Erkki Säkö

Validity of clinical diagnosis in dementia: a prospective clinicopathological study.

With neuropathological diagnosis as the point of reference, the accuracy of clinical diagnosis was studied in a series of 58 demented patients. Alzheimers 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 Hachinskis Ischaemic Score in differentiating between Alzheimers 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.

Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride.

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.

Brain muscarinic receptors in senile dementia

Muscarinic receptors were analyzed in various post-mortem brain samples of 39 patients with different types of dementia and of 30 age-matched controls by the specific binding of [3H]QNB. The diagnoses were verified neuropathologically. The binding of [3H]QNB was significantly decreased in the hippocampus, amygdala and nucleus accumbens in patients with Alzheimers disease (AD) and with combined type of dementia (CD), whereas in patients with multi-infarct dementia (MID) the binding was not significantly decreased in the limbic areas but only in the caudate nucleus. Of the clinical variables, orofacial dyskinesias in patients with AD but not with MID correlated with low brain weight and with the decreased [3H]QNB binding in the striatum and frontal cortex. The results reveal some differences between AD and MID. Changes in muscarinic receptor binding show that the cholinergic neurons in the limbic system are especially vulnerable in patients with AD and CD.

Testing of Variants of the MTHFR and ESR1 Genes in 1798 Finnish Individuals Fails to Confirm the Association with Migraine with Aura

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.

Alzheimer's disease: neuropathological correlates of cognitive and motor disorders

Correlations between clinical symptoms and changes in brain neuropathology were investigated in 34 patients with Alzheimers disease, who were compared with 17 non‐demented, age‐matched controls. The patients were originally found in a community survey of dementia and were followed up prospectively until death. A highly significant correlation emerged between the severity of dementia and the numbers of plaques and tangles in the material as a whole, but no essential difference was found between severely and less severely demented patients. Low brain weight correlated highly with many clinical symptoms and signs and the severity of dementia. A multiple regression model consisting of plaques and tangles in amygdala, gyrus frontalis medius, gyrus angularis, and gyrus temporalis medius, plaques of gyrus rectus, tangles of the hippocampus, gyrus precentralis and gyrus cinguli together with brain weight, emerged to link dementia to neuropathological changes at the level of maximum significance. Dyskinetic movements were associated with damage of several brain areas, implying a multiple etiology.

Brain dopamine D-2 receptors in senile dementia

Brain dopamine D-2 receptors were analysed in the caudate nucleus, putamen and nucleus accumbens in 49 patients with different types of neuropathologically verified dementia and in 39 controls by the binding of3H-spiroperidol. The binding was significantly decreased in all brain areas in patients with Alzheimers disease (AD), while the changes in patients with multi-infarct dementia (MID) or combined dementia (CD) were non-significant. According to a Scatchard analysis, this decrease in binding was due to the reduced number of receptors. On the other hand, the binding of3H-spiroperidol was significantly increased in those patients who had received neuroleptic drugs. Significant correlations between3H-spiroperidol binding and neuropathological changes were seen only in AD patients in the nucleus accumbens. The nucleus accumbens was also the only brain area in which there was a significant correlation between dopamine D-2 and the number of muscarinic receptors in AD patients. The findings of this study on dopamine D-2 receptors suggest the involvement of the nigrostriatal dopaminergic system in AD but not in the other two major types of dementia.

Chromosome 19p13 loci in Finnish migraine with aura families.

Chromosomal area 19p13 contains two migraine associated genes: a Cav2.1 (P/Q‐type) calcium channel α1 subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A region on 19p13 separate from CACNA1A was recently reported to be a major locus for migraine and subsequently, the INSR gene was associated with MA and MO. Our aim was to clarify the role of these loci in MA families by analyzing 72 multigenerational Finnish MA families, the largest family sample so far. We hypothesized that the potential major contribution of the 19p13 loci should be detected in a family sample of this size, and this was confirmed by simulations. We genotyped eight polymorphic microsatellite markers surrounding the INSR and CACNA1A genes on 757 individuals. Using parametric and non‐parametric linkage analysis, none of the studied markers showed any evidence of linkage to MA either under locus homogeneity or heterogeneity. However, marginally positive lod scores were observed in three families, and thus for these families the results remain inconclusive. The overall conclusion is that our study did not provide evidence of a major MA susceptibility region on 19p13 and thus we were not able to replicate the INSR locus finding.

