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Biomedical subjects

Michel D Ferrari

Publications and source records attributed to Michel D Ferrari.

At least 19 recordsLinked to original sources
PubMed2016

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Atlases as Topic↗
PubMed2004

A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.

Animals↗
PubMed2004

Migraine as a risk factor for subclinical brain lesions.

CONTEXT: Clinical series have suggested an increased prevalence of cerebral infarction and white matter lesions (WMLs) in migraine patients. It is not known whether these lesions are prevalent in the general migraine population. OBJECTIVES: To compare the prevalence of brain infarcts and WMLs in migraine cases and controls from the general population and to identify migraine characteristics associated with these lesions. DESIGN: Cross-sectional, prevalence study of population-based sample of Dutch adults aged 30 to 60 years. PARTICIPANTS: Randomly selected patients with migraine with aura (n = 161), patients with migraine without aura (n = 134), and controls (n = 140), who were frequency matched to cases for age, sex, and place of residence. Nearly 50% of the cases had not been previously diagnosed by a physician. MAIN OUTCOME MEASURES: Brain magnetic resonance images were evaluated for infarcts, by location and vascular supply territory, and for periventricular WMLs (PVWMLs) and deep WMLs (DWMLs). The odds ratios (ORs) and 95% confidence intervals (CIs) of these brain lesions compared with controls were examined by migraine subtype (with or without aura) and monthly attack frequency (<1 attack, > or =1 attack), controlling for cardiovascular risk factors and use of vasoconstrictor migraine agents. All participants underwent a standard neurological examination. RESULTS: No participants reported a history of stroke or transient ischemic attack or had relevant abnormalities at standard neurological examination. We found no significant difference between patients with migraine and controls in overall infarct prevalence (8.1% vs 5.0%). However, in the cerebellar region of the posterior circulation territory, patients with migraine had a higher prevalence of infarct than controls (5.4% vs 0.7%; P =.02; adjusted OR, 7.1; 95% CI, 0.9-55). The adjusted OR for posterior infarct varied by migraine subtype and attack frequency. The adjusted OR was 13.7 (95% CI, 1.7-112) for patients with migraine with aura compared with controls. In patients with migraine with a frequency of attacks of 1 or more per month, the adjusted OR was 9.3 (95% CI, 1.1-76). The highest risk was in patients with migraine with aura with 1 attack or more per month (OR, 15.8; 95% CI, 1.8-140). Among women, the risk for high DWML load (top 20th percentile of the distribution of DWML load vs lower 80th percentile) was increased in patients with migraine compared with controls (OR, 2.1; 95% CI, 1.0-4.1); this risk increased with attack frequency (highest in those with > or =1 attack per month: OR, 2.6; 95% CI, 1.2-5.7) but was similar in patients with migraine with or without aura. In men, controls and patients with migraine did not differ in the prevalence of DWMLs. There was no association between severity of PVWMLs and migraine, irrespective of sex or migraine frequency or subtype. CONCLUSIONS: These population-based findings suggest that some patients with migraine with and without aura are at increased risk for subclinical lesions in certain brain areas.

Brain↗
PubMed2004

Toward a molecular genetic classification of familial hemiplegic migraine.

The genetics of migraine is a fascinating and rapidly moving research area. Familial hemiplegic migraine, a rare subtype of migraine with a Mendelian pattern of inheritance, is caused by mutations in the chromosome 19 CACNA1A gene or in the chromosome 1 ATP1A2 gene. Familial migraine variants are classified on the basis of clinical, descriptive criteria, but this is insufficient. In the future, a diagnostic classification based on mutation-analysis is needed.

Humans↗
PubMed2004

Prioritizing treatment attributes and their impact on selecting an oral triptan: results from the TRIPSTAR Project.

Seven oral triptans, which differ on a range of attributes important for treatment selection, are now available for treating migraine. US neurologists were surveyed to assess the relative importance of treatment attributes, prespecified by clinical relevance and availability of controlled study data, for selecting among oral triptans. Using a multiattribute decision model, we combined these data on the importance of treatment attributes with information on the relative performance of the oral triptans derived from a recent meta-analysis of controlled clinical trials.

