Late-stage Parkinson's Disease Research Articles

The late stage of Parkinson's –results of a large multinational study on motor and non-motor complications

IntroductionThere is little information on the late stages of parkinsonism. MethodsWe conducted a multicentre study in 692 patients with late stage parkinsonism in six European countries. Inclusion criteria were disease duration of ≥7 years and either Hoehn and Yahr stage ≥4 or Schwab and England score of 50 or less. ResultsAverage disease duration was 15.4 (SD 7.7) years and mean total UPDRS score was 82.7 (SD 22.4). Dementia according to MDS-criteria was present in 37% of patients. Mean levodopa equivalence dose was 874.1 (SD 591.1) mg/d. Eighty two percent of patients reported falls, related to freezing (16%) or unrelated to freezing (21% of patients) or occurring both related and unrelated to freezing (45%), and were frequent in 26%. Moderate-severe difficulties were reported for turning in bed by 51%, speech by 43%, swallowing by 16% and tremor by 11%. Off-periods occurred in 68% and were present at least 50% of the day in 13%, with morning dystonia occurring in 35%. Dyskinesias were reported by 45% but were moderate or severe only in 7%. Moderate-severe fatigue, constipation, urinary symptoms and nocturia, concentration and memory problems were encountered by more than half of participants. Hallucinations (44%) or delusions (25%) were present in 63% and were moderate-severe in 15%. The association with overall disability was strongest for severity of falls/postural instability, bradykinesia, cognitive score and speech impairment. ConclusionThese data suggest that current treatment of late stage parkinsonism in the community remains insufficiently effective to alleviate disabling symptoms in many patients.

Efficacy and safety of safinamide as an add-on therapy to L-DOPA for patients with Parkinson's disease: A randomized, double-blind, placebo-controlled, phase II/III study

IntroductionSafinamide is a reversible and selective monoamine oxidase-B (MAO-B) and sodium channel inhibitor with demonstrated efficacy in mid-to late-stage Parkinson's disease (PD) as an adjunct to l-DOPA. This study aimed to confirm the efficacy and safety of safinamide in PD patients with wearing-off. MethodsThis 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study included Japanese PD patients with wearing-off on l-DOPA treatment. Patients were randomized to receive placebo (P), safinamide 50 mg/day (S50), or safinamide 100 mg/day (S100). The primary endpoint was the change from baseline in mean daily ON-time without troublesome dyskinesias (ON-time). Other measures included the changes in mean daily OFF-time, the unified Parkinson's disease rating scale (UPDRS) score, and the PDQ-39 summary index. ResultsA total of 406 subjects were randomized, of whom 349 completed the study. Baseline characteristics were balanced. Differences in the change of mean daily ON-time at Week 24 compared with the P group were 1.39 h (p = 0.0002) in the S50 group and 1.66 h (p < 0.0001) in the S100 group. Changes from baseline in mean daily OFF-time, UPDRS Part II total score (OFF phase), UPDRS Part III total score (ON phase), and UPDRS Part I also showed significant improvements. Adverse events occurred in 58.9%, 60.2%, and 61.4% of the P, S50, and S100 groups, respectively. The most common adverse drug reactions were dyskinesias (2.1%, 8.3%, and 10.6%) and visual hallucinations (1.4%, 3.0%, and 4.5%). ConclusionAs an adjunct to l-DOPA, safinamide safely increased ON-time and improved PD symptoms/signs in PD patients with wearing-off.

Functional outcomes after total joint arthroplasty are related to the severity of Parkinson\u2019s disease: a mid-term follow-up

