Designer receptors: therapeutic adjuncts to cell replacement therapy in Parkinson’s disease

Cell replacement for restoring neuronal populations in Parkinson’s disease has been demonstrated as a potential therapeutic strategy over several decades of studies; however, a number of issues regarding sources of replacement neurons and optimization of therapeutic efficacy in vivo have hampered clinical implementation. In this issue of the JCI, Dell’Anno and colleagues evaluated the use of induced dopaminergic (iDA) neurons that were generated by direct fibroblast reprogramming for transplantation and demonstrated that postmitotic iDA neurons stably and functionally integrate into host striatum to produce motor improvements in 6-OHDA rats, a Parkinson’s disease model. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs) in iDA grafts to noninvasively increase dopamine release from grafted neurons, the authors were able to remotely control transplanted neurons and enhance therapeutic efficacy. This initial proof-of-concept study is the first application of DREADD technology to treat neurodegenerative dysfunction, and by using DREADDs as an adjunct to iDA cell therapy, it presents a novel strategy to overcome some current caveats of cell replacement therapy.The loss of nigral dopaminergic (DA) cells in Parkinson’s disease (PD) was discovered in the mid-twentieth century (1), and DA cell replacement was quickly posited as a potential therapeutic strategy. By the late 1970s, proof-of-function studies emerged and showed that intrastriatal transplantation of fetal ventral mesenphalic (VM) tissue could survive in the dopamine-depleted striatum and improve motor function deficits in PD animal models (2). Clinical trials with VM tissue and cell suspensions have been undertaken for nearly 30 years; however, there has yet to be an approved clinical cell replacement therapy for PD. These efforts have not been for naught; a number of clinical trials have demonstrated long-term beneficial effects on motor symptoms (10+ years) and provided valuable lessons (3, 4). The hope for an effective cell replacement therapy for PD has survived the test of time, and efforts are consistently being revised and improved. However, many questions — primarily over technical optimization — have prevented widespread clinical implementation.     

Gait speed and related factors in Parkinson’s disease

[Purpose] The aim of this study was to investigate the relationship between gait speed and various factors in ambulatory patients with idiopathic Parkinson’s disease. [Subjects] Fifty ambulatory patients with idiopathic Parkinson’s disease who were admitted to an outpatient clinic were included in this cross-sectional study. [Methods] The Hoehn and Yahr Scale was used for measurement of the disease severity. Gait speed was measured by the 10-Meter Walk Test. Mobility status was assessed by Timed Up and Go Test. The Hospital Anxiety and Depression Scale was used for evaluation of emotional state. Cognitive status was examined with the Mini-Mental State Examination. The Downton Index was used for fall risk assessment. Balance was evaluated with the Berg Balance Scale. Comorbidity was measured with the Cumulative Illness Rating Scale. The 36-Item Short Form Health Survey was completed for measurement of quality of life. [Results] The mean age was 66.7 (47–83) years. Twenty-eight (56%) patients were men. Gait speed was correlated positively with height, male gender, Mini-Mental Examination score, Berg Balance Scale score and physical summary scores of the 36-Item Short Form Health Survey. On the other hand, there was a negative correlation between gait speed and age, disease severity, TUG time, Downton Index, fear of falling, previous falls and the anxiety and depression scores of the Hospital Anxiety and Depression Scale. There was no correlation between gait speed and comorbidity. [Conclusion] The factors related with the slower gait speed are, elder age, clinically advanced disease, poor mobility, fear of falling, falling history, higher falling risk, and mood disorder.Key words: Gait, Fear of falling, Parkinson’s disease     

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson’s disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD.METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days.RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen.CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.TRIAL REGISTRATION. Clinical Trials.gov {"type":"clinical-trial","attrs":{"text":"NCT00866502","term_id":"NCT00866502"}}NCT00866502.FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).     

