Among the few independently replicated genetic associations in migraine are polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and oestrogen receptor (ESR1) genes. We studied the contribution of these genes to migraine susceptibility by genotyping six MTHFR and 26 ESR1 polymorphisms in 898 unrelated migraine with aura (MA) patients and in 900 unrelated healthy controls. There were no differences in the genotype distributions of the previously migraine-associated SNPs C677T (MTHFR) and G2014A (ESR1) between cases and controls (P-values 0.83 and 0.55, respectively). Thus, we were not able to replicate the previous findings, although our study had considerable power. However, five of the ESR1 SNPs (rs6557170, rs2347867, rs6557171, rs4870062 and rs1801132) that were in strong linkage disequilibrium were nominally associated with MA (uncorrected P-values 0.007-0.034). These results did not, however, remain significant after taking multiple testing into account. Thus it seems unlikely that the studied genes are involved in migraine susceptibility, at least in this sample.
The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.
SUMMARY With neuropathological diagnosis as the point of reference, the accuracy of clinical diagnosis was studied in a series of 58 demented patients. Alzheimer's disease and multi-infarct dementia were recognised with sensitivities and specificities exceeding 70%, whereas combined dementia as a separate group was relatively unreliably diagnosed. The value of Hachinski's Ischaemic Score in differentiating between Alzheimer's disease and vascular dementias was demonstrated. Its performance was to some extent improved by assigning new weights to the items. In a logistic regression model, fluctuating course, nocturnal confusion, and focal neurological symptoms emerged as features with the best discriminating value, and helped to diagnose correctly 89% of the Alzheimer and 71% of the vascular dementia patients.The major form of dementia in old age is senile dementia of Alzheimer type (SDAT), the most common type of Alzheimer's disease (AD). The neuropathological picture is characterised by three microscopical changes: neurofibrillary tangles and neuritic plaques in the neo-and paleocortex, together with granulovacuolar degeneration in the hippocampus.' Multi-infarct dementia, the second most common cause of dementia, is due to multiple gross or microscopic infarcts, often widely spread throughout the brain tissue.2 In addition, many demented old people show a combination of changes, all of which may contribute to the dementing process. The most important combination is that of AD and ischaemic infarcts, or combined dementia.' A solid diagnostic differentiation of these conditions can only be made by a postmortem neuropathological examination. Brain biopsy can be used to identify the Alzheimer process during life, but this invasive procedure is not acceptable as a routine diagnostic method in senescence. Thus, the clinical identification of the major forms of senile dementia must be largely based on a careful analysis of clinical data.3It is therefore of interest to investigate the accuracy of clinical diagnosis using neuropathological diagnosis as the point of reference.4 6 retrospective study by Todorov et al4 comprised 776 patients studied during a period of ten years. In that study, the sensitivity of the clinical diagnosis was 28% for SDAT, 57% for multi-infarct dementia, and 30% for combined cases; the corresponding specificities were 43%, 39%, and 48%. Thus, the accuracy of clinical diagnosis proved poor. It would seem likely that better accuracy might be reached in a prospective study with uniform diagnostic criteria throughout the study period. We now report results of a prospective analysis of 58 demented patients. The systematic approach devised by Hachinski etal.' was evaluated as a method to differentiate between AD and vascular dementia.
Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.
Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.
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