BackgroundPerforming total joint arthroplasty (TJA) in Parkinson’s disease (PD) patients may encounter a higher complication rate or worse functional outcomes compared with common patients. The relationship between PD and clinical outcomes after TJA is not fully understood.MethodsRetrospectively, we used manual charts to investigate the clinical outcomes in 41 patients including 24 total hip arthroplasty (THA) patients (28 hips) and 18 total knee arthroplasty (TKA) patients (22 knees) with a diagnosis of PD from 2009 to 2016. The stage of PD was confirmed by Hoehn and Yahr scale. Prosthesis survivorship was estimated with revision for any reason as the endpoint.ResultAll the clinical outcomes improved significantly (p < 0.05). Subgroup analysis revealed worse functional outcomes in mid- or end-stage PD patients. Sixteen short-term mild to moderate complications were noted. Two revisions were conducted for hip periprosthetic osteolysis and postoperative knee pain. The prosthesis survivorship at 60 months for TJA, total hip arthroplasty (THA), or total knee arthroplasty (TKA) was 91.6%, 94.1%, and 87.5%, respectively.ConclusionPatients with PD who underwent TJA would result in excellent pain relief and gain of function. However, patients at late-stage PD may suffer from functional loss. The effectiveness of TJA in patients with severe PD remains a concern. Physician should help delay the progression of PD which may optimize and stabilize the functional outcomes of TJA.

Inflammasome and α-synuclein in Parkinson's disease: A cross-sectional study

BackgroundAlpha-synuclein and inflammatory pathology are evident in Parkinson's disease (PD) but, their link to disease pathogenesis needs further elucidation. ObjectivesTo explore α-synuclein-mediated inflammation in the serum of PD patients and its link with disease severity. MethodsSerum levels of IL-1β, NLRP3, total and phosphorylated α-synuclein were compared. ResultsIL-1β, NLRP3 levels were significantly increased in PD. We also observed a linear correlation of NLRP3 with α-synuclein. Phosphorylated α-synuclein levels were significantly elevated in later stages of PD. ConclusionsThe α-synuclein-NLRP3 mediated inflammation may underline the pathophysiology of PD and might serve as a novel therapeutic target in PD.

Objective sleep measures between patients with Parkinson's disease and community-based older adults

ObjectivesPrevious studies comparing objective sleep measures between patients with Parkinson's disease (PD) and control participants were limited by their small sample size. The purpose of this study was to compare objective sleep measures between large-scale cohorts of PD outpatients and community-based older adults. MethodsIn this cross-sectional study, we measured sleep parameters for 157 PD patients using an actigraph on the non-dominant wrist for six consecutive nights (95 Hoehn–Yahr stage I/II; 62 Hoehn–Yahr stage III–V). Moreover, two consecutive nights of actigraphy were performed on 1101 community-based control participants aged ≥60 years. ResultsIn multivariable analysis, sleep efficiency (SE) was significantly lower in patients with late-stage PD by 17.5% [95% confidence interval: 15.3%–19.7%] and early-stage PD by 9.4% [7.6%–11.1%] compared to the controls (67.1% and 75.3% vs. 84.6%, respectively). Similar results were observed for wake after sleep onset (WASO) and fragmentation index (FI). Total sleep time and sleep onset latency (SOL) were significantly shorter in patients with late- and early-stage PD stage compared to the controls. Among PD patients, significant association trends between advancement of individual Hoehn–Yahr stages and worsened sleep measures of SE, WASO, and FI were observed independently of age, gender, levodopa equivalent dose, and motor function parameter. ConclusionThis study demonstrated significant and quantitative differences in objective sleep quality and quantity between PD patients and control participants. Furthermore, with advancement of disease stages, objectively measured sleep quality worsened in PD patients.

Effects of carnosine and lipoic acid in the late stage of Parkinson’s disease in rats

The late stage of Parkinson’s disease is characterized by massive neuronal loss in the substantia nigra (SN) and degeneration of the dopaminergic innervation in the striatum. There is a need to assess the neuroprotective effect of antioxidants (AO) at this stage of the disease. The aim of our study was to assess the efficacy of two AO, carnosine and lipoic acid (LA), in the rat model of late-stage parkinsonism. The pathology was induced by a unilateral injection of 6-hydroxydopamine (6-OHDA) into the SN of the right brain hemisphere. AO were administered 4 times, starting on day 14 following the injection of the toxin. We investigated the effect of the injected drugs on the behavior of rats, the loss of neurons in the SN and the metabolism of biogenic neurotransmitter amines. Both AO dampened the development of 6-OHDA-induced neurological and behavioral symptoms. 6-OHDA induced a 90% drop (p = 0.01) in the levels of dopamine (DA) and its metabolites in the right striatum and caused death of over 95% of neurons (p = 0.01) in the SN of the right hemisphere (p = 0.01). AO did not have a significant effect on the number of neurons in the SN but caused an increase in the levels of DA metabolites, as compared to their levels in the animals exposed to 6-OHDA. Elevated DA (a 5.8-fold increase, p = 0.007) was observed only in the animals treated with carnosine. LA stimulated a 23% decline in serotonin levels (p = 0.06) and a 36% increase (p = 0.009) in its metabolite, 5-hydroxyindolacetic acid (5-HIAA). We conclude that although carnosine and LA did not have a direct neuroprotective effect, they could relieve the symptoms. This suggests that these AO could be used as an adjunctive component to antiparkinsonian therapy.