Mild and marked executive dysfunction and falls in people with Parkinson’s disease

BackgroundExecutive dysfunction and risk of falling are hallmarks of Parkinson’s disease (PD). However, it is unclear how executive dysfunction predisposes people with PD to falling.ObjectivesTo: (i) identify sensorimotor, balance, and cardiovascular risk factors for falls that discriminate between those with normal executive function and those with mild and marked executive dysfunction in people with PD and (ii) determine whether mild and marked executive dysfunction are significant risk factors for falls when adjusting for PD duration and severity and freezing of gait (FOG).MethodsUsing the Frontal Assessment Battery, 243 participants were classified into normal executive function (n = 87), mild executive dysfunction (n = 100), and marked executive dysfunction (n = 56) groups. Participants were asked if they had episodes of FOG in the last month and were assessed with the Movement Disorders Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), the Hoehn and Yahr Scale, the physiological profile assessment, and tests of orthostatic hypotension, coordinated stability, and gait and were then followed-up prospectively for falls for 32–52 weeks.ResultsSeveral PD-specific (elevated Hoehn and Yahr stage, higher MDS-UPDRS scale scores, a history of FOG, Postural Instability and Gait Difficulty subtype, and longer PD duration), sensorimotor (poor vision, knee extension weakness, slow simple reaction time), and balance (greater postural sway and poor controlled leaning balance) factors discriminated among the normal executive function and mild and marked executive dysfunction groups. Fall rates (mean ± SD) differed significantly among the groups (normal executive function: 1.0 ± 1.7; mild executive dysfunction: 2.8 ± 5.2; marked executive dysfunction: 4.7 ± 7.3) with the presence of both mild and marked executive dysfunction identified as significant risk factors for falls when adjusting for three measures of PD severity (Hoehn and Yahr scale scores, disease duration, and FOG).ConclusionsSeveral PD-specific, sensorimotor, and balance factors differed significantly among the normal, mild, and marked executive dysfunction groups and both mild and marked executive dysfunction were identified as independent risk factors for falls in people with PD.     

Can Parkinson’s disease be cured by stimulating neurogenesis?

There have been many attempts at slowing down or even reversing the neurodegenerative process of Parkinson’s disease (PD). To date, there are no treatments of proven value in this regard. One underexplored route to slow the neurodegenerative process is the use of agents that may stimulate neurogenesis in the subventricular zone. In animal models of PD, PDGF-BB has been shown to restore/protect against dopaminergic deficits caused by neurotoxins via increased neurogenesis in the subventricular zone. Previous work suggests that these new cells are not themselves dopaminergic but have trophic effects on residual dopaminergic cells in the substantia nigra. In this issue of the JCI, Paul et al. evaluate this agent in individuals with PD and show that i.c.v. administration of PDGF-BB is safe and well tolerated. This study lays the foundation for formal dose-finding studies and clinical trials to assess the efficacy of this agent as a potential neuroprotective treatment for PD.     

Network modulation following sham surgery in Parkinson’s disease

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson’s disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify “sham-susceptible” subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.     

Gene therapy for Parkinson’s disease

Significant progress has been made in the field of gene therapy for Parkinson’s disease (PD). Successful vehicles for gene transfer into the central nervous system have been developed and clinical efficacy and safety have both been shown in various animal models of PD. Further optimisation of dosing, timing and location of gene therapy delivery as well as the ability to regulate and prolong gene expression will be important for the commencement of human trials. Current gene therapy models for PD have focused on two treatment strategies. One is the replacement of biosynthetic enzymes for dopamine synthesis and the second strategy is the addition of neurotrophic factors for protection and restoration of dopaminergic neurones. Concepts of neuroprotection and restoration of the nigrostriatal pathway will become important themes for future genetic treatment strategies for PD and may include, in addition to neurotrophic factors, genes to prevent apoptosis or detoxify free radical species. This review will highlight the recent literature on gene therapy for PD and summarise general approaches to gene therapy.     

