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I Shoulson

Publications and source records attributed to I Shoulson.

At least 19 recordsLinked to original sources
PubMed1998

Experimental therapeutics of neurodegenerative disorders: unmet needs.

Viewpoint The experimental therapeutics of neurodegenerative disorders is in its infancy, but neuroprotective strategies are already being applied in healthy persons at high risk of developing disease as well as in patients with manifest illness. Knowledge of etiology and pathogenesis, improved design of clinical trials, the development of biological markers, the advent of genetic animal models, the enhanced identification of susceptibility factors, and more effective drug delivery-such advances have improved the prospects for forestalling onset of illness and clinical decline in the growing numbers of people affected by neurodegenerative disorders.

Alzheimer Disease↗
PubMed1998

Where do we stand on neuroprotection? Where do we go from here?

Neuroprotective therapies are interventions that produce enduring benefits by favorably influencing underlying etiology or pathogenesis of neurodegenerative disorders. Neuroprotection remains an unachieved goal of experimental therapeutics. A variety of pathogenetic mechanisms and propagating factors have been implicated in the emergence and progression of Parkinson's disease (PD). Antioxidative strategies have been the focus of neuroprotective trials for PD, but interpretation of the outcomes has been controversial. Traditional end points that respond to enhanced dopaminergic activity may not be suitable for distinguishing symptomatic from neuroprotective effects. Inferences supporting neuroprotective effects in clinical trials would be strengthened by attention to unmet therapeutic needs or relevant clinical end points that are not currently amenable to dopaminergic treatments. Progressive postural instability and intellectual impairment (dementia) represent two major unmet therapeutic needs in PD that are worthy outcomes in therapeutic trials. Imaging tools such as [18F]-dopa PET and [123I] B-CIT SPECT may provide valid and reliable biologic markers of nigrostriatal degeneration. Controlled clinical trials focused on unmet therapeutic needs, and involving valid biologic markers is expected to play a central role in development of neuroprotective therapy for PD.

Antioxidants↗
PubMed1998

DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism.

In 1987, the DATATOP clinical trial was initiated to examine the benefits of deprenyl (selegiline) and alpha-tocopherol in slowing the progression of Parkinson's disease (PD). After 14 +/- 6 (mean +/- SD) months of controlled observation, deprenyl 10 mg/day was found to significantly delay the time until enough disability developed to warrant the initiation of levodopa therapy. This effect was largely sustained during the overall 8.2 years of observation, including open-label deprenyl treatment and a second treatment randomization to continue deprenyl or switch to placebo. There were no accompanying benefits of deprenyl in postponing levodopa-related adverse effects or extending life. Alpha-tocopherol produced no benefits. The 2.1% per year mortality rate of the DATATOP cohort was remarkably low, about the same as an age-matched population without PD. Neuroprotective therapy remains an elusive goal for the experimental therapeutics of PD. Advances in understanding pathogenesis, a robust pipeline of rational treatments, and the advent of valid and reliable biologic markers hold promise in the coming decade for developing and achieving neuroprotective therapies for PD.

Antioxidants↗
PubMed1997

A controlled trial of fluoxetine in nondepressed patients with Huntington's disease.

To examine the antidepressant specificity of fluoxetine in Huntington's disease (HD), we carried out a randomized, double-blind, placebo-controlled trial of this medication in nondepressed HD patients. Thirty patients with early HD who were depressed (Hamilton Depression Inventory < 16) were randomized to placebo (N = 13) or fluoxetine 20 mg/day (N = 17) and were followed up for 4 months. Outcome measures included changes in total functional capacity (TFC) and in standardized neurological, cognitive, and behavioral ratings. After adjustment for the higher education level found in the placebo group at baseline, no differences between the treatment groups were found in TFC, neurological, or cognitive ratings. Fluoxetine-treated patients did show a slight reduction in agitation and in the need for routine. Although fluoxetine may be a useful antidepressant in depressed HD patients, it failed to exert substantial clinical benefits in nondepressed HD patients.

Adult↗
PubMed1996

A controlled trial of remacemide hydrochloride in Huntington's disease.

We conducted a randomized, double-blind, placebo-controlled tolerability study of a N-methyl-D-aspartate (NMDA) glutamate receptor ion-channel blocker, remacemide hydrochloride, in 31 independently ambulatory patients (18 men, 13 women) with Huntington's disease (HD). Subjects were randomized to receive either placebo or active remacemide at dosages of 200 mg/day or 600 mg/day. The primary outcome measure was the proportion of subjects able to complete the study with the assigned treatment. Remacemide was generally well tolerated, and no significant differences between the treatment arms were found in the primary outcome measure. A trend toward improvement in chorea was observed among subjects administered remacemide 200 mg/day. Based on the tolerability and safety demonstrated during this short-term trial, remacemide warrants more extended controlled investigation in patients with HD.