Animals↗
PubMed2004

Priorities for triptan treatment attributes and the implications for selecting an oral triptan for acute migraine: a study of US primary care physicians (the TRIPSTAR Project).

BACKGROUND: Physicians treating patients with migraine can now choose from among 7 triptans, which differ on a range of attributes that may be important for treatment selection. OBJECTIVE: The aims of this study were to determine the relative importance of treatment attributes of the available triptans and assess their impact on deciding the most appropriate treatment for a particular patient with migraine. METHODS: As part of the TRIPSTAR project, US primary care physicians were surveyed to elicit their views on the relative importance of a prespecified set of treatment attributes for making treatment choices in clinical practice. The treatment attributes assessed were those for which data from controlled clinical trials were available for subsequent comparison. The resulting attribute-importance weights were then combined with data on the performance of individual triptans across these attributes in a multiattribute decision model to assist selection of an oral triptan. RESULTS: Efficacy attributes were considered more important than tolerability or consistency of effect in selecting an oral triptan. For triptan-naive but not triptan-experienced patients, tolerability was considered significantly more important than consistency (30% [95% CI, 27%-34%] vs 21% [19%-24%]). Sustained pain-free status and freedom from cardiovascular (chest) adverse events were the most important efficacy and tolerability attributes for both patient categories. When the relative importance of the treatment attributes was combined in a multiattribute decision model with meta-analysis data from controlled trials, almotriptan, eletriptan, and rizatriptan were significantly closer to the hypothetical ideal triptan than the reference product, sumatriptan 100 mg. CONCLUSION: Multiattribute decision-making models (such as that used in the TRIPSTAR project) that determine and apply the relative importance of treatment attributes to drug selection have considerable potential value as a decision support tool in the treatment of acute migraine.

Acute Disease↗
PubMed2004

Recent findings in headache genetics.

PURPOSE OF REVIEW: The progress in headache genetics, especially migraine genetics, recently jumped ahead with some major discoveries. RECENT FINDINGS: Family and epidemiological studies further strengthen the genetic contribution to migraine and two recent observations gave new molecular insights in the disease. Studies on the genetics of familial hemiplegic migraine revealed, in addition to the previously identified familial hemiplegic migraine type 1 gene CACNA1A on chromosome 19, the familial hemiplegic migraine type 2 gene ATP1A2, encoding the alpha2-subunit of sodium/potassium pumps. Recent genome screens in families with migraine identified susceptibility loci on chromosomes 4, 6, 11 and 14. SUMMARY: The findings in familial hemiplegic migraine confirm that dysfunction in ion transport is a key factor in migraine pathophysiology and might help us in the elucidation of migraine molecular pathways. The identification of several migraine susceptibility loci underline its genetically complex nature.

Calcium Channels↗
PubMed2003

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages--3rd-6th decades.

PURPOSE: To depict various brain lesions that have been described in patients who have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with prospective standardized magnetic resonance (MR) imaging in patients of different age groups. MATERIALS AND METHODS: Forty patients with CADASIL in different age groups (20-30 years, n = 5; 31-40 years, n = 4; 41-50 years, n = 16; 51-60 years, n = 15) underwent transverse MR imaging with T1-weighted dual fast spin-echo, fluid-attenuated inversion-recovery, and T2*-weighted gradient-echo sequences. Images were analyzed by one neuroradiologist for the presence of areas of hyperintensity, lacunar infarcts, microbleeds, and subcortical lacunar lesions (SLLs) in different anatomic locations. Descriptive statistics were obtained for the presence of MR imaging abnormalities in various brain areas and for distribution according to age. RESULTS: The mean age of the 40 mutation carriers (21 women, 19 men) was 45 years +/- 10 (SD). In patients with CADASIL who were 20-30 years old, characteristic hyperintense lesions in the anterior temporal lobe (100% [five of five]) and SLLs (20% [one of five]) were the only abnormalities seen on MR images. In patients who were 30-40 years old, lacunar infarcts were found in 75% (three of four) of cases. More areas of hyperintensity were noted, and they frequently involved the external capsule, basal ganglia, and brainstem. In patients 41-50 years old, microbleeds were observed in 19% (three of 16). In patients older than 50 years, areas of hyperintensity (100% [15 of 15]), SLLs (73% [11 of 15]), lacunar infarcts (93% [14 of 15]), and microbleeds (47% [seven of 15]) were frequently observed. CONCLUSION: The four types of brain lesions that are observed in patients with CADASIL were seen in patients of different age groups.

