Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson's disease.

BACKGROUND: Rasagiline, an MAO-B inhibitor, is indicated for the treatment of Parkinson's disease (PD). In this post hoc analysis, the efficacy, safety and tolerability of rasagiline as an adjunct to levodopa were compared with placebo in elderly (≥70 years) and younger (<70 years) patients with PD. METHODS: Data were pooled from the Parkinson's Rasagiline: Efficacy and Safety on the Treatment of 'OFF' and Lasting effect in Adjunct therapy with Rasagiline Given Once daily randomized, double-blind, placebo-controlled trials with the primary efficacy end-point being the reduction from baseline in daily OFF time. Secondary efficacy end-points included scores for Clinical Global Improvement (CGI)-Examiner during ON time, Unified Parkinson's Disease Rating Scale (UPDRS)-ADL during OFF time, UPDRS-Motor during ON time and total daily ON time with and without troublesome dyskinesia. Tolerability was evaluated from adverse events (AEs) in the two age groups. RESULTS: Rasagiline decreased daily OFF time versus placebo (P<0.01) and improved CGI-Examiner score (P=0.001) and UPDRS-Motor ON score (P<0.05). Changes in UPDRS-ADL OFF score and total daily ON time without dyskinesia also favoured rasagiline but were not significant. Between-group comparisons (≥70 vs. <70 years) showed that efficacy was unaffected by age for all end-points (P>0.1), and rasagiline was well tolerated amongst both groups of patients with a comparable incidence of total and dopaminergic AEs (P>0.1). CONCLUSIONS: Adjunct rasagiline is efficacious and well tolerated in elderly non-demented patients (≥70 years) with moderate to advanced PD. Confirmation of the efficacy and safety of rasagiline in the elderly patient subgroup is especially relevant because of the increasing number of elderly patients with PD.

Interest in predictive testing for Parkinson's disease: impact of neuroprotective therapy.

As predictive testing for Parkinson's disease (PD) becomes available, it will be important to understand in whom such testing will be used. To address this issue, we conducted a mail survey of 138 first-degree relatives of PD patients. In the absence of treatment, 60% reported that they would either "definitely" or "probably" be interested in predictive testing. In the setting of a clinical trial, this number increased to 71% (p=0.04) and when neuroprotective therapy is available, interest increased to 90% (p<0.001). Interest in predictive testing for PD is moderate in the absence of effective therapy, and goes up significantly when both clinical trial participation and neuroprotective therapy are offered.

Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation.