Influence of fear of falling on gait and balance in Parkinson’s disease

Abstract

Purpose: To study the relationship of fear of falling (FoF) with gait characteristics and balance in individuals with Parkinson's disease (PD). Method: Seventy-nine non-demented individuals (62 males) with PD were studied. Their mean age was 69.22?±?8.93 years. The average time since diagnosis was 8.27?±?5.31 years. FoF was assessed by the Activities-specific Balance Confidence (ABC) Scale in which high scores indicate less FoF. Gait was measured using a computerized walkway. Balance was measured by timed tests including the 5-step test, 360 degree turn, timed sideways walk, and timed up and go test. Participants were divided into two groups based on their ABC score (high FoF, ABC score <69; low FoF, ABC score ≥69). Gait characteristics and balance measures of the two groups were compared. Results: Gait speed and stride length for forward walking (p?<?0.0005 for both) and backward walking (p?=?0.001 and 0.002, respectively) were lower for those with a high level of FoF compared to those with a low level of FoF. The time to take five steps (p?=?0.025), time to turn (p?<?0.0005), time to walk sideways (p?=?0.001), and time to complete the up and go test (p?=?0.003) were longer in those with a high level of FoF than in those with a low level of FoF. Number of steps to complete the turn (p?=?0.001) and steps to walk sideways (p?=?0.002) were greater in those with a high level of FoF than in those with a low level FoF. Conclusions: Gait and balance of individuals with PD with a high level of FoF were poorer than those with a low level of FoF, regardless of previous fall history.

• Implications for Rehabilitation

• The results demonstrates that fear of falling (FoF) is related to gait and balance in individuals with PD.

• Clinicians should be aware that FoF has a negative impact on gait and balance in individuals with PD.

     

Cell secretome based approaches in Parkinson’s disease regenerative medicine

ABSTRACT

Introduction: The available therapeutic strategies for Parkinson’s disease (PD) rely only on the amelioration of the symptomatology of the disease, lacking neuroprotection or neuroregeneration capacities. Therefore, the development of disease modifying strategies is extremely important for the management of PD in the long term.

Areas covered: In this review, the authors provide an overview of the current therapeutic approaches for PD and the emerging use of stem cell transplantation as an alternative. Particularly, the use of the secretome from mesenchymal stem cells (MSCs), as well as some methodologies used for the modulation of their paracrine signaling, will be discussed. Indeed, there is a growing body of literature highlighting the use of paracrine factors and vesicles secreted from different cell populations, for this purpose.

Expert opinion: Secretome from MSCs has shown its potential as a therapy for PD. Nevertheless, in the coming years, research should focus in several key aspects to enable the translation of this strategy from the bench to the bedside.     

Biomechanical analysis of sit-to-walk in different Parkinson’s disease subtypes

BackgroundThe Parkinson’s disease Postural Instability and Gait Difficulty subtype is well-known to exhibit higher levels of gait and postural instability and higher frequency of falls. However, no studies have investigated the impact of Parkinson’s disease subtypes when performing a highly-challenging postural task, such as sit-to-walk. This task is often used daily and can highlight balance impairments. Thus, the aim of this study was to compare Tremor Dominant and Postural Instability and Gait Difficulty subtypes during sit-to-walk measured by performance, kinematic and kinetic analyses.MethodsTwenty-four people with Parkinson’s disease participated in this study, and were divided into two groups: Tremor Dominant (n = 14) and Postural Instability and Gait Difficulty subtype (n = 10). They performed the sit-to-walk under a time constraint (to pick up a phone placed 4 meters away in order to answer an urgent call). Sit-to-walk overall performance, kinetic and kinematic data were assessed as outcome measures.FindingsThe Postural Instability and Gait Difficulty group demonstrated a slower anteroposterior center-of-mass velocity at seat-off, a longer duration of transitional phase and poorer movement fluidity. Furthermore, the Postural Instability and Gait Difficulty group showed a longer sit-to-walk total time. These results indicate that the Postural Instability and Gait Difficulty group performed the task slowly and split the task into two subtasks (sit-to-stand and walking), rather than performing a single, continuous task.InterpretationThe Postural Instability and Gait Difficulty group is unable to perform the sit-to-walk continuously, which might reflect the clinical impairments observed in this Parkinson’s disease subtype.     

