Study of levodopa response in Parkinson's disease: Observations on rates of motor progression.

INTRODUCTION: It is important to understand how the rate of motor progression in PD relates to dopaminergic treatment. METHODS: The methods for this study comprised prospective defined off state measurements of the levodopa response at 3-year intervals over a mean 13.3-year period in 34 patients enrolled before treatment initiation. RESULTS: Despite worsening of on and off scores, the magnitude of the l-dopa short-duration response is maintained as the disease progresses. A linear mixed-effects regression analysis of off phase motor scores showed a yearly deterioration of 2.3% of the maximum disability score. Greater motor disability at the commencement of treatment was an independent predictor of faster progression. Demented patients had worse motor function than those without dementia (P = 0.02), and motor deficit appeared to accelerate toward the end of the disease course in patients who had died. CONCLUSIONS: These observations should inform clinical trial design for drugs with possible neuroprotective properties.

Longitudinal study of levodopa in Parkinson's disease: effects of the advanced disease phase.

Thirty-four patients have been studied from the time of initiation of pharmacological treatment in a long-term prospective study of levodopa effects and disease progression in Parkinson's disease. Objective motor scoring of the response to levodopa in defined off states was performed every 3 years. The mean time from the initiation of levodopa treatment to the most recent measurements was 18.2 years. Of 8 patients who are still alive, only 3 had none of the features of the advanced disease phase (dementia, hallucinations, frequent falling). Off-phase motor function worsened at a yearly rate of 1.9% of the maximum disability score, although the plots of the serial scores showed that the magnitude of the levodopa response is well preserved. There was little difference in the rate of progression between patients with tremor-dominant and non-tremor-dominant motor subtypes. Those who developed dementia had more rapid deterioration of motor scores, with significantly worse off-phase (P = .008) and on-phase (P = .03) motor function. A graph of serial scores of patients who have died, aligned for time of death, showed an upward curving trend of motor disability in the last 5 years of the disease course. Its advanced phase may reveal that Parkinson's disease has an exponential pattern of progression.

Longitudinal study of the levodopa motor response in Parkinson's disease: relationship between cognitive decline and motor function.

In this prospective study of 34 patients with Parkinson's disease (PD), measurements of the short duration levodopa motor response have been performed every 3 years in defined off states. The mean time from initiation of levodopa treatment was 14.8 years, and 17 patients survived to the latest assessment stage. Off phase motor function worsened at a yearly rate of 2.2% of the maximum disability score. The magnitude of the levodopa response is well preserved as the disease progresses, and patients who developed motor fluctuations maintained better on phase motor function than nonfluctuators (P = 0.01). Ten patients, of whom 5 survive, developed dementia. There was no difference in pretreatment disability or initial levodopa response between demented and nondemented subjects. However, dementia was associated with worse on and off motor disability scores after 11 and 14 years (P < 0.001), and a smaller levodopa response magnitude after 14 years (P = 0.008). The plot of sequential scores shows the association between cognitive decline and accelerating increase in motor disability. This suggests that the advanced phase of PD, when Lewy body pathology involves the cerebral cortex, progresses in an exponential rather than linear fashion.

Inferring the long duration response to levodopa in Parkinson's disease.

INTRODUCTION: The long duration response to levodopa in Parkinson's disease outlasts drug elimination by days to weeks. Though a substantive part of anti-parkinsonian motor benefit, it cannot easily be observed. OBJECTIVES: To infer the magnitude of the long duration response during the first decade of Parkinson's disease and identify factors that influence it. METHODS: Serial practically defined off scores of 24 patients from a longitudinal study of levodopa short duration response were used to establish their rate of motor progression. A line of notional untreated disability (as if drug treatment had never been given) with the same progression gradient was the basis for calculation of the long duration response. Predictors of mean long duration response amplitude were identified using a multiple linear regression model. RESULTS: Over a mean treatment period of 16.6 ±â€¯4.4 years, annual increase in motor disability was 2.3% of the maximum score. The long duration response composed 49% of total levodopa response during the first decade of treatment, and this proportion was significantly higher soon after commencing levodopa (p = 0.001). Higher pre-treatment motor score (r = 0.60) and lower MMSE (r = 0.60) were the main predictors of a larger long duration response. There was little correlation between long and short duration responses. CONCLUSIONS: Long duration responses contribute almost half of the total levodopa benefit during the first decade of treatment. An appreciation of both long and short duration components of drug symptomatic effects is important in clinical trial design to investigate possible neuroprotective treatments.

