Frequency and outcomes of gastrostomy insertion in a longitudinal cohort study of atypical parkinsonism.

BACKGROUND: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) show a high prevalence and rapid progression of dysphagia, which is associated with reduced survival. Despite this, the evidence base for gastrostomy is poor, and the optimal frequency and outcomes of this intervention are not known. We aimed to characterise the prevalence and outcomes of gastrostomy in patients with these three atypical parkinsonian disorders. METHOD: We analysed data from the natural history and longitudinal cohorts of the PROSPECT-M-UK study with up to 60 months of follow-up from baseline. Survival post-gastrostomy was analysed using Kaplan-Meier survival curves. RESULTS: In a total of 339 patients (mean age at symptom onset 63.3 years, mean symptom duration at baseline 4.6 years), dysphagia was present in >50% across all disease groups at baseline and showed rapid progression during follow-up. Gastrostomy was recorded as recommended in 44 (13%) and performed in 21 (6.2%; MSA 7, PSP 11, CBS 3) of the total study population. Median survival post-gastrostomy was 24 months compared with 12 months where gastrostomy was recommended but not done (p = 0.008). However, this was not significant when correcting for age and duration of symptoms at the time of procedure or recommendation. CONCLUSIONS: Gastrostomy was performed relatively infrequently in this cohort despite the high prevalence of dysphagia. Survival post-gastrostomy was longer than previously reported, but further data on other outcomes and clinician and patient perspectives would help to guide use of this intervention in MSA, PSP and CBS.

Emergency presentations of movement disorders.

Movement disorders are typically perceived as being gradually progressive conditions that are managed in outpatient settings. However, they may manifest de novo with an acute severe phenotype or an acute decompensation. A movement disorder becomes an emergency when it evolves acutely or subacutely over hours to days; delays in its diagnosis and treatment may cause significant morbidity and mortality. Here we address the clinical presentation, diagnosis and management of those movement disorder emergencies that are principally encountered in emergency departments, in acute receiving units or in intensive care units. We provide practical guidance for management in the acute setting where there are several treatable causes not to be missed. The suggested medication doses are predominantly based on expert opinion due to limited higher-level evidence. In spite of the rarity of movement disorder emergencies, neurologists need to be familiar with the phenomenology, potential causes and treatments of these conditions. Movement disorder emergencies divide broadly into two groups: hypokinetic and hyperkinetic, categorised according to their phenomenology. Most acute presentations are hyperkinetic and some are mixed.

History and future challenges of the subthalamic nucleus as surgical target: Review article.

For many years the subthalamic nucleus had a poor reputation among neurosurgeons as a result of the acute movement disorders that develop after its lesion or manipulation through different surgical procedures. However, this nucleus is now considered a key structure in relation to parkinsonism, and it is currently one of the preferred therapeutic targets for Parkinson's disease. The implication of the subthalamic nucleus in the pathophysiology of chorea and in the parkinsonian state is thought to be related to its role in modulating the basal ganglia, a fundamental circuit in movement control. Indeed, recent findings have renewed interest in this anatomical structure. Accordingly, this review aims to present a history of the subthalamic nucleus, evolving from the classic surgical concepts associated with the avoidance of this structure, to our current understanding of its importance based on findings from more recent models. Future developments regarding the relationship of the subthalamic nucleus to neuroprotection are also discussed in this review. © 2018 International Parkinson and Movement Disorder Society.

DBS in pediatric patients: institutional experience.