Acetamides↗
PubMed1996

Assessment of coenzyme Q10 tolerability in Huntington's disease.

We performed a 6-month open-label trial to evaluate the tolerability and efficacy of coenzyme Q10 (CoQ) in 10 patients with Huntington's disease (HD). Subjects were evaluated at baseline, 3 months, and 6 months using the HD Rating Scale (HDRS), the HD Functional Capacity Scale (HDFCS), and standardized neuropsychological measures. Adverse events (AEs) were assessed by telephone interview every month. CoQ doses ranged from 600 to 1,200 mg per day. All subjects completed the study, although four subjects reported mild AEs, including headache, heartburn, fatigue, and increased involuntary movements. There was no significant effect of the treatment on the clinical ratings. The good tolerability of CoQ suggests that it is a good candidate for evaluation in long-term clinical trials designed to slow the progression of HD.

Activities of Daily Living↗
PubMed1996

Coexistence of Huntington's disease and familial amyotrophic lateral sclerosis: case presentation.

We present the clinical, molecular genetic and neuropathological findings of an 81-year-old man with concurrent Huntington's disease (HD) and familial amyotrophic lateral sclerosis (FALS). His mother had been diagnosed clinically as having ALS. There was no known family history of HD, but a maternal uncle had died in a chronic care psychiatric hospital. The diagnosis of HD in the patient was suspected at age 66, after 8 years of personality change, hallucinations, agitation, cognitive decline and choreoathetosis. No symptoms of motor neuron disease were noticed at that time, but progressive weakness developed later. Postmortem examination revealed cerebral atrophy, marked atrophy of basal ganglia (grade 3), and atrophy of brain stem and spinal cord. The neostriatum displayed massive neuronal loss and gliosis. The neocortex showed changes characteristic of Alzheimer's disease. Pathological lesions also included loss of neurons and gliosis in the anterior horns, Clarke's columns and the hypoglossal nuclei; degeneration of the lateral corticospinal tracts, dorsal spinocerebellar tracts and fasciculus gracilis; and rare Bunina bodies and ubiquitin-positive filamentous skeins in motor-neuron perikarya. Molecular analysis demonstrated chromosome 4p16.3 expansion of trinucleotide repeats characteristic of HD. Analysis of Cu,Zn superoxide dismutase gene and heavy neurofilament subunit gene failed to demonstrate mutations. The concurrence of HD and FALS in our patient and three previously reported cases did not appear to be associated with cosegregation in other family members.

Aged↗
PubMed1996

Clinical research in neurology. From observation to experimentation.

Clinical research in neurology may be based on observation or intervention. Basic science and observational clinical studies often address questions of cause and pathogenesis, whereas interventional clinical experiments normally are required to establish the safety, tolerability, and efficacy of therapies. This article outlines various study paradigms and discusses the concepts of intervention, randomization, blinding, and control in the context of clinical trial design. Accurate interpretation of trial results is predicated on the care with which experimental therapeutic studies are designed and conducted.

Bias↗
PubMed1995

Functional decline in Huntington's disease.

We prospectively evaluated 129 patients with manifest Huntington's disease (HD) to determine the rate of illness progression and the clinical features that correlate with functional decline. A single examiner evaluated each patient using the HD Functional Capacity Scale. Standardized motor performance was also assessed in 94 of the patients (73%) using the HD Rating Scale. Total Functional Capacity declined at a rate of 0.63 +/- 0.75 U per year. As functional capacity worsened, chorea lessened, and dystonia intensified. There was no correlation between rate of functional decline and age at onset of HD, body weight, gender of affected parent, or history of neuroleptic use.

Adolescent↗
PubMed1995

A prospective evaluation of cognitive decline in early Huntington's disease: functional and radiographic correlates.

We examined prospectively the relationship between progressive disability in Huntington's disease (HD) and concomitant alterations in neuropsychological functioning and brain imaging indices in a cohort of 60 patients who were enrolled and followed for 30 to 42 months in a controlled clinical trial. Standardized measures of functional capacity and neuropsychological performance were collected, and CT was performed, at regular intervals every 6 to 12 months. Psychomotor skills showed the most significant and consistent decline among the cognitive functions assessed. Memory disturbances were already present at the time of enrollment, but memory did not deteriorate until patients reached advanced stages. Other cognitive operations, such as visual construction and semantic knowledge, manifested small and variable changes over time. CT indices of striatal atrophy correlated only with changes in psychomotor function, while the CT index of frontal atrophy weakly predicted memory and semantic knowledge scores at 42 months. These results confirmed earlier cross-sectional findings and extended our knowledge of the evolution of cognitive dysfunction in HD.