Galanin receptor-1 knockout mice exhibit spontaneous epilepsy, abnormal EEGs and altered inhibition in the hippocampus.

Galanin is a widely-distributed neuropeptide that acts as an endogenous anticonvulsant. We have recently generated a galanin receptor type 1 knockout mouse (Galr1(-/-)) that develops spontaneous seizures. Our aim here was to characterize the seizures by making electroencephalogram (EEG) recordings from this animal, and also to elucidate the cellular basis of its epileptic phenotype by studying the neurophysiology of CA1 pyramidal neurons in acute hippocampal slices. EEGs showed that major seizures had a partial onset with secondary generalization, and that paroxysms of spike-and-slow waves occurred and were associated with hypoactivity. The interictal EEG was also abnormal, with a marked excess of spike-and-slow waves. Slice experiments showed that resting potential, input resistance, intrinsic excitability, paired-pulse facilitation of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs), stimulus--response plots for EPSCs, and several properties of spontaneous miniature EPSCs and IPSCs were all unchanged in the mutant mouse compared with wildtype. However, the frequency of miniature IPSCs was significantly reduced in the mutants. These results suggest that impaired synaptic inhibition in the hippocampus may contribute to the local onset of seizures in the Galr1(-/-) mouse.

Longitudinal study of the motor response to levodopa in Parkinson's disease.

In this prospective study of 34 patients with Parkinson's disease, measurements of the short duration levodopa motor response have been performed in defined off states at 3 yearly intervals over a mean period of 11.4 years from the point of commencement of levodopa treatment. Twenty-two patients were still available for study; 10 had died and 2 were lost to follow-up. The levodopa motor response amplitude increases over the first 5 years of treatment, and thereafter, on and off scores worsen in parallel with conservation of the response. Patients who developed motor fluctuations within the first 5 years of treatment had, on average, a stronger response to levodopa with significantly better on phase motor function (P = 0.003). Although the proportion of "midline" motor disability (affecting gait, balance, and cranial motor function) increases with time, these deficits do not actually become unresponsive to levodopa. Patients who developed dementia had a significantly more rapid decline in motor function. The latest graph of serial scores for the whole cohort shows an upward curving or exponential increase in motor disability after the first decade of treatment. Applying a notional untreated disability line to this graph--an estimate of the disability that would have accrued if drugs had never been given--we suggest that the long-duration response to levodopa eventually runs down with disease progression.

Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease.

Thirty-four patients with Parkinson's disease were followed for a mean period of 8 years from the time of initiation of levodopa medication. Levodopa response was charted from the starting point of pharmacological treatment to give a longitudinal point of view of the changes that evolve as the disease progresses. Objective measurements of the motor response to levodopa test-doses were made at approximately three yearly intervals. Motor fluctuations developed in 58% of the patient group after a mean treatment period of 35 months. Dyskinesia developed in parallel with fluctuations but appeared on average 7 months before symptomatic wearing-off effects of levodopa doses. The patients with motor fluctuations had significantly better responses to levodopa. By contrast, nonfluctuators were more prone to develop increasing midline motor disability affecting speech, gait and balance. Comparison of test-dose and pretreatment scores suggested that a substantial long-duration response to levodopa remains after many years of treatment, and that lateralized motor deficits show a stronger long duration response than midline ones. Motor fluctuations are a consequence of disease progression but their early development is, on balance, associated with better long-term functional ability because these patients have the greater capacity to respond to pharmacological treatment.