RESUMEN
BACKGROUND: Parkinson's disease (PD) first diagnosed at older age reportedly has different clinical characteristics and survival rates than when it is first diagnosed at younger age. We compared these features among PD patients who initiated anti-parkinsonian drugs at age 75-85 years (elderly) with those who started treatment at age 50-74 years (younger). METHODS: We used a population-based cohort of 4449 incident cases of PD patients aged 50-85 at treatment initiation, based on a pharmacy registry of Maccabi Health Maintenance Organization, with definite/probable/possible certainty of having PD. Mean follow-up was 3.9 ± 2.6 years. The two age groups were compared for time/risk to levodopa and to death, using Kaplan-Meier curves and Cox regression. Gender-specific standardized mortality rates (SMRs) accounting for Israeli death rates were also compared. RESULTS: One-half of the entire cohort (n = 2148) were elderly (>75 years) and more likely to be given levodopa (Hazard Rate (HR) = 1.48, P < 0.05), had a significantly higher frequency of comorbidities (e.g., heart disease, hypertension and cancer), and had a 3-fold increased risk to die (HR = 2.97, P < 0.05) within the same follow-up time as the youngers. Accounting for the general Israeli population death rates, female PD patients had a significantly lower risk to die compared to males especially females who were elderly at treatment initiation (SMR = 1.53 for females vs. 1.73 for males, P < 0.05). CONCLUSIONS: PD patients first diagnosed and treated at >74 years of age comprise a unique cluster for inclusion into drugs studies, mortality risk analyses and for projection of disease burden.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/mortalidad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Estimating rates of Parkinson's disease (PD) is essential for health services planning and studies of disease determinants. However, few PD registries exist. We aimed to estimate annual prevalence and incidence of PD in a large Israeli population over the past decade using computerized drug purchase data. Based on profiles of anti-parkinsonian drugs, age at first purchase, purchase density, and follow-up time, we developed a refined algorithm for PD assessment (definite, probable or possible) and validated it against clinical diagnoses. We used the prescription database of the second largest Health Maintenance Organization in Israel (covers ~25% of population), for the years 1998-2008. PD rates by age, gender and year were calculated and compared using Poisson models. The algorithm was found to be highly sensitive (96%) for detecting PD cases. We identified 7,134 prevalent cases (67% definite/probable), and 5,288 incident cases (65% definite/probable), with mean age at first purchase 69 ± 13 years. Over the years 2000-2007, PD incidence rate of 33/100,000 was stable, and the prevalence rate increased from 170/100,000 to 256/100,000. For ages 50+, 60+, 70+, median prevalence rates were 1%, 2%, 3%, respectively. Incidence rates also increased with age (RR = 1.76, 95%CI 1.75-1.77, ages 50+, 5-year interval). For ages 50+, rates were higher among men for both prevalence (RR = 1.38, 95%CI 1.37-1.39) and incidence (RR = 1.45, 95%CI 1.42-1.48). In conclusion, our refined algorithm for PD assessment, based on computerized drug purchases data, may be a reliable tool for population-based studies. The findings indicate a burden of PD in Israel higher than previously assumed.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Femenino , Humanos , Incidencia , Israel/epidemiología , Masculino , Persona de Mediana Edad , Grupos de Población , Prevalencia , Adulto JovenRESUMEN
Our studies have provided new insights into the biological mechanism of neuroprotection of the anti-Parkinson drug, rasagiline [N-propargyl-(1R)-aminoindan], involving the association of Bcl-2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal-induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N-propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCepsilon mRNA; induction of Bcl-X(L), Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCgamma, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro-caspase-3 and poly(ADP-ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC-dependent cell survival activity of rasagiline. Structure activity studies have established that N-propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron-chelating property for the treatment and/or prevention of neurodegenerative diseases.
Asunto(s)
Indanos/farmacología , Fármacos Neuroprotectores/farmacología , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Humanos , Indanos/química , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/química , Pargilina/análogos & derivados , Pargilina/farmacología , Propilaminas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
This study provides new insights into neuroprotection involving interaction of protein kinase C (PKC) pathway with Bcl-2 family proteins. Using a model of serum deprivation, we investigated the mechanism by which the anti-Parkinson/monoamine oxidase (MAO)-B inhibitor drug, rasagiline, exerts its neuroprotective effect in rat pheochromocytoma PC12 cells. Here, we report that rasagiline (0.1-10 microM) decreased apoptosis via multiple protection mechanisms, including the stimulation of PKC phosphorylation; up-regulation of PKCalpha and PKC mRNAs, induction of Bcl-xL, Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and down-regulation of Bad and Bax mRNAs. Moreover, rasagiline inhibited the cleavage and activation of procaspase-3 and poly (ADP-ribose) polymerase (PARP), whereas the PKC inhibitor, GF109203X, reversed these actions. Similarly, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC in rasagiline-induced cell survival. Furthermore, these studies have established that PKC- and Bcl-2-dependent neuroprotective activity of rasagiline is dependent on its propargyl moiety, because propargylamine had similar effects with the same potency.