ABSTRACT
Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.
Subject(s)
Chromosomes, Human, Pair 1/genetics , Dihydroxyphenylalanine/analogs & derivatives , Genetic Linkage/genetics , Supranuclear Palsy, Progressive/genetics , Aged , Brain Chemistry/physiology , Caudate Nucleus/diagnostic imaging , DNA/genetics , Female , Glucose/metabolism , Humans , Lod Score , Male , Middle Aged , Pedigree , Phenotype , Positron-Emission Tomography , Putamen/diagnostic imaging , Radiopharmaceuticals , Supranuclear Palsy, Progressive/diagnostic imagingABSTRACT
Parkinson's disease (PD) is a common neurodegenerative disorder that produces progressive disability despite symptomatic treatment. Several strategies, including stereotaxic brain lesions, deep brain stimulation, transplants of dopamine cells and administration of neurotrophic factors, have been proposed to improve efficacy and to counteract the progression of the disease. We here report the effects of repetitive intracerebral infusion of basic fibroblast growth factor (bFGF) and glial-derived neurotrophic factor, up to 1 year, in Cynomolgus monkeys with long standing asymmetric parkinsonism produced by unilateral intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The treatment with neurotrophic factors was initiated when the parkinsonian deficits were stable, 6 months after the administration of MPTP. The evaluation of the response to the neurotrophic factors was performed by blind observers using: clinical scales that measured global motor deficit, motor ability in both hands, apomorphine-induced rotation, determination of the levels of monoamine metabolites in cerebrospinal fluid, and 6-F18-fluoro-l-DOPA (F-DOPA) uptake in the striatum and histology. Both factors, but bFGF more so, improve motor behavior, dopamine metabolism, striatal F-DOPA uptake, and the number of dopamine neurons. The procedure is well tolerated and provides a strong background for efficacy and safety of this treatment in patients with PD.
