Polygenic risk provides biological validity for the ICHD-3 criteria among Finnish migraine families.

BACKGROUND: Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine. METHODS: We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project. RESULTS: Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk. CONCLUSIONS: The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.

The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families.

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.

Optimal digital filters for analyzing the mid-latency auditory P50 event-related potential in patients with Alzheimer's disease.

BACKGROUND: Filtering is an effective pre-processing technique for improving the signal-to-noise ratio of ERP waveforms. Filters can, however, introduce substantial distortions into the time-domain representations of ERP waveforms. Inappropriate filter parameters may lead to the presence of statistically significant but artificial effects, whereas true effects may appear as insignificant. NEW METHOD: The present study aimed to determine the optimal digital filters for analyzing the auditory P50 component in patients with Alzheimer's disease. To provide evidence of the optimal filter settings, different high-pass and low-pass filters were applied to ERP waveforms obtained from a conditioning-testing paradigm. The results facilitate practical recommendations for selection of filters that maximize the signal-to-noise ratio of the P50 components without introducing significant distortions. RESULTS: The present study confirms that filter parameters have a significant effect on the amplitude and gating measures of the P50 component. Setting the high-pass cut-off at 0.1Hz and the low-pass cut-off at 90Hz (or above) is recommended for P50 component analyses. COMPARISON WITH EXISTING METHODS: The majority of ERP studies on sensory gating report using high-pass filters with 10-Hz cut-offs to measure P50 suppression. Such a high cut-off appeared to induce significant distortions into the ERP waveforms; thus, the authors advise against using these excessive high-pass cut-offs. CONCLUSIONS: Filtering broadband signals, such as ERP signals, necessary results in time-domain distortions. However, by adjusting the filter parameters carefully according to the components of interest, it is possible to minimize filter artifacts and obtain more easily interpretable ERP waveforms.

Multimodal event-related potentials in occupational chronic solvent encephalopathy.

The aim of this study was to test a multimodal event-related potential (ERP) paradigm in chronic solvent encephalopathy (CSE) to develop a sensitive method for the clinical diagnostics to CSE. The study comprised 11 CSE patients and 13 healthy controls. We used three tasks: an auditory odd-ball (AUD), a visual detection (VIS), and a recognition memory (MEM) task. The auditory and visual stimuli were presented in single- and dual-task conditions. The auditory P300 amplitude in single-task condition was smaller in the patient group than in the control group at the parietal (Pz) but not at the frontal midline electrode location. The auditory P300 response in the dual task condition AUD+VIS was unrecognizable in 8 of 11 patients and in 1 of 13 controls and in the AUD+MEM condition in 10 of 11 patients and in 4 of 13 controls. In the AUD+MEM condition, the auditory P300 amplitude at Pz was smaller in the patient group than in the control group. Reaction time for auditory stimuli in both dual conditions as well as for visual stimuli in AUD+VIS condition were in the patient group prolonged. The ERP results indicate that CSE patients present with slowed performance speed and difficulties in allocation of attention. Based on ERP results, the disturbance in brain activity in CSE seems to affect posterior aspects of the frontoparietal continuity. The multimodal paradigm seems promising as a tool for the clinical diagnostics of CSE.

Occupational chronic solvent encephalopathy in Finland 1995-2007: incidence and exposure.

PURPOSE: The aim of the study was to define the incidence of chronic solvent encephalopathy (CSE) in Finland during 1995-2007, evaluate the duration and nature of exposure, and identify the work tasks where CSE is encountered. METHODS: Data were from the register and patient records at the Finnish Institute of Occupational Health. The Finnish Job-Exposure Matrix (FINJEM) and National Statistics were used to estimate the incidence of CSE in exposed workforce. RESULTS: CSE cases during 1995-2007 numbered 129. The annual incidence has decreased from 8.6 to 1.2/million employed, i.e. from 18 to 3 patients per year. The number of suspected patients has, however, remained constant (mean 38.6/year). The mean age at diagnosis was 52.8, the mean duration of exposure 28.4 years, and the mean occupational exposure limit years (OELY) 10.5. During 1995-2007, the mean age increased annually by 0.6 and years of exposure by 0.8, but OELY remained constant. In comparison to FINJEM, the highest incidence was in workers exposed to aromatic hydrocarbons. Relative to workforce in occupations with solvent exposure, CSE was most frequent in wooden surface finishers and in industrial, metal, or car painters followed by floor layers and lacquerers. CONCLUSIONS: The incidence of CSE has declined due to legislative, technical, and hygienic actions. CSE is most probable in spray painting tasks with main exposure to aromatic hydrocarbons, when occupational solvent exposure exceeds 20 years, and the age of the worker is above 45. Our results indicate slower CSE development at lower exposure levels.

Magnetic resonance imaging in occupational chronic solvent encephalopathy.

PURPOSE: The aim of this study was to characterize the magnetic resonance imaging (MRI) findings in chronic solvent encephalopathy (CSE) patients and to study whether the findings are associated with solvent exposure indices. METHODS: The brain MRI scans of 71 CSE patients were independently re-evaluated and rated by two experienced neuroradiologists. All the work tasks were analyzed and the chemical composition of lifetime exposure was categorized. RESULTS: The MRI scans of 27/71 CSE patients (38%) were classified as abnormal. Brain atrophy in any brain area was found in 17/71 CSE patients (24%). Abnormal white matter hyperintensities (WMH) were found in 20/71 CSE patients (28%). Cerebral and cerebellar brain atrophy was associated with the duration of exposure in years, and vermian atrophy was associated with alcohol consumption. Periventricular and brainstem WMH were related to age. CONCLUSIONS: Slight brain atrophy is associated with CSE and there is a correlation between brain atrophy and the duration of exposure in years. However, all the MRI findings in CSE are non-specific and thus MRI is useful mainly in the differential diagnosis of CSE.

P300 of auditory event related potentials in occupational chronic solvent encephalopathy.

This retrospective study characterized the P300 component of the auditory event related potential (ERP) and assessed its diagnostic value in occupational chronic solvent encephalopathy (CSE). The P300 was recorded on 86 CSE patients by the classical oddball paradigm. In addition to the laboratory's reference values, we used an age and education matched control group that consisted of 104 blue-collar workers with no known occupational solvent exposure. The association of P300 values with solvent exposure indices, major depression, alcohol consumption, and neuropsychological parameters was studied. The P300 amplitude was lower in CSE patients (mean 7.5 microV; S.D. 3.6) compared to laboratory controls (mean 11.8 microV; S.D. 4.1; F(1,167)=24.4; p<0.001, 95% CI -4.4 to -1.8) and to matched controls (mean 9.0 microV; S.D. 4.0; p=0.007, 95% CI -2.6 to -0.4). The P300 latency was longer in the CSE patients (mean 358 ms; S.D. 28) compared to laboratory controls (mean 339 ms; S.D. 19, F(1,167)=7.6, p=0.006, 95% CI 3.12-18.7) but did not differ from matched controls (mean 358 ms; S.D. 22; p=0.947, 95% CI -7.4 to 6.9). The solvent exposure indices, major depression, or alcohol consumption did not associate with the P300 values. The P300 amplitude correlated positively with the Digit Symbol test. All the amplitude values in the patient group and in the matched control group were classified as normal (i.e. age corrected mean+/-2.5S.D.) against the laboratory's reference values. Thirty percent of the latencies in the CSE patient group and 26% in the matched control group were classified as abnormal. At group level, the decreased P300 amplitudes in CSE patients may reflect solvent-related pathophysiology. However, the P300 measured with the classical oddball paradigm does not seem to be sensitive at individual level or useful in clinical practice.