The Association of Iron and the Pathologies of Parkinson's Diseases in MPTP/MPP+-Induced Neuronal Degeneration in Non-human Primates and in Cell Culture.

Despite much efforts in the last few decades, the mechanism of degeneration of dopamine (DA) neurons in the substantia nigra (SN) in Parkinson’s disease (PD) remains unclear. This represents a major knowledge gap in idiopathic and genetic forms of PD. Among various possible key factors postulated, iron metabolism has been widely suggested to be involved with fueling oxidative stress, a known factor in the pathogenesis of PD. However, the correlation between iron and DA neuron loss, specifically in the SN, has not been described in experimental animal models with great detail, with most studies utilizing rodents and, rarely, non-human primates. In the present study, aiming to gain further evidence of a pathological role of iron in PD, we have examined the correlation of iron with DA neuron loss in a non-human primate model of PD induced by MPTP. We report a significant iron accumulation accompanied by both DA degeneration in the SN and motor deficits in the monkey that displayed the most severe PD pathology and behavioral deficits. The other two monkeys subjected to MPTP displayed less severe PD pathologies and motor deficits, however, their SN iron levels were significantly lower than controls. These findings suggest that high iron may indicate and contribute to heightened MPP+-induced PD pathology in late or severe stages of PD, while depressed levels of iron may signal an early stage of disease. Similarly, using a cell culture preparation, we have found that high doses of ferric ammonium citrate (FAC), a factor known to enhance iron accumulation, increased MPP+-induced cell death in U251 and SH-SY5Y cells, and even in control cells. However, at low dose FAC restored or increased the viability of U251 and SH-SY5Y cells in the absence or presence of MPP+. These observations imply that high levels of iron likely contribute to or heighten MPP+ toxicity in the later stages of PD. While we report reduced iron levels in the earlier stages of MPTP induced PD, the significance of these changes remains to be determined.

Role of the endolysosomal system in Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting 1-1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E-L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin-mediated synaptic endocytosis, an integral part of the neuronal E-L system, is probably the main early target as evident in auxilin, RME-8, and synaptojanin-1 mutations that cause PD. Autophagy, another important pathway in the E-L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life-time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi-compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α-synuclein and LRRK2, key proteins involved in PD, function in different steps of the E-L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E-L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue "Synuclein".

Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD symptomology is recognized as heterogeneous and in addition to motor function decline includes cognitive, mood, sleep, and metabolic disorders. Previous studies showed early reductions in anxiety and locomotion in the A53T mice model of PD. Since inflammation and astrogliosis are an integral part of PD pathology and impair proper neuronal function, we were keen to investigate if behavioral changes in A53T mice are accompanied by increased inflammation and astrogliosis in the hippocampus (Hipp) and motor cortex (mCtx) brain regions involved in the regulation of anxiety and locomotion, respectively. To test this, we used 3-, 5-, and 7-month-old A53T mice to examine anxiety-like behavior, locomotion, and expression of inflammation and astrogliosis markers in the Hipp and mCtx. Further, we examined the presence of alpha-synuclein accumulation in orexin neurons and orexin neuronal loss. The data show early reductions in anxiety-like behavior as well as increased locomotor activity, which was accompanied by inflammation and astrogliosis in the Hipp and mCtx. Due to the persistence of the orexin neuron population in A53T mice and the involvement of orexin in anxiety and locomotor regulation, we hypothesized that chemogenetic modulation of orexin neurons would reverse the observed reductions in anxiety-like behavior and the increases in locomotor activity in these animals. We showed that chemogenetic activation of orexin neurons in A53T mice restores anxiety-like behavior back to control levels without affecting locomotor activity, whereas the inhibition of orexin neurons reverses the elevated locomotor activity without any effects on anxiety-like behavior. This study exemplifies the complex role of orexin neurons in this model of PD and demonstrates the novel finding that changes in locomotor and anxiety-like behavior are accompanied by inflammation and astrogliosis. Together, these data suggest that the orexin system may play a significant role in early and late stages of PD.

