RESUMEN

Coenzyme Q10 (CoQ(10)), a potential neuroprotective compound, was previously investigated at a dosage of 600 mg/day in Huntington's disease (HD) patients and demonstrated a trend toward slowing disease progression. Higher CoQ(10) dosages may prove beneficial. We investigated the tolerability and blood levels associated with 1,200, 2,400, and 3,600 mg/day of CoQ(10) in HD and healthy subjects. Twenty-eight subjects (20 HD, 8 healthy) enrolled in a 20-week open-label trial. Subjects started on 1,200 mg/day of CoQ(10), increasing every 4 weeks by 1,200 mg to a maximum dosage of 3,600 mg/day. Monthly evaluations included review of adverse events and CoQ(10) blood levels. Twenty-three subjects (82%) achieved the target dosage of 3,600 mg/day. Six subjects (2 healthy, 4 HD) withdrew prematurely (gastrointestinal (GI) symptoms in 3, worsening HD in 2, and 1 because of a fall). All three serious adverse events occurred in a single subject, and were deemed unrelated to CoQ(10). The most common adverse events seen were GI symptoms. Mean (± SD) CoQ10 blood levels achieved over the course of the trial were as follows: 1.26 ± 1.27 µg/mL (baseline, n = 28), 5.59 ± 2.24 µg/mL (1,200 mg/day, week 4, n = 26), 6.38 ± 3.25 µg/mL (2,400 mg/day, week 8, n = 25), 7.49 ± 4.09 µg/mL (3,600 mg/day, week 12, n = 23), and 6.78 ± 3.36 µg/mL (3,600 mg/day, week 20, n = 20). CoQ(10) was well tolerated with over 80% of subjects achieving the target dosage. Dosages of 2,400 mg/day may provide the best balance between tolerability and blood level achieved. Further studies examining the efficacy of 2,400 mg/day are planned.

Asunto(s)

Enfermedad de Huntington/tratamiento farmacológico , Ubiquinona/análogos & derivados , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Resultado del Tratamiento , Ubiquinona/administración & dosificación , Ubiquinona/efectos adversos , Ubiquinona/uso terapéutico

RESUMEN

We conducted case-control and prospective longitudinal studies to examine risk factors and predictors of disease progression for ALS. Ninety-five subjects with ALS and 106 healthy control subjects were enrolled. All subjects completed a risk factor questionnaire at enrollment. The ALS subjects were prospectively followed for one year to define factors that influence the rate of disease progression, measured by rate of change in percent predicted forced vital capacity (%FVC) and the ALS functional rating scale (ALSFRS) score. The association of each potential risk factor with ALS was determined using univariate logistic regression. A random slope model was used to determine the association of each risk factor with disease progression. The demographic characteristics of ALS subjects and controls at enrollment did not differ. Significant risk factors for ALS included reported exposure to lead (p = 0.02) and pesticides (p = 0.03). Disease progression was faster in the ALS subjects having bulbar onset and a shorter time period between onset of symptoms and diagnosis. Pertinent variables not associated with either causation or progression of ALS included physical activity, cigarette smoking and a history of physical trauma or other clinical disorders.

Asunto(s)

Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/fisiopatología , Adulto , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/patología , Estudios de Casos y Controles , Estudios de Cohortes , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo

RESUMEN

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons. We tested the hypothesis that proteomic analysis will identify protein biomarkers that provide insight into disease pathogenesis and are diagnostically useful. To identify ALS specific biomarkers, we compared the proteomic profile of cerebrospinal fluid (CSF) from ALS and control subjects using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). We identified 30 mass ion peaks with statistically significant (p < 0.01) differences between control and ALS subjects. Initial analysis with a rule-learning algorithm yielded biomarker panels with diagnostic predictive value as subsequently assessed using an independent set of coded test subjects. Three biomarkers were identified that are either decreased (transthyretin, cystatin C) or increased (carboxy-terminal fragment of neuroendocrine protein 7B2) in ALS CSF. We validated the SELDI-TOF-MS results for transthyretin and cystatin C by immunoblot and immunohistochemistry using commercially available antibodies. These findings identify a panel of CSF protein biomarkers for ALS.

Asunto(s)

Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteómica/métodos , Adulto , Algoritmos , Cistatina C , Cistatinas/líquido cefalorraquídeo , Femenino , Humanos , Inmunohistoquímica/métodos , Juniperus/metabolismo , Masculino , Persona de Mediana Edad , Neuronas Motoras/metabolismo , Proteína 7B2 Secretora Neuroendocrina/líquido cefalorraquídeo , Prealbúmina/líquido cefalorraquídeo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Médula Espinal/patología

RESUMEN

Motor neuron diseases (MND) are a heterogeneous group of disorders that includes amyotrophic lateral sclerosis (ALS) and result in death of motor neurons. These diseases may produce characteristic perturbations of the metabolome, the collection of small-molecules (metabolites) present in a cell, tissue, or organism. To test this hypothesis, we used high performance liquid chromatography followed by electrochemical detection to profile blood plasma from 28 patients with MND and 30 healthy controls. Of 317 metabolites, 50 were elevated in MNDpatients and more than 70 were decreased (p < 0.05). Among the compounds elevated, 12 were associated with the drug Riluzole. In a subsequent study of 19 subjects with MND who were not taking Riluzole and 33 healthy control subjects, six compounds were significantly elevated in MND, while the number of compounds with decreased concentration was similar to study 1. Our data also revealed a distinctive signature of highly correlated metabolites in a set of four patients, three of whom had lower motor neuron (LMN) disease. In both datasets we were able to separate MND patients from controls using multivariate regression techniques. These results suggest that metabolomic studies can be used to ascertain metabolic signatures of disease in a non-invasive fashion. Elucidation of the structures of signature molecules in ALS and other forms of MND should provide insight into aberrant biochemical pathways and may provide diagnostic markers and targets for drug design.