M. Del Zompo

THERAPEUTIC EFFICACY OF APOMORPHINE COMBINED WITH AN EXTRACEREBRAL INHIBITOR OF DOPAMINE RECEPTORS IN PARKINSON'S DISEASE

Apomorphine in combination with a peripheral dopamine receptor blocker (domeperidone) was administered to four parkinsonian patients in a double-blind placebo-controlled study. The therapeutic efficacy of apomorphine was not reduced by domperidone, while nausea, drowsiness, sedation, and arterial hypotension were prevented. Combination of domperidone with dopamine agonists may result in more effective treatment of Parkinsons disease.

Thyroid abnormalities during lithium treatment

Thyroid function was evaluated in 150 Sardinian outpatients at different stages of lithium treatment. A visible and/or palpable goitre was found in 51% of patients, and there was no apparent correlation with the duration of treatment. No cases of symptomatic hypothyroidism were observed, but subclinical hypothyroidism was present in 19% of patients. The prevalence of specific antithyroid antibodies was positively correlated with age and duration of lithium treatment, and was higher in women. Subclinical hypothyroidism was observed in 53% of antibody‐positive lithium‐treated patients. Carbamazepine in combination with lithium was associated with significantly lower levels of total T4 and T3 than with lithium alone, and the ratios between total and free hormones were also decreased.

Selective MPP+ uptake into synaptic dopamine vesicles: possible involvement in MPTP neurotoxicity.

1 In the present study we provide evidence for a saturable, Mg2+/ATP‐ and temperature‐dependent, tetrabenazine‐, dopamine‐, and amphetamine‐sensitive uptake of 1‐methyl‐4‐phenylpyridinium ion (MPP+) in synaptic vesicles from mouse striatum. 2 Similarity in the properties of the vesicular uptake suggests that in the striatum dopamine and MPP+ share the vesicular carrier. 3 The presence of MPP+ vesicular uptake in dopamine‐rich regions such as striatum, olfactory, tubercles and hypothalamus, as well as its absence in cerebellum, cortex and pons‐medulla, suggest that monoamine vesicular carriers differ between highly and poorly dopamine‐innervated regions. 4 The restriction of active MPP+ uptake to the dopaminergic regions, which reflects the previously shown distribution of [3H]‐MPP+ binding sites in mouse brain membranes, indicates MPP+ as a marker of the vesicular carrier for dopamine in dopaminergic neurones. 5 A role in MPP+ neurotoxicity is suggested for this region‐specific, vesicular storage of the toxin.

Linkage between X-chromosome markers and manic-depressive illness. Two Sardinian pedigrees.

ABSTRACT– Pedigrees of manic‐depressive patients in treatment at the Lithium Clinic of the Institute of Clinical Pharmacology, University of Cagliari, were evaluated for linkage between major affective illness and the protan‐deulan‐glucose‐6‐phosphatc‐dehydrogenase region of the X‐chromosome. Two informative pedigrees were found, investigated and analyzed for linkage using a multigenerational model and considering age‐dependent penetrance. The results are consistent with the hypothesis of X‐linkage in major affective illness.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimers disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10−10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10−7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Fifteen-year follow-up of thyroid function in lithium patients

Objective: To study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. Method: Patients (no.=150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for thyroid circulating thyroid antibodies, hypothyroidism, hyperthyroidism, and thyroidectomy, during a further period of lithium exposure of up to 15 yr. Results: Annual rates of newly developed circulating thyroid antibodies and hypothyroidism were 1.7 and 1.5%, respectively. Subjects with thyroid antibodies had a higher chance of requiring substitution treatment with levothyroxine for hypothyroidism compared with subjects with no evidence of thyroid antibodies (6.4% annual rate compared to 0.8%; relative risk: 8.4; 95% confidence interval: 2.9–24.0). One case of hyperthy-roidism was observed over 976 patient-yr. Three patients underwent thyroidectomy during follow-up (two for multinodular goiter and one for multi-centric papillary carcinoma). Conclusions: Lithium may be associated with hypothyroidism in particular in the presence of circulating thyroid antibodies. Incidence of thyroid antibodies is comparable with that reported for the general population. Hyperthyroidism and thyroid cancer are rare.

