Factors contributing to caregivers' stress and burden in Parkinson's disease.

BACKGROUND AND OBJECTIVE: To analyze the main determinants of burden and stress in caregivers of Spanish Parkinson's disease (PD) patients. METHODS: One-hundred and twenty-one non-demented patients with PD (57.9% males; 70.9 ± 8.2 years old) were included in this cross-sectional, monocenter, evaluation study. Caregivers (n = 121; 71.9% females; 60.2 ± 15 years old) were assessed using the Zarit Caregiver Burden Inventory (ZCBI) and Caregiver Strain Index (CSI). Multiple linear regression methods were used to evaluate factors contributing to caregivers' stress and burden: (i) PD motor dysfunction (ON-state Hoehn & Yahr/Unified Parkinson's Disease Rating Scale [UPDRS] part III and motor complications [UPDRS part IV]); (ii) Mood (Beck Depression Inventory [BDI]); (iii) Non-motor symptoms (Non-Motor Symptoms Scale [NMSS]); (iv) Disability (Schwab & England Activities of Daily Living Scale [ADLS]); and (v) Socio-demographic and other disease-related variables. RESULTS: Zarit Caregiver Burden Inventory and CSI mean scores were 16 ± 13.9 and 2.1 ± 2.3, respectively. High correlation was found between ZCBI and CSI (r = 0.819; P < 0.0001). Moderate to severe burden (ZCBI > 40) was present in 9.1% of caregivers; 5.8% had high levels of stress (CSI ≥ 7). Moderate to strong correlations were observed between patient-related variables (Hoehn&Yahr, UPDRS-III, UPDRS-IV, BDI, NMSS, and ADLS) and ZCBI and CSI (P < 0.0001). Linear regression methods showed that ADLS had the strongest influence on ZCBI and CSI, followed by BDI on ZCBI. CONCLUSIONS: Disability (ADLS) and mood (BDI) of patients with PD are the main factors contributing to burden and stress in caregivers.

The powerful pre-treatment effect: placebo responses in restless legs syndrome trials.

OBJECTIVE: To investigate whether dopaminergic pre-treatment alters placebo and dopamine agonist responses in restless legs syndrome (RLS). METHODS: Two large, multi-centre trials (SP790 and SP792; registration numbers NCT00136045 and NCT00135993) on the efficacy of rotigotine in RLS reported supplemental International RLS (IRLS) sum score data for pre-treated and drug-naïve patients, allowing for the estimation of the regression slope of the clinical response (change in the IRLS sum score) on baseline IRLS sum score. RESULTS: In both trials, patients pre-treated with dopaminergic medications tended to have blunted responses after placebo administration compared with drug-naïve patients. In the SP790 study, the pre-treated group had a negative slope (i.e. the response observed after placebo administration decreased as the baseline IRLS sum score increased), whereas the slope was positive in drug-naïve patients (slope, -0.43 vs. 0.28; P = 0.027). In the SP792 study, the two slopes were parallel (P = 0.84), but the magnitude of the response after placebo administration was smaller in the pre-treated group (6.31 vs. 10.49; P = 0.0089). Pre-treatment had no significant effect on rotigotine-group responses in either of the two studies. CONCLUSIONS: In RLS trials, dopaminergic pre-treatment tends to increase the apparent effect of new dopaminergic drugs by decreasing the placebo effect in the placebo arm without substantially modifying the placebo effect in the active treatment arm. This observation highlights that placebo-controlled trials are not necessarily placebo-effect controlled trials.

Duodenal levodopa/carbidopa infusion therapy in patients with advanced Parkinson's disease leads to improvement in caregivers' stress and burden.

