Young-onset Parkinson's disease revisited--clinical features, natural history, and mortality

The authors report on clinical features and mortality rates in a group of 149 patients with apparent idiopathic parkinsonism starting before the age of 40 years. Ten had juvenile parkinsonism (JP; onset before age 21 years) and 139 had young-onset Parkinson's disease (YOPD; onset at age 21 to 40 years). Included were 60 patients originally reported 10 years ago. Fifty percent of the JP group had a positive family history of parkinsonism in a first-degree relative, and clinical presentation was heterogeneous. Mortality risk was threefold that of the normal population. In the YOPD group, the mortality risk was double that of the normal population. Poor initial response to L-dopa was a risk factor for early death. In two previously reported patients, the diagnosis had been changed to multiple system atrophy and Machado-Joseph disease. After a median disease duration of 18 years, cognitive impairment was found in only 19% of YOPD patients (13% of those younger than 60 years and 43% of those 60 years or older). Age was the most important factor for development of dementia, but female sex and positive family history of parkinsonism also had more modest predictive value. After a disease duration of 10 years or less, only 5% of patients were experiencing falls and 30% freezing, but all patients had developed L-dopa-related fluctuations and dyskinesias. The authors conclude that the mortality rate in parkinsonism starting before the age of 40 is increased in comparison to the normal population and is similar to the general Parkinson's disease population. Intellectual function and postural reflexes are usually well preserved for many years despite a long history of parkinsonism and the early and frequent occurrence of treatment complications, provided the patients remain biologically and chronologically young.     

Dyskinetic cerebral palsy: a clinical and genetic study

The clinical features and family histories of 20 adults with dyskinetic cerebral palsy from 20 families were studied. The majority of the patients showed progressive neurological deterioration in adult life. In only three did the condition stabilise by 10 years of age and in seven there was deterioration after the age of 30. Two patients developed a secondary cervical spondylotic myelopathy. Four patients had affected relatives and there were similar proportions of affected parents and siblings. The family data suggest genetic heterogeneity with autosomal recessive and dominant variants. The existence of an X-linked form cannot be excluded, and the demonstration of an increased paternal age effect among single cases suggests that some of these may arise because of fresh dominant genetic mutation.     

Comparison of HPLC and enzymatic recycling assays for the measurement of oxidized glutathione in rat brain

OBJECTIVE: The aim of this study was to investigate audiologic features and the lesion site of sensorineural deafness with mitochondrial DNA mutation at position 3243. STUDY DESIGN: Case review. SETTING: The study was conducted at the Kochi Medical School. PATIENTS: A case of sensorineural deafness in a patient who had a mitochondrial DNA mutation was presented. The incidence of deafness and diabetes mellitus (DM) was very high in the patient's family, but she did not have DM. MAIN OUTCOME MEASURES: The patient's mitochondrial DNA was examined. Furthermore, the pure-tone audiogram, the Bekesy audiogram, an auditory brain stem response, and the electrocochleogram were analyzed. RESULTS: The patient's mitochondrial DNA had a point mutation at codon 3243 (A-->G). The pure-tone audiogram showed moderate sensorineural deafness. An auditory brain stem response showed normal latencies. The electrocochleogram showed an enhanced negative summating potential. CONCLUSIONS: It was speculated that the lesion site of the auditory system was the inner ear. The possible sites in the inner ear were hair cells, the stria vascularis, and the endolymphatic sac.     

Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease

The cause of neurodegeneration in Parkinson's disease (PD) remains unknown. However, isoquinoline derivatives structurally related to the selective dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinim (MPP+), have emerged as candidate endogenous neurotoxins causing nigral cell death in Parkinson's disease. Isoquinoline derivatives are widely distributed in the environment, being present in many plants and foodstuffs, and readily cross the blood-brain barrier. These compounds occur naturally in human brain where they are synthesized by non-enzymatic condensation of biogenic amines (e.g. catecholamines and phenylethylamine) with aldehydes, and are metabolized by cytochrome P450s and N-methyltransferases. In addition, isoquinoline derivatives are oxidized by monoamine oxidases to produce isoquinolinium cations with the concomitant generation of reactive oxygen species. Neutral and quaternary isoquinoline derivatives accumulate in dopaminergic nerve terminals via the dopamine re-uptake system, for which they have moderate to poor affinity as substrates. Several isoquinoline derivatives are selective and more potent inhibitors of NADH ubiquinone reductase (complex I) and alpha-ketoglutarate dehydrogenase activity in mitochondrial fragments than MPP+, and lipophilicity appears to be important for complex I inhibition by isoquinoline derivatives. However, compared with MPP+, isoquinoline derivatives are selective but less potent inhibitors of NADH-linked respiration in intact mitochondria, and this appears to be a consequence of their rate-limiting ability to cross mitochondrial membranes. Although both active and passive processes are involved in the accumulation of isoquinoline derivatives in mitochondria, inhibition of respiration is determined by steric rather than electrostatic properties. Compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPP+, isoquinoline derivatives show selective but relatively weak toxicity to dopamine-containing cells in culture and following systemic or intracerebral administration to experimental animals, which appears to be a consequence of poor sequestration of isoquinoline derivatives by mitochondria and by dopamine-containing neurones. In conclusion, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-like cytotoxic characteristics of isoquinoline derivatives and the endogenous/environmental presence of these compounds make it conceivable that high concentrations of and/or prolonged exposure to isoquinoline derivatives might cause neurodegeneration and Parkinson's disease in humans.     

The Maudsley Addiction Profile (MAP): a brief instrument for assessing treatment outcome

AIM: To develop a brief, multi-dimensional instrument for assessing treatment outcome for people with drug and/or alcohol problems. The Maudsley Addiction Profile (MAP) is the first instrument to be developed in the United Kingdom for this purpose. DESIGN: Field testing with quota-recruitment of problem drug users and problem alcohol users in treatment with researcher and clinician-administered test-retest interviews. SETTING: Two community and two inpatient services at the Bethlem Royal and Maudsley Hospital, London. PARTICIPANTS: Subjects (160 drug users and 80 alcohol users) interviewed by eight interviews (four researchers and four clinicians), each of whom interviewed 30 subjects on two occasions. MEASURES: Sixty items across substance use, health risk, physical/psychological health and personal/social functioning domains. FINDINGS: Average completion time of the MAP was 12 minutes. The questionnaire was acceptable to a majority of subjects and performed well with both researcher and clinician interviewers. Internal reliability and feasible concurrent validity assessments of the scales and items were highly satisfactory. Test-retest reliability was good, average intraclass correlation coefficients across eight substances were 0.94 and 0.81 across health risk, health problems, relationship conflict, employment and crime measures. CONCLUSIONS: The MAP can serve as a core research instrument with additional outcome measures added as required. The collection of a set of reliable quantitative measures of problems among drug and alcohol users by research or treatment personnel for outcome evaluation purposes need not be time-consuming.     

Langmuir-blodgett films of stilbazole complexes of iridium(I) and rhodium(I)

Complexes of 4-alkoxystilbazoles with iridium and rhodium form stable Langmuir layers at the air-water interface even when the alkoxy chain is relatively short (C₅–C₁₂). The surface pressure-area isotherms indicate that condensed molecular monolayers are obtained. The area per molecule of each compound in its monolayer form is typically 0.60 nm², which agrees well with the cross-sectional area of the [Ir(CO)₂CI] or [Rh(CO)₂CI] head group predicated using molecular models. This suggests that the molecules are oriented with the metal moiety close to the water surface and their alkoxystilbazole ‘rod’ protruding from the plane of the water surface. Such floating monolayers have been transferred on to solid substrates such as glass, aluminium (AI₂O₃/AI/Glass) and silicon (SiO₂/Si) at relatively high speed (10 mm min ^?1) to form Y-type LB assemblies. The UV–Visible absorption properties of these materials in solution and LB film form have been studied. LB films of these complexes yield bathochromically shifted spectra relative to the LB film spectrum of the uncomplexed stilbazole. Additionally, these spectra are often broader and hypsochromically shifted relative to their corresponding solution spectra as a result of the close molecular packing within the LB film and the associated dipole–dipole interactions. The electrically polar nature of the molecules described in this paper suggest that they may be suitable candidates for new pyroelectric materials. Thus the pyroelectric coefficient (the rate of change of electric polarisation with respect to temperature) has been measured for a polar multilayer LB film containing an iridium complex. A pyroelectric coefficient of 3.5 μCm^?2K^?1 (at 30 °C) has been measured, which is one of the highest reported valued for an LB film. Additionally, a low dielectric loss of around 0.01 has been found over the frequency range 50 Hz–1 kHz, indicating that such LB films may be usfeul materials for pyroelectric sensors.