepsy (PSE) and VIM. 5. Caution be used when taking headache as a symptom, since many of the precipitants of migrainous headache can also precipitate non-migrainous headache (NMH). 6. The list of visual precipitants of migraine is expanded (particularly flicker and pattern). 7. That colour (principally red) is a previously unreported precipitant of migraine. 8. The extended range of responses to flicker (the 'H' response) has no significant difference in its frequency of occurrence in patients and normal controls, which contradicts previous literature. 9. The mechanisms thought to underlie migraine serve to explain previously unexplained EEG findings. 10. Further research is needed and proposed.

Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder

Patients with Bipolar Disorder (BD) perform poorly on tasks of selective attention and inhibitory control. Although similar behavioural deficits have been noted in their relatives, it is yet unclear whether they reflect dysfunction in the same neural circuits. We used functional magnetic resonance imaging and the Stroop Colour Word Task to compare task related neural activity between 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with Major Depressive Disorder) and 48 healthy controls. Compared to controls, all individuals with familial predisposition to BD, irrespective of diagnosis, showed similar reductions in neural responsiveness in regions involved in selective attention within the posterior and inferior parietal lobules. In contrast, hypoactivation within fronto-striatal regions, implicated in inhibitory control, was observed only in BD patients and MDD relatives. Although striatal deficits were comparable between BD patients and their MDD relatives, right ventrolateral prefrontal dysfunction was uniquely associated with BD. Our findings suggest that while reduced parietal engagement relates to genetic risk, fronto-striatal dysfunction reflects processes underpinning disease expression for mood disorders. © 2011 Elsevier Inc.

The pupillary light reflex in migraine

The literature suggests that there may be pupil size and response abnormalities in migraine headache sufferers. We used an infra-red pupillometer to measure dynamic pupil responses to light in 20 migraine sufferers (during non-headache periods) and 16 non-migraine age and gender matched controls. There was a significant increase in the absolute inter-ocular difference of the latency of the pupil light response in the migraine group compared with the controls (0.062 s vs 0.025 s, p = 0.014). There was also a significant correlation between anisocoria and lateralisation of headache such that migraine sufferers with a habitual head pain side have more anisocoria (r= 0.59, p < 0.01), but this was not related to headache laterally. The pupil changes were not correlated with the interval since the last migraine headache, the severity of migraine headache or the number of migraine headaches per annum. We conclude that subtle sympathetic and parasympathetic pupil abnormalities persist in the inter-ictal phase of migraine. © 2005 The College of Optometrists.

Laminar distribution of β-amyloid (Aβ) peptide deposits in the frontal lobe in familial and sporadic Alzheimer's disease

To determine whether genetic factors influence frontal lobe degeneration in Alzheimer's disease (AD), the laminar distributions of diffuse, primitive, and classic β-amyloid (Aβ) peptide deposits were compared in early-onset familial AD (EO-FAD) linked to mutations of the amyloid precursor protein (APP) or presenilin 1 (PSEN1) gene, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The influence of apolipoprotein E (Apo E) genotype on laminar distribution was also studied. In the majority of FAD and SAD cases, maximum density of the diffuse and primitive Aβ deposits occurred in the upper cortical layers, whereas the distribution of the classic Aβ deposits was more variable, either occurring in the lower layers, or a double-peaked (bimodal) distribution was present, density peaks occurring in upper and lower layers. The cortical layer at which maximum density of Aβ deposits occurred and maximum density were similar in EO-FAD, LO-FAD and SAD. In addition, there were no significant differences in distributions in cases expressing Apo E ε4 alleles compared with cases expressing the ε2 or ε3 alleles. These results suggest that gene expression had relatively little effect on the laminar distribution of Aβ deposits in the frontal lobe of the AD cases studied. Hence, the pattern of frontal lobe degeneration in AD is similar regardless of whether it is associated with APP and PSEN1, mutation, allelic variation in Apo E, or with SAD.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

Sub-cortical sources of the somatosensory pathway are hypoactive in migraine interictally:a Functional Source Separation analysis

Background: Recent morpho-functional evidence pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brainstem remains to be determined. We used a Functional Source Separation algorithm of EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura (MO) patients. Methods: Twenty MO patients and 20 healthy volunteers (HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brainstem and FS16 at thalamic level) and two cortical (FS20 radial and FS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450-750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced sub-cortical brainstem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between the two groups. Conclusions: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergic system may underline the interictal cortical abnormal information processing in migraine. Further studies are needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO. Written informed consent to publication was obtained from the patient(s).