This gene transfer experiment is the first Parkinson's Disease (PD) protocol to be submitted to the Recombinant DNA Advisory Committee. The principal investigators have uniquely focused their careers on both pre-clinical work on gene transfer in the brain and clinical expertise in management and surgical treatment of patients with PD. They have extensively used rodent models of PD for proof-of-principle experiments on the utility of different vector systems. PD is an excellent target for gene therapy, because it is a complex acquired disease of unknown etiology (apart from some rare familial cases) yet it is characterized by a specific neuroanatomical pathology, the degeneration of dopamine neurons of the substantia nigra (SN) with loss of dopamine input to the striatum. This pathology results in focal changes in the function of several deep brain nuclei, which have been well-characterized in humans and animal models and which account for many of the motor symptoms of PD. Our original approaches, largely to validate in vivo gene transfer in the brain, were designed to facilitate dopamine transmission in the striatum using an AAV vector expressing dopamine-synthetic enzymes. Although these confirmed the safety and potential efficacy of AAV, complex patient responses to dopamine augmenting medication as well as poor results and complications of human transplant studies suggested that this would be a difficult and potentially dangerous clinical strategy using current approaches. Subsequently, we and others investigated the use of growth factors, including GDNF. These showed some encouraging effects on dopamine neuron survival and regeneration in both rodent and primate models; however, uncertain consequences of long-term growth factor expression and question regarding timing of therapy in the disease course must be resolved before any clinical study can be contemplated. We now propose to infuse into the subthalamic nucleus (STN) recombinant AAV vectors expressing the two isoforms of the enzyme glutamic acid decarboxylase (GAD-65 and GAD-67), which synthesizes the major inhibitory neurotransmitter in the brain, GABA. The STN is a very small nucleus (140 cubic mm or 0.02% of the total brain volume, consisting of approximately 300,000 neurons) which is disinhibited in PD, leading to pathological excitation of its targets, the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr). Increased GPi/SNpr outflow is believed responsible for many of the cardinal symptoms of PD, i.e., tremor, rigidity, bradykinesia, and gait disturbance. A large amount of data based on lesioning, electrical stimulation, and local drug infusion studies with GABA-agonists in human PD patients have reinforced this circuit model of PD and the central role of the STN. Moreover, the closest conventional surgical intervention to our proposal, deep brain stimulation (DBS) of the STN, has shown remarkable efficacy in even late stage PD, unlike the early failures associated with recombinant GDNF infusion or cell transplantation approaches in PD. We believe that our gene transfer strategy will not only palliate symptoms by inhibiting STN activity, as with DBS, but we also have evidence that the vector converts excitatory STN projections to inhibitory projections. This additional dampening of outflow GPi/SNpr outflow may provide an additional advantage over DBS. Moreover, of perhaps the greatest interest, our preclinical data suggests that this strategy may also be neuroprotective, so this therapy may slow the degeneration of dopaminergic neurons. We will use both GAD isoforms since both are typically expressed in inhibitory neurons in the brain, and our data suggest that the combination of both isoforms is likely to be most beneficial. Our preclinical data includes three model systems: (1) old, chronically lesioned parkinsonian rats in which intraSTN GAD gene transfer results not only in improvement in both drug-induced asymmetrical behavior (apomorphine symmetrical rotations), but also in spontaneous behaviors. In our second model, GAD gene transfer precedes the generation of a dopamine lesion. Here GAD gene transfer showed remarkable neuroprotection. Finally, we carried out a study where GAD-65 and GAD-67 were used separately in monkeys that were resistant to MPTP lesioning and hence showed minimal symptomatology. Nevertheless GAD gene transfer showed no adverse effects and small improvements in both Parkinson rating scales and activity measures were obtained. In the proposed clinical trial, all patients will have met criteria for and will have given consent for STN DBS elective surgery. Twenty patients will all receive DBS electrodes, but in addition they will be randomized into two groups, to receive either a solution containing rAAV-GAD, or a solution which consists just of the vector vehicle, physiological saline. Patients, care providers, and physicians will be blind as to which solution any one patient receives. All patients, regardless of group, will agree to not have the DBS activated until the completion and unblinding of the study. Patients will be assessed with a core clinical assessment program modeled on the CAPSIT, and in addition will also undergo a preop and several postop PET scans. At the conclusion of the study, if any patient with sufficient symptomatic improvement will be offered DBS removal if they so desire. Any patients with no benefit will simply have their stimulators activated, which would normally be appropriate therapy for them and which requires no additional operations. If any unforeseen symptoms occur from STN production of GABA, this might be controlled by blocking STN GABA release with DBS, or STN lesioning could be performed using the DBS electrode. Again, this treatment would not subject the patient to additional invasive brain surgery. The trial described here reflects an evolution in our thinking about the best strategy to make a positive impact in Parkinson Disease by minimizing risk and maximizing potential benefit. To our knowledge, this proposal represents the first truly blinded, completely controlled gene or cell therapy study in the brain, which still provides the patient with the same surgical procedure which they would normally receive and should not subject the patient to additional surgical procedures regardless of the success or failure of the study. This study first and foremost aims to maximally serve the safety interests of the individual patient while simultaneously serving the public interest in rigorously determining in a scientific fashion if gene therapy can be effective to any degree in treating Parkinson's disease.

Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy.

Although alpha-synuclein (alpha-syn) has been implicated as a major component of the abnormal filaments that form glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA), it is uncertain if GCIs are homogenous and contain full-length alpha-syn. Since this has implications for hypotheses about the pathogenesis of GCIs, we used a novel panel of antibodies to defined regions throughout alpha-syn in immunohistochemical epitope mapping studies of GCIs in MSA brains. Although the immunostaining profile of GCIs with these antibodies was similar for all MSA brains, there were significant differences in the immunoreactivity of the alpha-syn epitopes detected in GCIs. Notably, carboxy-terminal alpha-syn epitopes were immunodominant in GCIs, but the entire panel of antibodies immunostained cortical Lewy bodies (LBs) in dementia with LBs brain with similar intensity. While the distribution of alpha-syn labeled GCIs paralleled that previously reported using silver stains, antibodies to carboxy-terminal alpha-syn epitopes revealed a previously undescribed burden of GCIs in the MSA hippocampal formation. Finally, Western blots demonstrated detergent insoluble monomeric and high-molecular weight alpha-syn species in GCI rich MSA cerebellar white matter. Collectively, these data indicate that alpha-syn is a prominent component of GCIs in MSA, and that GCIs and LBs may result from cell type specific conformational or post-translational permutations in alpha-syn.