INTRODUCTION: DBS is initially used for treatment of essential tremor and Parkinson's disease in adults. In 1996, a child with severe life-threatening dystonia was offered DBS to the internal globus pallidus (GPi) with lasting efficacy at 20 years. Since that time, increasing number of children benefited from DBS. PATIENTS AND METHODS: We retrospectively evaluated our database of patients who underwent DBS from 2011 to 2017. All patients ≤ 17 years of age at the time of implantation of DBS were included in this series. Subjective Benefit Rating Scale (SBRS), Hoehn Yahr Scale (HYS), Fahn Marsden Rating Scale (FMRS), Clinical Global Impressions Scales (CGI), and Yale Global Tic Severity Scale (YGT) were used to evaluate clinical outcome. RESULTS: Between May 2014 and October 2017, 11 children underwent DBS procedure in our institution. Six of them were female and five of them were male. Mean age at surgery was 11.8 ± 4.06 years (range 5-17 years). In our series, four patients had primary dystonia (PDY) (36.3%), three patients had secondary dystonia (SDY) (27.2%), two patients had JP (18.1%), and two patients had Tourette Syndrome (TS) (18.1%). Two JP patients underwent bilateral STN DBS while the other nine patients underwent bilateral GPi DBS. SBRS scores were 1.75 ± 0.5 for patients with PDY, 3 ± 0 for patients with JP, 2.5 ± 0.7 for patients with TS, and 2 ± 1 for patients with SDY. Mean FMRS reduction rate was 40.5 for patients with dystonia. Significant improvement was also defined in patients with TS and JP after DBS. None of the patients experienced any intracerebral hemorrhage or other serious adverse neurological effect related to the DBS. Wound complications occurred in two patients. CONCLUSION: There are many literatures that support DBS as a treatment option for pediatric patients with medically refractory neurological disorders. DBS has replaced ablative procedures as a treatment of choice not only for adult patients, but also for pediatric patients. Wound-related complications still remain the most common problem in pediatric patients. Development of smaller and more flexible hardware will improve quality of children's life and minimize wound-related complications in the future.

A minimally invasive catheter-based ultrasound technology for therapeutic interventions in brain: initial preclinical studies.

OBJECTIVE Minimally invasive procedures may allow surgeons to avoid conventional open surgical procedures for certain neurological disorders. This paper describes the iterative process for development of a catheter-based ultrasound thermal therapy applicator. METHODS Using an ultrasound applicator with an array of longitudinally stacked and angularly sectored tubular transducers within a catheter, the authors conducted experimental studies in porcine liver, in vivo and ex vivo, in order to characterize the device performance and lesion patterns. In addition, they applied the technique in a rodent model of Parkinson's disease to investigate the feasibility of its application in brain. RESULTS Thermal lesions with multiple shapes and sizes were readily achieved in porcine liver. The feasibility of catheter-based focused ultrasound in the treatment of brain conditions was demonstrated in a rodent model of Parkinson's disease. CONCLUSIONS The authors show proof of principle of a catheter-based ultrasound system that can create lesions with concurrent thermode-based measurements.

Differential behavioral outcomes following neonatal versus fetal human retinal pigment epithelial cell striatal implants in parkinsonian rats.

Following the failure of a Phase II clinical study evaluating human retinal pigment epithelial (hRPE) cell implants as a potential treatment option for Parkinson's disease, speculation has centered on implant function and survival as possible contributors to the therapeutic outcomes. We recently reported that neonatal hRPE cells, similar to hRPE cells used in the Phase II clinical study, produced short-lived in vitro and limited in vivo trophic factors, which supports that assumption. We hypothesize that the switch from fetal to neonatal hRPE cells, between the Phase I and the Phase II clinical trial may be partly responsible for the later negative outcomes. To investigate this hypothesis, we used two neonatal hRPE cell lots, prepared in a similar manner to neonatal hRPE cells used in the Phase II clinical study, and compared them to previously evaluated fetal hRPE cells for behavioral changes following unilateral striatal implantation in 6-hydroxydopamine-lesioned rats. The results showed that only fetal, not neonatal, hRPE cell implants, were able to improve behavioral outcomes following striatal implantation in the lesioned rats. These data suggest that fetal hRPE cells may be preferential to neonatal hRPE cells in restoring behavioral deficits.

Neonatal human retinal pigment epithelial cells secrete limited trophic factors in vitro and in vivo following striatal implantation in parkinsonian rats.

