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.

[Functional neuroimaging in the diagnosis of patients with Parkinsonism: Update and recommendations for clinical use]. / Neuroimagen funcional en el diagnóstico de pacientes con síndrome parkinsoniano: actualización y recomendaciones para el uso clínico.

Functional Neuroimaging has been traditionally used in research for patients with different Parkinsonian syndromes. However, the emergence of commercial radiotracers together with the availability of single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET) have made them available for clinical practice. Particularly, the development of clinical evidence achieved by functional neuroimaging techniques over the past two decades have motivated a progressive inclusion of several biomarkers in the clinical diagnostic criteria for neurodegenerative diseases that occur with Parkinsonism. However, the wide range of radiotracers designed to assess the involvement of different pathways in the neurodegenerative process underlying Parkinsonian syndromes (dopaminergic nigrostriatal pathway integrity, basal ganglia and cortical neuronal activity, myocardial sympathetic innervation), and the different neuroimaging techniques currently available (scintigraphy, SPECT and PET), have generated some controversy concerning the best neuroimaging test that should be indicated for the differential diagnosis of Parkinsonism. In this article, a panel of nuclear medicine and neurology experts has evaluated the functional neuroimaging techniques emphazising practical considerations related to the diagnosis of patients with uncertain origin parkinsonism and the assessment Parkinson's disease progression.

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.

Multiple cranial neuropathy associated with herpes simplex virus infection and anti-GM2 immunoglobulin M antibodies.

Antiganglioside antibodies can appear after several acute infections and are often associated with various clinical patterns of Guillain-Barré syndrome. Thus, for example, cytomegalovirus infection has been associated with anti-GM2 antibodies and Guillain-Barré syndrome variants with severe sensory loss and cranial nerve involvement. We report on a patient who developed multiple cranial neuropathy associated with herpes simplex virus infection and anti-GM2 immunoglobulin M antibodies.

Dopaminergic function and progression of Parkinson's disease: PET findings.

Recent PET studies in Parkinson's disease (PD) have shown that the progression of neurodegeneration follows an exponential decay pattern. Most of the damage to the nigrostriatal dopamine system occurs during the presymptomatic phase of the disease and the first few years following symptom onset. The progressive loss of dopaminergic neurons is accompanied by several functional adaptive changes in surviving nerve terminals, which lead to increased dopamine turnover and raise the risk of treatment-related motor complications. Younger PD patients seem to have more efficient compensatory mechanisms and a slower rate of progression of neurodegeneration.

PET demonstrates reduced dopamine transporter expression in PD with dyskinesias.

OBJECTIVE: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. METHODS: Thirty-six patients with PD with motor fluctuations were assessed with PET using [(11)C]-d-threo-methylphenidate (MP) and [(11)C]-(+/-) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. RESULTS: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 +/- 0.36, dyskinesia 1.39 +/- 0.28; mean +/- SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 +/- 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 +/- 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. CONCLUSIONS: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias.

[Placebo, placebo effect and clinical trials]. / Placebo, efecto placebo y ensayos clínicos.

Recent studies have begun to unveil some of the biochemical bases of the placebo effect. Thus, while placebo analgesia is related to the release of endogenous opioids, placebo-induced dopamine release leads to motor improvement in Parkinson's disease. A theory proposes that the placebo effect is mediated by the activation of the reward circuitry. These biochemical findings indicate that the placebo effect is real, and suggest that many ethical arguments and controversies regarding the use of placebos should perhaps be reconsidered. While it may be advisable to minimize the placebo effect in clinical trials in order to estimate the pure effect of the active treatment, acting in the patient's best interest may require maximizing the placebo effect in the usual clinical setting.

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.

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.

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.

Familial and sporadic Parkinson's disease usually display the same clinical features.

We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's disease (PD) in patients presenting over the age of 40 years. Familial PD cases were tested for alpha-synuclein or parkin mutations as appropriate. No mutations were found in any of the families investigated. We found no between-group differences in the age at onset of PD, the pattern or severity of parkinsonian features, the dose of antiparkinsonian medications or treatment related complications. Cases of familial and sporadic PD in our cohort of patients display similar clinical features. This may suggest similar etiologies for both familial and sporadic PD.

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.