BACKGROUND: Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson's disease (PD). However, the impact of DLI on caregivers' stress and burden has not been reported. METHODS: We evaluated prospectively open-label seven advanced PD patients (65.7 ± 9.6 years, 71.4% men) treated with DLI. Schwab & England Activities of Daily Living Scale (ADLS), 39-item Parkinson's disease QoL Questionnaire Summary Index score (PDQ-39SI), Zarit Caregiver Burden Interview (ZCBI), and Caregiver Strain Index (CSI) were used. Comparisons were made between scores obtained at baseline and those at a mean follow-up of 31.4 ± 7.9 months (range, 23-42). RESULTS: In patients, mean ± SD ADLS was increased from 50 ± 8.2 to 80 ± 11.6 (P = 0.014), and mean ± SD PDQ-39SI was decreased from 53.7 ± 11.9 to 33.6 ± 12.8 (P = 0.018). In caregivers, ZCBI decreased from 43 ± 13.3 to 20.7 ± 12.1 (P = 0.018) and CSI from 6.3 ± 2.5 to 1.6 ± 0.9 (P = 0.018). At baseline, 57.1% of caregivers reported moderate to severe burden (ZCBI 41-88) compared to 28.6% at the end of the follow-up (P = 0.015); at that time, no caregiver reported high level of stress (CSI ≥ 7) compared to 57.1% at baseline (P = 0.046). There were significant correlations between ZCBI and CSI improvement (r = 0.813, P = 0.026), ZCBI and PDQ-39SI (r = 0.875, P = 0.01), and ZCBI and ADLS (r = 0.813, P = 0.026). CONCLUSIONS: Duodenal levodopa infusion-related clinical improvement in patients with advanced PD leads to substantial reductions in caregivers' stress and burden.

Long-term exposure to duodenal levodopa/carbidopa infusion therapy improves quality of life in relation especially to mobility, activities of daily living, and emotional well-being.

BACKGROUND: Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson's disease (PD). However, in which aspects improve the patients their QoL has been poorly documented. METHODS: We evaluated 39-item Parkinson's disease Quality of Life Questionnaire Summary Index score (PDQ-39SI) changes analyzing its different domains in nine patients with advanced PD treated with DLI. RESULTS: All the patients (64.7 ± 11.1 years, 55.5% men) improved PDQ-39SI 6 months after beginning with DLI (29.7 ± 8.6, P = 0.008) and after median duration infusion of 25.3 ± 8.8 months (34.8 ± 11.2, P = 0.008) compared with baseline (55.6 ± 11.5). All domains except social support improved significantly at 6 months. Mobility (P = 0.012), activities of daily living (P = 0.015), and emotional well-being (P = 0.008) improved significantly at the end of the follow-up. CONCLUSIONS: DLI improves QoL in patients with advanced PD after short- and long-term exposure. Whereas all domains except social support improve after 6 months under DLI, only mobility, activities of daily living and emotional well-being improve significantly after long-term exposure to DLI.

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study.

Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinson's disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease.

The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.

Placebo effect and dopamine release.

The placebo effect can be encountered in a great variety of medical conditions, but is particularly prominent in pain, depression and Parkinson's disease. It has been shown that placebo responses play a part in the effect of any type of treatment for Parkinson's disease, including drug therapy, deep brain stimulation and dopamine tissue transplantation. Recent studies have demonstrated that the placebo effect in Parkinson's disease is related to the release of substantial amounts of endogenous dopamine in both the dorsal and ventral striatum. As the ventral striatum is involved in reward processing, these observations suggest that the placebo effect may be linked to reward mechanisms. In keeping with this placebo-reward model, most recent experiments have shown activation of the reward circuitry in association with placebo responses in other disorders. In addition, as dopamine is the major neurotransmitter in the reward circuitry, the model predicts that the release of dopamine in the ventral striatum could be involved in mediating placebo responses not only in Parkinson's but also in other medical conditions.

Effect of dopamine loss and the metabolite 3-O-methyl-[18F]fluoro-dopa on the relation between the 18F-fluorodopa tissue input uptake rate constant Kocc and the [18F]fluorodopa plasma input uptake rate constant Ki.

Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants K(i) and K(occ). This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of K(occ), this last assumption is violated by the presence of the FD metabolite 3-O-methyl-[18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a downward bias. It was found that both K(i) and K(occ) are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the K(occ) determination. These findings imply that K(i) and K(occ) provide different assessments of disease severity and that, as disease progresses, K(i) and especially K(occ) become more related to DA storage capacity and less to the DA synthesis rate.

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.

Tardive dyskinesia in dopa-responsive dystonia: a reappraisal of the dopamine hypothesis of tardive dyskinesia.