Disease stage dependency of motor and non-motor fluctuations in Parkinson's disease.

Recent data suggested a decrease in non-motor fluctuations in late-stage Parkinson's disease (PD), but systematic data on non-motor fluctuations over the whole disease course are mainly lacking. We performed a meta-analysis of two studies with very similar cross-sectional cohort designs, namely the German multicenter Non Motor Fluctuation in PD study and the Swedish part of the European multicenter study Care for Late Stage Parkinsonism. We included only patients with documented motor fluctuations in the analyses. Disease stage was estimated using the Hoehn and Yahr score, motor symptoms using the Unified PD Rating Scale part III motor score and non-motor symptom (NMS) fluctuations using the modified version of the NMS scale assessing a broad range of NMS in motor On and Off state. We included 101 patients (55% men; median age: 71 (interquartile range, IQR 65-78) years with Hoehn and Yahr stages ranging from 1 to 5 [median (IQR) 3.0 (2.0-4.0); distribution of patients in Hoehn and Yahr stages was n = 42 (42%) in stages 2/3 and n = 48 (48%) in stages 4/5]. We found a clear dependency of non-motor burden on Hoehn and Yahr stage with increasing symptom severity, but decreasing fluctuation amplitudes for motor and NMS (difference of symptom severity between On and Off state) with disease stage progression. Indeed, in Hoehn and Yahr stage 5, we did not detect significant NMS fluctuations. Multivariate regression with major demographic and clinical covariates confirmed these results. In conclusion, NMS fluctuations showed a similar disease stage dependency as observed for motor fluctuations with decreasing fluctuation amplitude with disease progression.

Satisfaction with Care in Late Stage Parkinson's Disease.

In late stage Parkinson's disease (PD) (i.e., Hoehn and Yahr (HY) stages IV-V), both motor and nonmotor symptoms (NMS) are pronounced, and the patients become increasingly dependent on help in their daily life. Consequently, there is an increasing demand on health-care and social care resources for these patients and support for their informal caregivers. The aim of this study was to assess satisfaction with care in late stage PD patients and to identify factors associated with satisfaction with care. Moreover, to assess their informal caregivers' satisfaction with support and to identify factors associated with caregivers' satisfaction with support. Factors potentially associated with satisfaction with care/support were assessed in 107 late stage PD patients and their informal caregivers (n=76) and entered into multivariable logistic regression analyses. Fifty-eight (59%) of the patients and 45 (59%) of the informal caregivers reported satisfaction with their overall care/support. Patients satisfied with their care reported higher independence in activities of daily living (ADL) (Katz ADL index; P=0.044), less depressive symptoms (Geriatric Depression Scale, GDS-30; P=0.005), and higher individual quality of life (QoL) (Schedule for the Evaluation of Individual Quality of Life Questionnaire, SEIQoL-Q; P=0.036). Multivariable logistic regression analyses identified depressive symptoms (P=0.015) and independence in ADL (P=0.025) as independently associated with satisfaction with care. For informal caregivers, the analyses identified patients' HY stage (P=0.005) and caregivers' QoL (Alzheimer's Carers Quality of Life Inventory, ACQLI; P=0.012) as independently associated with satisfaction with caregiver support. The results indicate that an effective both pharmacological and nonpharmacological PD therapy is important, to adequately treat motor and NMS (e.g., depressive symptoms) in order to improve depressive symptoms and patient independence in ADL. This may benefit not only the patients, but also their informal caregivers.