Reliability of regional cerebral blood flow activation to cognitive tasks in elderly normal subjects.

The assessment of cerebral blood flow (CBF) using noninvasive 133Xe techniques provides an indirect measurement of cortical metabolic activity. The utility of this method in longitudinal clinical studies depends on the stability and reproducibility of resting and activated flow measures. We evaluated CBF in a sample of 16 elderly normal subjects (aged 54-73 years) at rest and during task performance in two sessions separated by an average of 9 weeks. Resting global CBF was lower in the second session, a finding consistent with the known effects of habituation previously reported. Regionally specific activated CBF did not change with repeated measurements. The results provide evidence that the 133Xe technique is reliable and of potential utility in evaluating the effect of the natural course of brain disease, as well as the effects of therapeutic interventions on brain activity.

Contemporary approaches to the pharmacotherapeutic management of Parkinson's disease: an overview.

A number of unresolved issues complicate the effective management of patients with Parkinson's disease (PD). Chief among these is the role of neuroprotective versus symptomatic pharmacologic interventions. Until the etiology of PD is further defined, consensus on appropriate management of this illness is unlikely. Clinicians may best serve their patients by taking a pragmatic approach to the treatment of PD that utilizes potentially beneficial interventions in eligible patients. Such an approach would incorporate possible neuroprotective (e.g., selegiline, dopamine agonists, sustained-release levodopa) and dopamine-sparing (e.g., combination levodopa/dopamine agonist therapy) strategies whenever possible while retaining adequate symptomatic control.

Sentence comprehension and praxis deficits in Parkinson's disease.

We evaluated the ability of nondemented patients with idiopathic Parkinson's disease (PD) to interpret various aspects of sentences and to perform learned limb and oral gestures. The patients were significantly compromised in their ability to answer simple questions about sentences such as "The eagle chased the hawk that was fast. Which bird was chased?" A discriminant analysis revealed that up to 73% of PD patients differ from control subjects in their ability to perform this task. Patients with PD were also significantly compromised in their gestural performance, and a discriminant analysis indicated that a praxis deficit may be evident in up to 64% of patients. We conclude that language and gestural processing impairments are frequent in patients with PD.

Magnetic resonance imaging in Parkinson's disease and parkinsonian syndromes.

High field strength magnetic resonance imaging (MRI) provides a noninvasive means of evaluating patients with parkinsonism. Using strict clinical criteria, we began a prospective study of patients with Parkinson's disease (PD) and parkinsonian syndromes (PS) including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and atypical parkinsonism (ATYP). We detected moderate to severe putaminal hypointensity more frequently in PS than in PD and controls, although putaminal hypointensity did not distinguish between MSA, PSP, or ATYP. Signal intensity in the lateral substantia nigra did not differ significantly among patients with PD, PS, or controls and was therefore not a useful MRI marker. Pars compacta width was significantly narrower in both PD and PS. Subcortical and periventricular hyperintense foci were more abundant in PD and PS than controls. Atrophy of the brainstem occurred only in patients with PS.

Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson's disease.

Olfactory dysfunction occurs in most patients with idiopathic Parkinson's disease (PD). In this study, we sought to determine whether such dysfunction is also present in progressive supranuclear palsy (PSP), a condition which shares a number of motor symptoms with PD and is commonly misdiagnosed as PD. We administered the University of Pennsylvania Smell Identification Test, a standardized test of odor identification ability, to 21 PSP patients; 17 also received a forced-choice odor detection threshold test. We compared the olfactory test scores to those obtained from PD patients and normal controls matched to the PSP patients on the basis of age, sex, and smoking habits. Overall, the olfactory function of the PSP patients was markedly superior to that of the PD patients and did not differ significantly from that of the normal controls. There was no association in either the PSP or PD patient groups between (1) the olfactory test scores and (2) measures of motor symptom severity, disease stage, and medication usage. These findings demonstrate that patients with PSP and PD differ markedly in their ability to smell and suggest that olfactory testing may be useful in their differential diagnosis.

Olfactory function in Parkinson's disease subtypes.

