H. Przuntek

Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients

Abstract Interleukin-1β (IL-1β), interleukin-2 (IL-2), and interleukin-6 (IL-6) were measured in the cerebrospinal fluid (CSF) and plasma of 12 control subjects, 11 sporadic Alzheimers disease (AD) and 22 de novo Parkinsons disease (PD) patients using high sensitivity enzyme-linked immunosorbent assays (ELISA). IL-1β and IL-6 contents were significantly elevated in the CSF of de novo PD and AD patients in comparison to the control group. In contrast, the plasma levels were not significantly affected. IL-2 contents in the CSF and plasma samples were unchanged in the three groups compared. Because the two cytokines IL-1β and IL-6 are known to play a key role in the interaction between the nervous and immune system, e.g. in the so-called acute phase response, our results support the involvement of immunological events in the complex process of neurodegeneration in AD and PD.

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo- controlled, randomized phase II trial

In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Increased susceptibility to sporadic Parkinson's disease by a certain combined α‐synuclein/apolipoprotein E genotype

Parkinsons disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, α‐synuclein (α‐SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimers disease, as well as striking structural similarities of α‐SYN and apolipoprotein E, which is a major risk factor for late‐onset Alzheimers disease, prompted us to investigate the influence of different α‐SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the α‐SYN gene (NACP‐Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apoε4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early‐onset PD patients (age at onset, <50 years) than in late‐onset PD. Regarding the combination of the Apoε4 allele and allele 1 of the α‐SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8‐fold increased relative risk for developing PD during their lives. Ann Neurol 1999;45:611–617

MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) gives rise to motor deficits in humans and other primates which closely resemble those seen in patients with Parkinsons disease. These deficits are associated with a relatively selective loss of cells in the pars compacta of the substantia nigra and severe reductions in the concentrations of dopamine, noradrenaline and serotonin in the striatum. Similarly, in mice of various different strains the administration of MPTP also induces a marked loss of dopaminergic cells with severe depletion of biogenic amines, but higher doses of MPTP are required to produce these effects in mice than in primates. This review summarises advances made in understanding the biochemical events which underlie the remarkable neurotoxic action of MPTP. Major steps in the expression of neurotoxicity involve the conversion of MPTP to the toxic agent 1-methyl-4-phenylpyridinium ion (MPP+) by type B monoamine oxidase (MAO-B) in the glia, specific uptake of MPP+ into the nigro-striatal dopaminergic neurones, the intraneuronal accumulation of MPP+, and the neurotoxic action of MPP+. This is exerted mainly through the inhibition of the enzymes of the respiratory chain (Complex I), the disturbance of Ca2+ homeostasis, and possibly by the formation of free radicals. The relevance of the MPTP model to idiopathic Parkinsons disease is discussed.

Facial expression recognition in people with medicated and unmedicated Parkinson's disease.

Recognition of facial expressions of emotion was investigated in people with medicated and unmedicated Parkinsons disease (PD) and matched controls (unmedicated PD, n=16; medicated PD, n=20; controls, n=40). Participants in the medicated group showed some visual impairment (impaired contrast sensitivity) and performed less well on perception of unfamiliar face identity, but did not show significant deficits in the perception of sex, gaze direction, or familiar identity from the face. For both Parkinsons disease groups, there was evidence of impaired recognition of facial expressions in comparison to controls. These deficits were more consistently noted in the unmedicated group, who were also found to perform worse than the medicated group at recognising disgust from prototypical facial expressions, and at recognising anger and disgust in computer-manipulated images. Although both Parkinsons disease groups showed impairments of facial expression recognition, the consistently worse recognition of disgust in the unmedicated group is consistent with the hypothesis from previous studies that brain regions modulated by dopaminergic neurons are involved in the recognition of disgust.

Knowing no fear.

People with brain injuries involving the amygdala are often poor at recognizing facial expressions of fear, but the extent to which this impairment compromises other signals of the emotion of fear has not been clearly established. We investigated N.M., a person with bilateral amygdala damage and a left thalamic lesion, who was impaired at recognizing fear from facial expressions. N.M. showed an equivalent deficit affecting fear recognition from body postures and emotional sounds. His deficit of fear recognition was not linked to evidence of any problem in recognizing anger (a common feature in other reports), but for his everyday experience of emotion N.M. reported reduced anger and fear compared with neurologically normal controls. These findings show a specific deficit compromising the recognition of the emotion of fear from a wide range of social signals, and suggest a possible relationship of this type of impairment with alterations of emotional experience.

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open‐label, baseline‐controlled pilot study

An exploratory, prospective, open‐label study of fumaric acid esters (FAE, Fumaderm®) was conducted in patients with relapsing–remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6‐week baseline, 18‐week treatment (target dose of 720 mg/day), 4‐week washout, and a second 48‐week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0–6.0 and at least one gadolinium‐enhancing (Gd+) lesion on T1‐weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine‐hole peg test (9‐HPT). Effects of FAE on intracellular cytokine profiles, T‐cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non‐compliance, and follow‐up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4‐week washout period. EDSS scores, AI, and 9‐HPT remained stable or slightly improved from baseline in all patients. Measures of T‐cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds

OBJECTIVE Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the α1A-subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype METHODS The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. RESULTS Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. CONCLUSIONS This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia.

Elevated plasma levels of homocysteine in Parkinson's disease.

Significantly elevated plasma levels of homocysteine, but not cysteine and cysteinylglycine, were found in treated parkinsonian patients compared to controls. Elevated levels of homocysteine may be either caused by an unknown endogenous metabolic disturbance or by antiparkinsonian treatment, because no association to severity or duration of disease was found. Based on the results of this study one may speculate that homocysteine may be an independent risk factor for vascular disease in Parkinson’s disease.

Riluzole in Huntington's disease: a 3‐year, randomized controlled study

We conducted a randomized double‐blind trial of riluzole in Huntingtons disease to investigate the efficacy of this antiexcitotoxic drug in slowing disease progression.