The influence of one session of low frequency rTMS on pre-supplementary motor area metabolites in late stage Parkinson's disease

ObjectiveTo study the effect of Low Frequency repetitive Transcranial Magnetic Stimulation (LF rTMS) on brain metabolites in late stage Parkinson's disease (PD) patients (disease duration at least 4 years and Hoehn and Yahr (1969) score at least 2 in OFF). Several neuroimaging data support a role for pre-Supplementary Motor Area (pre-SMA) involvement in the pathogenesis of Parkinson's disease. Proton magnetic resonance spectroscopy (1H-MRS) measures in vivo metabolites, but results in PD brain remain conflicting and little is known of the effect of LF rTMS thereupon. MethodsWe investigate the neurochemical profile of the right pre-SMA in 17 late stage PD patients (11 male and 6 female, mean age of 71 years) before and after one session of sham controlled 1 Hz rTMS (1000 pulses, 16 minutes), focusing on the tNAA/tCr and tCho/tCr ratios. ResultsThe tNAA/tCr ratio was unaffected by one session of LF rTMS. We did observe a significant effect of real LF rTMS on the tCho/tCr ratio, inversely correlated with disease duration, and not related to the presence of dyskinesias. As expected, one session of LF rTMS did not affect clinical outcome. ConclusionsLF rTMS at the right pre-SMA in late stage Parkinson's disease patients does not alter tNAA/tCr, but influences tCho/tCr ratio, in particular in patients with shorter disease duration. SignificancePre-SMA LF rTMS seems to influence membrane turnover, more importantly in patients with shorter disease duration. Larger LF rTMS treatment studies applying multiple sessions are needed.

Dopaminergic modulation of striatal function and Parkinson's disease.

The striatum is richly innervated by mesencephalic dopaminergic neurons that modulate a diverse array of cellular and synaptic functions that control goal-directed actions and habits. The loss of this innervation has long been thought to be the principal cause of the cardinal motor symptoms of Parkinson's disease (PD). Moreover, chronic, pharmacological overstimulation of striatal dopamine (DA) receptors is generally viewed as the trigger for levodopa-induced dyskinesia (LID) in late-stage PD patients. Here, we discuss recent advances in our understanding of the relationship between the striatum and DA, particularly as it relates to PD and LID. First, it has become clear that chronic perturbations of DA levels in PD and LID bring about cell type-specific, homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity. Second, perturbations in DA signaling also bring about non-homeostatic aberrations in synaptic plasticity that contribute to disease symptoms. Third, it has become evident that striatal interneurons are major determinants of network activity and behavior in PD and LID. Finally, recent work examining the activity of SPNs in freely moving animals has revealed that the pathophysiology induced by altered DA signaling is not limited to imbalance in the average spiking in direct and indirect pathways, but involves more nuanced disruptions of neuronal ensemble activity.

Clinical utility of SUDOSCAN in predicting autonomic neuropathy in patients with Parkinson's disease

IntroductionAutonomic neuropathy is common in Parkinson's disease (PD). We evaluated whether SUDOSCAN, a novel electrophysiological device that provides a simple and quantitative assessment of sudomotor function, was able to detect PD-related autonomic neuropathy. We also used the device to examine potential risk factors for PD-related autonomic neuropathy. MethodsForty-three hospitalized patients in the later stages of PD underwent assessments including a clinical history, the Unified Parkinson's Disease Rating Scale (UPDRS), the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT), and measurement of homocysteine (HCY) and vitamin B12 levels. Sudomotor function was assessed by measuring electrochemical skin conductance (ESC) using SUDOSCAN. Forty-two healthy participants served as controls. ResultsESC of the limbs, and especially the hands, was significantly lower in PD patients than in controls and was significantly correlated with SCOPA-AUT results. ESC was strongly negatively correlated with PD duration. The results also indicated that levodopa exposure and a higher HCY level may be risk factors for PD-related autonomic neuropathy. ConclusionsSUDOSCAN was able to effectively identify autonomic neuropathy in PD patients. ESC was decreased in PD patients and was correlated with PD-related autonomic symptoms. These findings suggest that SUDOSCAN could be a promising new method for assessing PD-related autonomic neuropathy.