Carbamazepine in the treatment of partial epileptic seizures in infants and young children: a preliminary study.

Summary: The study included 19 pediatric patients 3 months to 14 years of age (mean 6.3 years) successively hospitalized for partial epileptic seizures. There were 12 patients with psychomotor epilepsy and 7 patients with other focal or secondary generalized epilepsy. Carbamazepine (CBZ) was the first and only drug in 18 patients and the subsequent but only drug in 1 patient. The blood concentrations of CBZ and carbamazepine‐10, 11‐epoxide (CBZ‐E) were determined by applying the gas‐liquid chromatographic method sensitive enough for small amounts of the drug metabolites. During the mean follow‐up of 12 months (range 6–23 months) the frequency of seizures was reduced by 75% to 100% ih 11 of 19 patients and 50% to 74% in 2 more patients. In the youngest patients (0–3 years of age) the treatment result was statistically better (p, < 0.05) than in older ones. The mean peroral daily dosage in cases with reduction of frequency of 50% or more was 10.4 mg/kg body weight, and the mean blood concentration was 17.5 μM, whereas the respective figures in cases without any good result were 9.2 mg/kg and 14.4 μM. With a CBZ concentration of 12 μM or more, the clinical effect was statistically significantly better (p, lt; 0.039) than with lower concentrations. Children with CBZ‐E concentrations of 2.7 μM or more showed statistically significantly better (p, < 0.037) results than those who had lower concentrations. The daily dosage was in linear correlation with CBZ blood concentration and CBZ‐E concentration for the first 2 weeks of therapy, but thereafter increasingly larger doses were needed (obviously because of an autoinduction phenomenon) to achieve concentrations corresponding to the increase in the daily dosage.

Comorbidity in Finnish migraine families

The objective of the study was to investigate comorbidity of migraine in Finnish migraine families. One thousand consecutive participants in the Finnish Migraine Gene Project reported their medical illnesses in addition to migraine and headache. Migraine patients (n=678) reported significantly more hypotension (OR 1.43, CI 95% 1.02–2.01), allergy (OR 1.83, CI 95% 1.34–2.51) and psychiatric disorders (OR 4.09, CI 95% 2.11–7.92) compared to their family members without migraine (n=322). Subgroup analyses demonstrated that especially women and the group fulfilling the criteria for both migraine with and without aura were likely to have additional disorders besides their migraine. Interestingly, male migraineurs with aura reported a significant association with stroke and epilepsy. Familial migraine is comorbid with hypotension, allergy and psychiatric disorders. The association between migraine with aura and stroke and epilepsy among men of the studied families warrants further study. Clinical, pathophysiological and genetic implications of these results are discussed.

Brain methionine- and leucine-enkephalin receptors in patients with dementia

Brain [3H]Met- and [3H]Leu-enkephalin binding was studied in patients with Alzheimers disease (AD) and vascular dementia (VD), and in age-matched controls. Brain areas investigated were the internal and external globus pallidus, amygdala, hippocampus and temporal cortex. In AD, the binding of both enkephalins decreased in all brain areas examined, except in the external globus pallidus for both enkephalins and in the internal globus pallidus for leucine-enkephalin. Scatchard analysis of amygdaloid samples showed a decrease in the number of receptors (Bmax) without any change in their affinity (Kd). In patients with VD, no significant changes in enkephalin binding were seen. Thus, in AD, enkephalin binding (mainly reflecting delta opioid receptor subtype) is decreased, especially in limbic areas.