Adult↗
PubMed1994

A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease.

Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.

Activities of Daily Living↗
PubMed1993

Dystonia in central pontine myelinolysis without evidence of extrapontine myelinolysis.

A 44-year-old female is described who developed persistent upper extremity and orolingual dystonia several weeks after suspected onset of central pontine myelinolysis (CPM), later confirmed by characteristic pontine lesions on MRI. No foci of the extrapontine myelinolysis were evident. This case confirms that dystonia may be a late and persistent sequela of CPM and may occur in the absence of visible lesions outside the brainstem.

Adult↗
PubMed1993

Quantitative longitudinal assessment of saccades in Huntington's disease.

While participating in a controlled study of baclofen as protective therapy, 39 Huntington's disease (HD) patients underwent measurements of horizontal saccade latency and velocity, repeated longitudinally over a 2-year period. Significant worsening of saccade latency and of mean velocity was detected in untreated patients. Although individual variation was great, initial velocity impairment was found to be more prominent in younger patients. Factors are identified that may affect the rate of decline in supranuclear oculomotor function, including age and the severity of illness at the time of initial assessment. We propose that serial quantitative measurement of saccade performance is a useful clinical marker of the rate of disease progression against which the efficacy of treatments may be tested.

Adult↗
PubMed1992

Neuroprotective clinical strategies for Parkinson's disease.

Increasing knowledge of the role of brain iron in health and disease has prompted consideration of therapeutic strategies aimed at attenuating the effects of iron and its untoward oxidative consequences. The success of this approach is critically dependent on a better understanding of the pathogenesis of Parkinson's disease. The controlled trial "Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism" (DATATOP) represents a clinical strategy to detect neuroprotective effects of antioxidative interventions. Validation of reliable biological markers of nigral degeneration is central to development of therapies that exert genuine neuroprotective effects in slowing the progression and preventing the onset of Parkinson's disease.

Drug Therapy, Combination↗
PubMed1992

An interim report of the effect of selegiline (L-deprenyl) on the progression of disability in early Parkinson's disease. The Parkinson Study Group.

The pathogenesis of Parkinson's disease (PD) has been linked to oxidative-mediated events including increased monoamine oxidase (MAO) and free-radical generation. We are investigating the ability of the MAO inhibitor, selegiline (deprenyl), and of the free-radical scavenger, tocopherol, to delay the onset of disability requiring levodopa therapy (primary end point) in patients with early PD. Eight hundred patients with early, untreated PD were enrolled in the multi-center placebo-controlled, double-blind clinical trial 'Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP)'. Subjects were assigned by 2 x 2 factorial design to receive selegiline (10 mg/day), tocopherol (2,000 IU/day), a combination of both drugs, or placebo, and followed to determine if and when disability occurred requiring levodopa therapy. After 12 +/- 5 months of observation, independent monitoring prompted a preliminary analysis indicating that selegiline 10 mg/day significantly extended the time to the primary end point. Selegiline therapy, alone or in combination with tocopherol, resulted in a 57% reduction in the rate of developing disability requiring levodopa therapy (p < 10(-10)) and a 50% reduction in the rate of loss of full-time employment (p = 0.01). Deterioration of motor and mental features was significantly less in selegiline-treated subjects. Adverse effects were minor and infrequent. We conclude from these preliminary results that selegiline (10 mg/day) delays the onset of disability associated with early, otherwise untreated PD. It remains unclear whether these benefits derive from mechanisms that are symptomatic (dopaminergic), protective (anti-neurotoxic), or both. The DATATOP study is ongoing to examine the long-term effects of selegiline and the independent and interactive effects of tocopherol.

Activities of Daily Living↗
PubMed1991

Heterogeneous dopamine receptor changes in early and late Huntington's disease.

Quantitative receptor autoradiography was used to study dopamine (DA) receptors in dorsal striatum and its projection regions in brains from individuals dying with Huntington's disease (HD) and controls. Heterogeneous loss of both D1 and D2 receptors was present in the striatum of early and late stage HD brains. The degree of receptor loss was greater for the D1 receptor than for the D2 receptor in early stage HD. The pattern of receptor loss did not correspond to heterogeneities identified with acetylcholinesterase staining. Progressive loss of D1 receptors in the internal globus pallidus and substantia nigra pars reticulata and D2 receptors in the external globus pallidus corresponded to advancing pathologic grade.

Adult↗