Therapeutical efficacy of a combination of apomorphine with sulpiride or metoclopramide in parkinsonism

In healthy volunteers the emetic effect of apomorphine (5–10 mg, i.m.) was prevented by haloperidol (2 mg), metoclopramide (10 mg) and sulpiride (100 mg), injected intramuscularly. In parkinsonian patients, apomorphine (1 mg) given alone ameliorated the neurological symptoms (30% improvement in the disability score), but the improvement was accompanied by nausea, vomiting, sedation or sleepiness. Haloperidol (2 mg) prevented not only the emetic effect of apomorphine (10 mg), but also its therapeutic efficacy in parkinsonism. Indeed, the disability score was worsened by the drug combination in some patients. Moreover, after haloperidol, apomorphine produced deep sedation and sleep. By contrast, in parkinsonian patients pretreated with metoclopramide (10 mg) or sulpiride (100 mg), apomorphine (10 mg) markedly diminished tremor and rigidity and failed to produce nausea, vomiting and sleepiness.

Association studies in candidate genes: Strategies to select SNPs to be tested

Objective: When numerous single nucleotide polymorphisms (SNPs) have been identified in a candidate gene, a relevant and still unanswered question is to determine how many and which of these SNPs should be optimally tested to detect an association with the disease. Testing them all is expensive and often unnecessary. Alleles at different SNPs may be associated in the population because of the existence of linkage disequilibrium, so that knowing the alleles carried at one SNP could provide exact or partial knowledge of alleles carried at a second SNP. We present here a method to select the most appropriate subset of SNPs in a candidate gene based on the pairwise linkage disequilibrium between the different SNPs. Method: The best subset is identified through power computations performed under different genetic models, assuming that one of the SNPs identified is the disease susceptibility variant. Results: We applied the method on two data sets, an empirical study of the APOE gene region and a simulated study concerning one of the major genes (MG1) from the Genetic Analysis Workshop 12. For these two genes, the sets of SNPs selected were compared to the ones obtained using two other methods that need the reconstruction of multilocus haplotypes in order to identify haplotype-tag SNPs (htSNPs). We showed that with both data sets, our method performed better than the other selection methods.

Six‐year follow‐up of thyroid function during lithium treatment

A cohort of patients at various stages of lithium treatment was followed up for 6 years in order to evaluate the course of thyroid abnormalities. Ultrasonography confirmed that lithium can increase thyroid size, especially in cigarette smokers, and that it can affect the texture of the gland. However, the incidence of clinical hypothyroidism or specific thyroid autoimmunity does not exceed that found in the general population. Repeated determinations of thyrotrophin (TSH) concentrations can prevent clinically relevant consequences. Addition of carbamazepine to lithium can counteract lithium‐induced subclinical hypothyroidism, possibly improving prophylactic efficacy in recurrent affective disorders.

Migraine and tumour necrosis factor gene polymorphism. An association study in a Sardinian sample

To assess the possibility of an association between TNF gene polymorphisms and migraine without aura, a case-control study was performed in a Sardinian sample.Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development. Several studies suggest that tumour necrosis factors (TNF) (TNF-α and lymphotoxin-alpha or TNF-ß) may be involved in the pathophysiology of migraine. The TNF-α and TNF-ß genes are located on chromosome 6p21.3 in the human leukocyte antigene (HLA) class III region. We evaluated 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls. The polymorphisms G308A of the TNF- α gene, and G252A of TNF-β gene were determined by NcoI restriction fragment length polymorphism analysis.We found a statistically significant difference in allele (p = 0.018; OR = 1.46 95 % CI: 1.066 to 2.023) and genotype (trend χ2 = 5.46, df = 1, p = 0.019) frequencies of TNF-β gene, between cases and controls. Allele and genotype frequencies of TNF-α polymorphism did not differ significantly between the two groups.These data suggest that subjects with the TNFB2 allele have a low risk of developing migraine without aura and/or that the polymorphism of the TNF-β gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.