Speech and Swallowing Problems in Parkinson’s Disease

Dysphagia (difficulty with swallowing) and dysarthria (impaired speech) are commonly seen, yet often underreported, symptoms in patients with Parkinson’s disease (PD). Early detection of dysphagia in patients with PD is important because progressive swallowing dysfunction may lead to aspiration pneumonia, malnutrition, dehydration, and choking. Similarly, changes in speech have a tremendous impact on a patient’s social abilities, often leading to isolation. Nurse practitioners play a critical role in assessment and implementation of nonpharmacological and pharmacological interventions through patient and caregiver education and collaboration with the care team.     

The role of social support in anxiety and depression among Parkinson’s disease patients

Abstract

Purpose: To explore how social support is associated with anxiety and depression in Parkinson’s disease (PD) patients controlling for gender, disease duration and disease severity. Methods: The sample consisted of 124 patients (52.4% male; mean age 68.1?±?8.4 years; mean disease duration 6.3?±?5.5 years). Anxiety and depression were measured with the Hospital Anxiety and Depression Scale, social support with the Multidimensional Scale of Perceived Social Support and disease severity with the Unified Parkinson Disease Rating Scale. Data were analyzed using linear regression. Results: Gender, disease duration, disease severity and social support explained 31% of the total variance in anxiety in younger PD patients but did not significantly contribute to the explanation of depression. In the older group, this model explained 41% of the variance in depression but did not significantly contribute to the explanation of anxiety. Conclusion: PD patients experience the positive influence of social support differently according to age. In the younger group, disease duration plays the primary role regarding anxiety. In the older group, poor social support especially from friends is associated with more depression after controlling for the relevant variables.

• Implications of Rehabilitation

• PD is a disease of older age with a neurodegenerative character and treatment should focus on increasing quality of life.

• Anxiety and depression are common co-morbidities in PD patients.

• The support network should also be screened regularly and involved in enhancing the quality of life.

     

Delusional misidentification in Parkinson’s disease: report of two cases and a review

Syndromes of delusional misidentification consist of disordered familiarity and have been reported in diverse diagnoses, including Parkinson’s disease. Although the most common delusional misidentification is Capgras syndrome, in which the sufferer believes a familiar person has been replaced by an identical imposter, other forms have been also described. The pathogenesis of delusions of misidentification appears to require dysfunction of or connection to a left cerebral cortical area involved in recognition of familiarity, and also right frontal cortex serving belief evaluation. Two cases of Parkinson’s disease with an unusual delusional misidentification, intermetamorphosis, are presented, along with their improvement with pimavanserin, a novel atypical antipsychotic medication.     

Frontal and subcortical contribution to visual hallucinations in dementia with Lewy bodies and Parkinson’s disease

Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson’s disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia.

Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones.

Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH.

Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.     

A new approach to disease-modifying drug trials in Parkinson’s disease

Translating new findings in the laboratory into therapies for patients is a slow and expensive process. The development of therapies for neurodegenerative diseases is further complicated by the difficulty in determining whether the drug truly retards the slow degenerative process or provides only symptomatic benefit. In this issue, Aviles-Olmos et al. describe a first in Parkinson’s disease (PD) patient study using a drug previously approved for diabetes treatment. In addition to suggesting that the drug may indeed be disease modifying in PD, their innovative approach suggests there may be more rapid and inexpensive avenues for testing novel therapies in PD.Taking new potentially disease-modifying therapies from studies in experimental animals to the clinic in patients with chronic neurodegenerative disorders requires a balance between optimal trial design and expense, and new methods are desperately needed. In this issue, Aviles-Olmos and colleagues describe a novel approach toward exploring the potential for disease-modifying effects in patients with Parkinson’s disease (PD) using a drug approved for the treatment of type 2 diabetes (1). They examined the drug exenatide, a glucagon-like peptide–1 (GLP-1) receptor agonist that has demonstrated promise in several animal models of PD (2). This work is remarkable not only because it is an attempt to examine the effectiveness of repurposing a drug that is already in clinical use, but also because it represents a cost-effective method. This is important because the clinical research community faces a challenge in developing proof of concept studies in a way that gives confidence to proceed to the necessary — and markedly more costly — double-blind, placebo-controlled trials.     

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using ¹¹C-DASB PET to evaluate serotonin terminal function and ¹¹C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.