Decreased olfactory function commonly occurs in idiopathic Parkinson's disease (PD), regardless of stage, treatment, or duration of disease. In the present study, we sought to determine whether different subtypes of PD, categorized according to well-defined clinical criteria, evidence different degrees of olfactory dysfunction. Significantly different scores on the University of Pennsylvania Smell Identification Test (UPSIT) were present between patients with benign PD and malignant PD (respective means [SD] = 22.51 [8.50] and 17.38 [6.29]) and between tremor-predominant PD and postural instability-gait disorder (PIGD)-predominant PD (23.43 [8.18] versus 17.35 [6.00]). No statistically significant differences in UPSIT scores were observed between young-onset and older-onset PD patients. Women outperformed men in most subtypes examined.

Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease.

BACKGROUND: Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD. METHODS: The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression. RESULTS: CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites. CONCLUSION: CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.

Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment of Parkinson's disease.

Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.

Binding of [99mTc]TRODAT-1 to dopamine transporters in patients with Parkinson's disease and in healthy volunteers.

UNLABELLED: [99mTc]TRODAT-1 is a radiolabeled tropane that binds dopamine transporters. The primary goal of this study was to determine whether its regional cerebral distribution could differentiate between patients with Parkinson's disease and healthy human volunteers. METHODS: The sample consisted of 42 patients with Parkinson's disease, 23 age-matched controls, and 38 healthy adults younger than 40 y old. SPECT scans of the brain were acquired on a triple-head gamma camera 3-4 h after the intravenous injection of 740 MBq (20 mCi) [99mTc]TRODAT-1. Mean counts per pixel were measured manually in subregions of the basal ganglia and normalized to the mean background counts to give specific uptake values ([SUVs] approximately k3/k4). Patient and control groups were also compared with automated statistical parametric mapping techniques. Logistic discriminant analyses were performed to determine the optimum uptake values for differentiating patients from age-matched controls. RESULTS: Quantitative image analysis showed that the group mean SUVs in patients were less than the mean values in controls for all regions (all Ps < 0.000001). There was overlap in the caudate as well as in the anterior-most portion of the putamen, but not in the posterior putamen, even when the asymptomatic sides of 5 patients with clinically defined hemi-Parkinson's disease were factored in. CONCLUSION: The findings indicate that Parkinson's disease can be detected with [99mTc]TRODAT by simply inspecting the images for uptake in the posterior putamen. Appropriate asymmetries seem to be visible with quantification in patients with clinically defined hemi-Parkinson's disease, even though changes in the putamen contralateral to the clinically unaffected side in these patients appear to precede the development of symptoms.

Update on the management of Parkinson's disease.

Parkinson's disease is one of the most common neurologic disorders. Recent advances have shed new light on the nature of the disease process and have led to new strategies for management. This article reviews the biology of Parkinson's disease, the diagnostic approach to patients with parkinsonism, pharmacologic treatments, and practical strategies for managing common clinical problems.

Dopamine supports sentence comprehension in Parkinson's Disease.

OBJECTIVE: To determine the role of dopamine in the executive resource component of sentence comprehension. METHODS: We studied sentence-picture matching in 20 right-handed, non-demented, native English speakers with mild Parkinson's disease (PD) when 'on' and 'off' their levodopa, taking into account disease duration to control for endogenous dopamine metabolism. We also administered a verbal working memory measure that does not involve specific grammatical manipulations. RESULTS: PD patients 'off' levodopa demonstrated a significant discrepancy in their comprehension of grammatically complex sentences compared to grammatically simpler sentences that was not evident when PD patients were 'on' levodopa. An error analysis demonstrated that impaired comprehension of grammatically complex sentences when 'off' levodopa was associated with poorer performance on foils requiring working memory resources. Performance on an independent measure of verbal working memory correlated only with comprehension of grammatically complex sentences during levodopa supplementation, but working memory according to this measure did not differ during 'on' and 'off' states. CONCLUSION: Dopamine supports the executive resources contributing to sentence comprehension in PD.

Does levodopa accelerate Parkinson's disease?

Therapeutic options for the treatment of Parkinson's disease (PD) have expanded tremendously over the last 5 years, although levodopa remains the gold standard of therapy. A major therapeutic controversy has been the question of levodopa's potential to cause toxic effects on nigrostriatal cells, thus potentiating the progression of the disease. The answer to that question will guide physicians in the timing of levodopa initiation and its dosage. The issue of levodopa toxicity was initially raised because of its potential to cause long term adverse effects (dyskinesias and motor fluctuations), which are not observed in untreated patients. Levodopa-induced toxicity can be related to its potential to produce free radicals, which are known to be toxic to cells, in the process of its conversion to dopamine. In vitro data reveals some evidence of the toxic effect of levodopa although recent studies suggest that levodopa toxicity is dependent on its concentration and can be ameliorated in the presence of glial cells. In vivo data from healthy animals and humans does not convincingly demonstrate levodopa toxicity. There is no evidence of levodopa-induced neurotoxicity in patients with PD. Despite the absence of toxic effect in patients with PD, levodopa can cause long term complications like motor fluctuations and dyskinesias and should be used judiciously in the minimal clinically effective dose. In this article we review evidence for and against levodopa neurotoxicity and the implications of the 'levo-dopa controversy' on clinical practice.