Dysphagia predicts poor outcome in late-stage Parkinson's disease

BackgroundFew data exist on the rate of clinical progression for Parkinson's disease (PD) patients who have entered a late stage of the disease. ObjectiveStudy the clinical progression of a late-stage PD (LSPD) population over one year follow-up. Methods50 LSPD patients (Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 in MED ON) underwent an extensive clinical assessment at baseline and after one year and an acute levodopa test at baseline. ResultsMean age of LSPD patients (female 46%) was 77.5 ± 5.9 years and mean disease duration was 15.5 ± 6.5 years. At baseline, 76% had levodopa-induced motor complications (MC), usually non-troublesome, 68% were demented, 54% had psychosis and 68% depression. Caregiver distress was high. l-dopa responsiveness was mild (18% ± 12 of improvement on MDS-UPDRS-III). After one-year, 20% of the patients were dead, institutionalized or HY 5. MDS-UPDRS-motor mean score worsened 7.2 ± 10.3 points although there was heterogeneity between patients, and there was a global worsening of non-motor symptoms, mostly in cognition/mood, urinary and gastrointestinal domains. Nevertheless, MC improved despite similar levodopa equivalent dose. Functional independence and quality of life worsened. Dysphagia severity at baseline predicted a poor outcome (death, institutionalization or HY 5) (Hazard ratio 2.3, 95% CI 1.12–4.4; p = 0.01), whereas magnitude of l-dopa response of LSPD patients did not. ConclusionsLSPD patients still present a significant, although heterogeneous, motor and non-motor progression over 1 year. Dysphagia severity predicts the occurrence of additional disease severity milestones and its management must be prioritized.

Clinical and nutritional correlations in Parkinson's disease: Preliminary report.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Malnutrition is an essential problem in the late stage of PD. Lowering of body mass is seen in 30% of patients, and malnutrition or the risk of malnutrition in 24% and 60%, respectively. The aim of the study was an analysis of the relationships between the parameters of the nutritional stage and the advancement of clinical symptoms in PD patients. A total of 40 patients (18 men, 22 women) with PD were analyzed, mean age: 70.7 years. In all patients, structured anamnesis, Nutrition Risk Screening (NRS 2002), body mass index (BMI), morphology, and basic biochemical tests were conducted. Skin fold thickness was also measured. The results were referred to the score of different scales. The study showed a lot of correlations between the severity of PD, mostly motor symptoms in the Unified Parkinson's Disease Rating Scale (UPDRS), and parameters characterizing the patient's nutritional status. We revealed a correlation between malnutrition and PD duration, and l-DOPA frequency intake. The global score of parts I, II and III of UPDRS were correlated with the nutritional status. The results confirmed the existence of more severe smell change and taste impairment in the late stage of PD, with more pronounced malnutrition. The duration of PD, motor and non-motor PD symptoms, and the frequency of l-DOPA intake closely correlate with the nutritional status. Understanding of the multifactorial interdependence might be useful in the estimation of the algorithm for monitoring the nutritional status of PD patients and taking early nutritional intervention.

Effect of Low versus High Frequency Subthalamic Deep Brain Stimulation on Speech Intelligibility and Verbal Fluency in Parkinson's Disease: A Double-Blind Study.

Subthalamic deep brain stimulation (STN-DBS) is an established treatment for late stage Parkinson's disease (PD). Speech intelligibility (SI) and verbal fluency (VF) have been shown to deteriorate following chronic STN-DBS. It has been suggested that speech might respond favourably to low frequency stimulation (LFS). We examined how SI, perceptual speech characteristics, phonemic and semantic VF and processes underlying it (clustering and switching) respond to LFS of 60 and 80 Hz in comparison to high frequency stimulation (HFS) (110, 130 and 200 Hz). In this double-blind study, 15 STN-DBS PD patients (mean age 65, SD = 5.8, 14 right handed, three females), were assessed at five stimulation frequencies: 60 Hz, 80 Hz, 110 Hz, 130 Hz and 200 Hz. In addition to the clinical neurological assessment of speech, VF and SI were assessed. SI and in particular articulation, respiration, phonation and prosody improved with LFS (all p < 0.05). Phonemic VF switching improved with LFS (p = 0.005) but this did not translate to an improved phonemic VF score. A trend for improved semantic VF was found. A negative correlation was found between perceptual characteristics of speech and duration of chronic stimulation (all p < 0.05). These findings highlight the need for meticulous programming of frequency to maximise SI in chronic STN-DBS. The findings further implicate stimulation frequency in changes to specific processes underlying VF, namely phonemic switching and demonstrate the potential to address such deficits through advanced adjustment of stimulation parameters.