Dopa-responsive dystonia, an autosomal-dominant disorder caused by mutations in the guanosine triphosphate (GTP)-cyclohydrolase I gene, is characterized by severe striatal dopamine depletion. Tardive dyskinesia, on the other hand, has often been associated with striatal dopamine overactivity. This article reports on a 44-year-old man with dopa-responsive dystonia who developed tardive dyskinesia on long-term haloperidol therapy. Nigrostriatal dopamine deficiency may be necessary for the development of tardive dyskinesia.

Presynaptic nigrostriatal function in genetically tested asymptomatic relatives from the pallido-ponto-nigral degeneration family.

Pallido-ponto-nigral degeneration (PPND) is a dominantly inherited disorder with parkinsonism. We performed PET with [18F]fluorodopa (FD) and, later, gene testing in 12 asymptomatic relatives at risk from a family with PPND and compared the striatal FD uptake constant (Ki) in them with 4 symptomatic individuals and 10 normal control subjects. Four relatives with positive linkage had a significantly reduced Ki from the normal control subjects but to a lesser degree than the symptomatic patients. The mean Ki in the relatives with negative linkage (n = 8) did not differ from normal control subjects. In conclusion, we identified reduced dopaminergic function in asymptomatic relatives with positive genetic linkage from the PPND family. Most of the reduction in this disorder occurs in the fifth decade, when the disease manifests clinically.

Striatal D2 receptors in symptomatic and asymptomatic carriers of dopa-responsive dystonia measured with [11C]-raclopride and positron-emission tomography.

We tested the hypothesis that asymptomatic carriers of dopa-responsive dystonia (DRD) have increased dopamine D2 receptors in the striatum that protect them from the clinical manifestations of dopaminergic deficiency. We examined striatal D2-receptor binding in (1) symptomatic subjects (treated and untreated) and (2) asymptomatic gene carriers. Using [11C]-raclopride PET, we found elevated striatal D2-receptor binding in both groups. In one of our drug-naive symptomatic subjects, 7 months of treatment with levodopa/carbidopa did not affect the receptor binding as measured on a second scan. We conclude that increased D2-receptor binding in DRD may be a homeostatic response to the dopaminergic deficit in subjects carrying the DRD gene, but is not the sole factor determining the clinical state of these individuals.

SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings.

The authors describe an Alberta family with levodopa-responsive parkinsonism without cerebellar abnormalities. Genetic testing showed expanded repeats for SCA-2; other mutations for parkinsonism were excluded. The expanded allele shows interruption of the CAG repeat with CAA. PET in two affected members showed reduced fluorodopa uptake in striatum and normal raclopride binding. Families with autosomal dominant, levodopa-responsive parkinsonism should be tested for the SCA-2 mutation.

Nigrostriatal dopamine system and motor lateralization.

The mechanism by which most people favor use of the right hand remains unknown. It has been proposed that asymmetries in the nigrostriatal dopamine system may be related to motor lateralization in humans. We explored this hypothesis in vivo by using [18F]fluorodopa positron emission tomography. Whereas the degree of right hand preference was found to correlate with left putamen dominance as assessed by asymmetry in fluorodopa uptake (K(i)), right caudate dominance was positively correlated with the level of performance during simultaneous bimanual movements in right-handed normal subjects. In addition, right-handed patients with Parkinson's disease with higher right than left caudate K(i) performed much better in bimanual movement tests than those in whom the K(i) value of the left caudate was higher than that of the right. These findings support the notion that the nigrostriatal dopaminergic system may play a role in motor lateralization, and suggest a functional model for bimanual movements. We propose that the skill for performing simultaneous bilateral hand movements in right-handed subjects might depend upon both the activation (through the dominant left putamen circuitry) of the left supplementary motor area (SMA), and the inhibition (through the right caudate circuitry) of motor programs stored in the right SMA.

New concepts and tools in imaging for the study of neurodegenerative disease.

Existing technologies permit the detection of changes in neurotransmitter and/or neuroreceptor expression. This may be useful for diagnosis, for monitoring disease progression, and for assessing the pathogenesis of complications associated with long-term treatment. Although the binding of [11C]raclopride to D2 receptors is subject to competition from endogenous dopamine, this can be exploited to estimate changes in synaptic levels of dopamine. Assessment of processes downstream to the receptor will require the development of new approaches.

Contributions of positron emission tomography to elucidating the pathogenesis of idiopathic parkinsonism and dopa responsive dystonia.