Adult↗
PubMed2003

Evaluation of diagnostic NOTCH3 immunostaining in CADASIL.

CADASIL is caused by mutations in the NOTCH3 gene. Although increasingly recognized as a disease entity, the diagnostic confirmation can be lengthy or inconclusive. Recently, NOTCH3 immunostaining of skin biopsy specimens has been introduced as a new diagnostic test. The aim of this study was to independently assess the diagnostic value of NOTCH3 immunostaining, and determine whether the degree of immunostaining correlates with other disease parameters. We determined NOTCH3 mutation carrier status in 62 symptomatic and asymptomatic individuals from 15 CADASIL families. Skin biopsy specimens of these individuals, as well as of a disease control group, were immunostained with NOTCH3 antibody and blindly analyzed by two independent observers to determine sensitivity and specificity. A semiquantitative NOTCH3 immunostaining score was correlated with clinical, genetic and MRI parameters. The sensitivity was 90.2% and 85.4%, respectively, for the two observers, the specificity 95.2% and 100%; both lower than previously reported. Certain NOTCH3 mutations may underlie false-negative results. False-positive results were found in a non-mutated control, and also in one disease control. There was no difference in immunostaining between symptomatic and asymptomatic NOTCH3 mutated individuals. Furthermore, the NOTCH3 immunostaining score did not correlate with clinical or MRI parameters. NOTCH3 immunostaining is a supportive, but not definitive, CADASIL diagnostic test, and should be interpreted in the context of clinical and radiological data. Confirmation by DNA analysis is requisite for positive results, and when there exists high clinical suspicion, also for negative results.

Adult↗
PubMed2003

Voxel-based morphometry in hypocretin-deficient narcolepsy.

STUDY OBJECTIVES: Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy. DESIGN: We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes. SETTING: Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London. PARTICIPANTS: Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects. MEASUREMENTS AND RESULTS: We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls. CONCLUSIONS: VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.

Adult↗
PubMed2003

Incipient CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited. OBJECTIVE: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years. DESIGN: Clinical characterization and blinded survey comparing MCs with non-MCs. SETTING: Referral center. PARTICIPANTS: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria. METHODS: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale. RESULTS: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps. CONCLUSIONS: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.

Adult↗
PubMed2003

Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.

Familial hemiplegic migraine (FHM) is a rare, severe, autosomal dominant subtype of migraine with aura. Up to 75% of FHM families have a mutation in the P/Q-type calcium channel Ca(v)2.1 subunit CACNA1A gene on chromosome 19p13. Some CACNA1A mutations also may cause epilepsy. Here, we describe novel missense mutations in the ATP1A2 Na(+),K(+)-ATPase pump gene on chromosome 1q23 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q mutation was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate. In this family, all available affected family members with FHM, benign familial infantile convulsions, or both, carry the ATP1A2 mutation. Like FHM linked to 19p13, FHM linked to 1q23 also involves dysfunction of ion transportation and epilepsy is part of its phenotypic spectrum.