A Pilgrim's Journey-When Parkinson's Disease Comes to an End in Nursing Homes.

Our interdisciplinary mixed-methods exploratory study was aimed at gaining empirical data on the medical and nursing demands of residents who are in a late stage of Parkinson Disease (PD) and are cared for in residential homes in Salzburg (Austria). In earlier studies it has been concluded that symptom burden of late stage PD patients is similar to or even higher compared with oncological patients. However, although all nine residents who took part in our study had severe limitations in performing their daily activities and experienced enormous restrictions in their mobility, they were quite content with their present living situations and did not show significant symptom burden. From the ethnographic family interviews that we conducted the following features emerged: a strong closeness in the family, an improved quality of life when the patients lived in the nursing home and fears about the future. Therefore, we concluded that living in a nursing home that provides for the needs of these patients is the best option for PD patients in the final stages of their disease as well as for their relatives.

BDNF provides many routes toward STN DBS-mediated disease modification.

The concept that subthalamic nucleus deep brain stimulation (STN DBS) may be disease modifying in Parkinson's disease (PD) is controversial. Several clinical trials that enrolled subjects with late‐stage PD have come to disparate conclusions on this matter. In contrast, some clinical studies in early‐ to midstage subjects have suggested a disease‐modifying effect. Dopaminergic innervation of the putamen is essentially absent in PD subjects within 4 years after diagnosis, indicating that any neuroprotective therapy, including STN DBS, will require intervention within the immediate postdiagnosis interval. Preclinical prevention and early intervention paradigms support a neuroprotective effect of STN DBS on the nigrostriatal system via increased brain‐derived neurotrophic factor (BDNF). STN DBS‐induced increases in BDNF provide a multitude of mechanisms capable of ameliorating dysfunction and degeneration in the parkinsonian brain. A biomarker for measuring brain‐derived neurotrophic factor‐trkB signaling, though, is not available for clinical research. If a prospective clinical trial were to examine whether STN DBS is disease modifying, we contend the strongest rationale is not dependent on a preclinical neuroprotective effect per se, but on the myriad potential mechanisms whereby STN DBS‐elicited brain‐derived neurotrophic factor‐trkB signaling could provide disease modification. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Study protocol: Care of Late-Stage Parkinsonism (CLaSP): a longitudinal cohort study

BackgroundParkinson’s disease (PD) is a chronic progressive disorder leading to increasing disability. While the symptoms and needs of patients in the early stages of their disease are well characterized, little information is available on patients in the late stage of the disease.Methods/designThe Care of Late-Stage Parkinsonism (CLaSP) study is a longitudinal, multicenter, prospective cohort study to assess the needs and provision of care for patients with late stage Parkinsonism and their carers in six European countries (UK, France, Germany, Netherlands, Portugal, Sweden). In addition, it will compare the effectiveness of different health and social care systems. Patients with Parkinsonism with Hoehn and Yahr stage ≥IV in the “On”-state or Schwab and England stage 50% or less are evaluated at baseline and three follow-up time-points. Standardised questionnaires and tests are applied for detailed clinical, neuropsychological, behavioural and health-economic assessments. A qualitative study explores the health care needs and experiences of patients and carers, and an interventional sub-study evaluates the impact of specialist recommendations on their outcomes.DiscussionThrough the combined assessment of a range of quantitative measures and qualitative assessments of patients with late stage parkinsonism, this study will provide for the first time comprehensive and in-depth information on the clinical presentation, needs and health care provision in this population in Europe, and lay the foundation for improved outcomes in these patients.Trial registrationThe protocol was registered at ClinicalTrials.gov as NCT02333175 on 07/01/2015.