The metabolic mapping of brain activity, using PET, confirms the conventional wisdom of neurophysiology. In studies of pathophysiology, PET has yielded evidence that has generated new hypotheses. Progression of the lesion detectable with fluorodopa, in human subjects exposed to MPTP, raises the possibility of a transient environmental event being a cause of progressive neurodegeneration. Studies with fluorodopa in Idiopathic Parkinsonism indicate that the rate of loss of neurons is faster initially, and then tends to approach the normal age-related decline. In dopa responsive dystonia, the finding of normal fluorodopa PET led to the prediction that the lesion would be functional rather than anatomical; this has been confirmed by the identification of a defect in dopamine synthesis in this disorder. Filally, new PET ligands show promise for future studies designed to unravel the pathogenesis of diseases involving the basal ganglia.

Drug-induced motor complications in dopa-responsive dystonia: implications for the pathogenesis of dyskinesias and motor fluctuations.

Dopa-responsive dystonia (DRD) is characterized by striatal dopamine depletion with preserved nigrostriatal terminals. Patients with DRD typically obtain a marked long-term benefit from low doses of levodopa, with no motor complications. By contrast, motor fluctuations and dyskinesias often occur in idiopathic parkinsonism (Parkinson's disease; PD). This suggests that nigrostriatal denervation may be necessary for the development of these levodopa-related motor complications. Six genetically confirmed DRD cases were studied. Three of the five patients who were on chronic levodopa therapy developed choreic dyskinesias, which disappeared on reduction of medication. Apomorphine also induced dyskinesias. In addition, two patients experienced acute dystonic reactions after exposure to dopamine receptor-blocking drugs. No patient showed dose-response motor flutuations during levodopa treatment. It is proposed that striatal dopamine deficiency might play a major role in the pathogenesis of drug-induced dyskinesias. Conversely, the loss of nigrostriatal dopamine terminals seems to be a prerequisite for the development of levodopa-related motor fluctuations.

The apolipoprotein E epsilon 4 allele increases the risk of drug-induced hallucinations in Parkinson's disease.

To determine whether the apolipoprotein E (APOE) epsilon 4 allele is a risk factor of drug-induced hallucinations in nondemented patients with Parkinson's disease (PD), the proportions of patients with hallucinations in groups with and without the APOE epsilon 4 allele were compared with a chi 2 test. The contribution of the APOE epsilon 4 allele to the occurrence of hallucinations was further evaluated by means of logistic regression models, adjusting for potential prognostic variables. Thirteen (76%) of the 17 patients who had the epsilon 4 allele had visual hallucinations, compared with 20 (23%) of the 88 patients without the epsilon 4 allele (p < 0.0001; odds ratio = 11.05; 95% CI 3.24-37.67). In addition, treatment with dopamine agonists also contributed to an increased risk of hallucinations (p = 0.0011). After adjustment for age, severity of parkinsonism, duration of treatment, dose of levodopa, and treatment with dopamine agonists, the association between the presence of the epsilon 4 allele and the occurrence of visual hallucinations remained significant (p = 0.0003). Nondemented PD patients with the APOE epsilon 4 allele have a high risk of developing drug-induced visual hallucinations. Further studies are needed to evaluate which proportion of these patients will end up developing dementia.

The role of the Lewy body in idiopathic Parkinsonism.

We have explored the role of Lewy bodies in idiopathic Parkinsonism (IP) to determine whether they are linked to cell death, or to a reactive and protective process associated with cell survival. We start with a definition of IP that is not dependent upon the presence of Lewy bodies. We have derived a mathematical model that predicts the age-specific annual incidence rates of IP under the assumption that the disorder arises from the ;Incidental Lewy Body State' (ILBS). We have compared these predicted rates with the corresponding rates expected from our model assuming that IP develops in normal subjects. Both of these predictions were then matched against the observed age-specific incidence rates for IP. The predicted rates based upon the premise that ILBS is linked to IP yielded a far closer fit to the observed data. Our analysis indicates that ILBS is sufficient to account for all cases of IP. Our findings further suggest that ILBS may also predispose to other neurodegenerative disorders that are characterized by neuronal loss and the presence of Lewy bodies in various regions of the brain. Finally, we conclude that Lewy bodies are likely to be associated with neuronal death, rather than representing a reactive, protective response to cell damage.