Adolescent↗
PubMed2003

Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an angiopathy caused by mutations in the NOTCH3 gene. Typical microvascular changes are found throughout the arterial tree, but the documented disease expression is confined to the central nervous system. In an ongoing CADASIL study, we noted a number of patients with early acute myocardial infarction (before the age of 50 years), as well as patients with electrocardiogram (ECG) abnormalities. We analyzed these data to determine whether myocardial ischemia is associated with NOTCH3 mutations. ECGs were recorded in mutated (n = 41) and nonmutated (n = 22) individuals from 15 genetically confirmed CADASIL families, and blindly classified according to the Minnesota code. Cardiologic history was assessed and cardiovascular disease risk factors were determined. Evidence for myocardial infarction was defined as a positive history for acute myocardial infarction and/or a Minnesota Code 1 (Q-waves) on ECG. We examined CADASIL myocardial tissue ultrastructurally and immunohistochemically for evidence of microangiopathy. We found that almost 25% (10/41) of mutation carriers had evidence of myocardial infarction, versus none of the 22 nonmutation carriers (p = 0.011). Five had a medical history of acute myocardial infarction, and 5 had current pathologic Q-waves on ECG. Acute myocardial infarction occurred at a mean age of 39.6 +/- 5.22 years, and predated major neurologic symptoms of CADASIL in all cases. Pathologic examination of myocardial tissue revealed typical CADASIL arteriopathic changes of the coronary microvasculature. To our knowledge, this is the first study showing that NOTCH3 mutation carriers may be at increased risk of early acute myocardial infarction, expanding CADASIL disease expression beyond the central nervous system to include the heart.

Acute Disease↗
PubMed2003

Cerebral hemodynamics and white matter hyperintensities in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease caused by mutations in the NOTCH3 gene on chromosome 19. On magnetic resonance imaging (MRI), subcortical white matter hyperintensities and lacunar infarcts are visualized. It is unknown whether a decrease in cerebral blood flow or cerebrovascular reactivity is primarily responsible for the development of white matter hyperintensities and lacunar infarcts. The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 +/- 10 years) and 22 nonmutated family members (mean age 39 +/- 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide. Mean baseline TCBF was significantly decreased in NOTCH3 mutation carriers. In young subjects, baseline TCBF was significantly lower than in nonmutation carriers (mean difference 124 mL/min). Furthermore, baseline TCBF did not differ significantly between mutation carriers with minimal and mutation carriers with moderate or severe white matter hyperintensities. No significant difference in mean cerebrovascular reactivity was found between mutation carriers and nonmutation carriers. This study suggests that a decrease in baseline TCBF in NOTCH3 mutation carriers precedes the development of white matter hyperintensities.

Adult↗
PubMed2003

Current perspectives on effective migraine treatments: are small clinical differences important for patients?

The introduction of 5-HT(1B/1D) agonists, i.e. triptans, the first drugs specifically developed for the treatment of acute migraine, has revolutionized the treatment of migraine attacks. Triptans have met the needs of many migraine patients, however given the lack of direct comparative trials including all triptans, a meta-analysis of results with all available triptans needed to be conducted. Similar clinical trial design, patient population characteristics and main endpoints certainly facilitated the performance of this meta-analysis. Results from 53 randomized, double-blind, controlled clinical trials on acute triptan therapy in 24,089 patients were compared with respect to the main efficacy and tolerability variables. At recommended doses, almotriptan 12.5 mg, eletriptan 80 mg and rizatriptan 10 mg provided the highest likelihood of consistent success.

Clinical Trials as Topic↗
PubMed2002

Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo.

We investigated whether 5 to 20mg per week oral methotrexate could slow down disease progression in 44 patients with inclusion body myositis in a randomized double-blind placebo-controlled study over 48 weeks. Mean change of quantitative muscle strength testing sum scores was the primary study outcome measure. Quantitative muscle strength testing sum scores declined in both treatment groups, -0.2% for methotrexate and -3.4% for placebo (95% confidence interval = -2.5% to +9.1% for difference). There were also no differences in manual muscle testing sum scores, activity scale scores and patients' own assessments after 48 weeks of treatment. Serum creatine kinase activity decreased significantly in the methotrexate group. We conclude that oral methotrexate did not slow down progression of muscle weakness but decreased serum creatine kinase activity.

Administration, Oral↗