Diagnostic accuracy of [99mTc]TRODAT-1 SPECT imaging in early Parkinson's disease.

We evaluated the diagnostic accuracy of SPECT imaging using [(99m)Tc]TRODAT-1 (TRODAT), a relatively inexpensive technetium-labeled dopamine transporter ligand, in distinguishing 29 patients with early PD from 38 healthy volunteers. Mean TRODAT uptake values were significantly decreased in the caudate (p=0.0097) and anterior and posterior putamen (p < 0.0001) of PD patients compared to controls. Using the posterior putamen as the main region of interest resulted in the greatest accuracy (sensitivity 0.79, specificity 0.92). These findings show that TRODAT imaging can accurately differentiate early PD patients from controls and has the potential to improve the diagnosis of patients with early signs of PD.

Sentence comprehension in Parkinson's disease: the role of attention and memory.

Sentence comprehension is a complex process involving at least attentional, memory, grammatical, and semantic components. We report three experiments designed to evaluate the impairments underlying sentence comprehension difficulties in nondemented patients with Parkinson's disease (PD). In the first experiment, we asked patients to answer simple questions about sentences which varied in terms of grammatical complexity and semantic constraint. We found that PD patients are significantly compromised in their ability to perform this task. Their difficulties became more prominent as grammatical complexity increased, but they were significantly assisted by semantic constraints that limited possible interpretations of a sentence. Analyses of individual patient profiles revealed heterogeneous performance across the group of PD patients and somewhat inconsistent performance for patients across testing sessions. In the second experiment, we tested the possibility that patients' heterogeneous performance on the sentence comprehension task is due to an impairment in memory or attention, cognitive domains known to be compromised in some PD patients. Although PD patients and control subjects differed on one memory measure, there were no significant correlations between attention and memory performance and the results of the sentence comprehension task. In the final experiment, we manipulated the sentences used in the first experiment in a fashion that stressed the need for memory and attention in a sentence. The results indicated that PD patients are significantly compromised in their ability to attend to certain critical grammatical features of a sentence. A regression analysis identified specific grammatical, semantic, and attentional mechanisms as significant contributors to PD patients' overall sentence comprehension, accounting for over 97% of the variance in their performance. We conclude that there are multiple sources of cognitive difficulty underlying PD patients' sentence comprehension impairment.

Cognitive resource limitations during sentence comprehension in Parkinson's disease.

Patients with idiopathic Parkinson's disease (PD) were asked to identify the agent of the action in orally presented sentences with subject-relative or object-relative center-embedded clauses while simultaneously performing a secondary task that was less resource-demanding (finger tapping) or more resource-demanding (recognition span). We found that a subgroup of PD patients with impaired sentence comprehension at baseline (no secondary task) did not differ from random in their accuracy understanding all types of sentences during the more demanding (recognition span) condition and also had difficulty understanding the most complex sentences during the less demanding (finger tapping) condition. Control subjects and PD patients without baseline sentence comprehension difficulty were random only in their comprehension of the most complex sentences under the more demanding (recognition span) secondary task condition. Examination of response latencies for accurately understood sentences revealed only an effect for the type of sentence, and this was equally evident across all groups of subjects and regardless of the condition under which the sentences were administered. The sensitivity of PD patients' sentence comprehension accuracy to secondary task resource demands is most consistent with the hypothesis that limited cognitive resources contribute to sentence comprehension difficulty in PD.

Primary treatment of comminuted intertrochanteric fractures of the hip with a Leinbach prosthesis.

The authors present 43 cases of comminuted intertrochanteric fracture, treated by replacement with a Leinbach prosthesis. The average age of the patient was 81 years, the average time of operation was 70.8 min, and the average blood loss was 502 cc. 88% of the patients were walking within 4-10 days. One deep infection occurred requiring removal of the prosthesis five months later. Based on this experience, the authors recommend consideration of the use of a Leinbach prosthesis in the primary treatment of the elderly patient with a comminuted intertrochanteric fracture of the hip.