Human retinal pigment epithelial (hRPE) cell implants into the striatum have been investigated as a potential cell-based treatment for Parkinson's disease in a Phase II clinical trial that recently failed. We hypothesize that the trophic factor potential of the hRPE cells could potentially influence the function and/or survival of the implants and may be involved in an alternative mechanism of action. However, it is unclear if hRPE cells secreted trophic factors when handled in the manner used in the clinical Phase II trial. To address these questions, we investigated two neonatal hRPE cell lots, cultured in a similar manner to hRPE cells used in a Phase II clinical study, and longitudinally determined brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2), and pigment epithelium-derived factor concentrations in vitro and following striatal implantation into 6-hydroxydopamine-lesioned rats. The results demonstrate short-lived BDNF and FGF2 concentrations in vitro from hRPE cells grown alone or attached to gelatin microcarriers (GM)s as well as limited trophic factor concentration differences in vivo following striatal implantation of hRPE-GM in 6-hydroxydopamine lesioned rats compared to sham (GM-only). The data suggest that trophic factors from neonatal hRPE cell implants likely did not participate in an alternative mechanism of action, which adds supports to a hypothesis that additional factors may have been necessary for the survival and/or function of hRPE implants and potentially the success of the Phase II clinical trial.

Subthalamic nucleus lesion improves cell survival and functional recovery following dopaminergic cell transplantation in parkinsonian rats.

Subthalamic nucleus (STN) modulation is currently the gold standard in the treatment of Parkinson's disease (PD) cases refractory to medication. Cell transplantation is a tissue-restorative approach and is a promising strategy in the treatment of PD. One of the obstacles to overcome in cell therapy is the poor dopaminergic cell survival. Our experiment investigates the impact of a partial subthalamotomy prior to ventral mesencephalic (VM) embryonic cell transplantation on dopaminergic cell survival and functional outcome. Unilateral dopamine depletion was carried out in rats, via medial forebrain bundle (MFB) injection of 6-hydroxydopamine, and half of the animals went on to receive unilateral excitotoxic lesions of the STN/Zone Incerta (ZI) causing partial lesion of these structures on the same side as the MFB lesion. All MFB-lesioned animals, with or without the STN/ZI lesion, received striatal ipsilateral embryonic VM cell grafts. The data suggest that the STN/ZI lesion could boost the dopamine cell survival in the grafts by 2.6-fold compared with the control grafted-only group. Moreover, performance on the drug-induced rotation and the spontaneous behavior tests were ameliorated on the STN/ZI-lesioned group to a significantly greater extent than the grafted-only group. These data suggest that the STN/ZI partial lesion optimized the striatal environment, promoting an improvement in cell survival. Further studies are needed to see whether the synergy between STN modulation via deep brain stimulation and cell therapy might have clinical applications in the management of PD.

Secondary Benefits of Microsurgical Intervention on the Vertebral Artery (V1 Segment) for Refractory Vertebrobasilar Insufficiency: Alleviation of Parkinsonism-Like Symptoms.

OBJECTIVE: The objective of this study was to investigate the outcomes of microneurosurgical interventions on V1 segment of the vertebral artery in patients with refractory vertebrobasilar insufficiency (VBI) due to dolicoarteriopathy and external compressions and to assess the secondary benefits of Parkinsonism-like symptoms. METHODS: Retrospective analysis encompassed 101 patients treated for vertebral artery dolicoarteriopathy or compression-related refractory VBI from 2016 to 2023. Of these, 16 patients exhibited drug-resistant Parkinsonism-like symptoms. The diagnostic evaluation included cerebral computed tomography/magnetic resonance angiography or digital subtraction angiography and brain computed tomography or magnetic resonance perfusion studies, corroborated by preoperative and 6- and 12-month postoperative Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 assessments. Data were analyzed through Turkey's "E-nabiz" system, employing Stata16 for statistical scrutiny. RESULTS: A significant reduction in Movement Disorder Society-Unified Parkinson's Disease Rating Scale scores was observed (preoperative: 26.75±10.91; 6 months: 23.09±9.24; 12 months: 22.5±8.73; P < 0.001). Postoperative follow-up denoted that 43.7% of patients ceased medication and 50% reduced antiparkinsonian drugs. The microneurosurgical approach resulted in complete remission of VBI-related symptoms in 84.6% of patients, with the rest showing partial or marked improvement. At 6 months postoperation, perfusion studies revealed posterior border zone or cerebellar perfusion enhancements in 81% (13 out of 16) of patients, with full symptom resolution, while the remaining 19% (3 out of 16) showed partial perfusion and clinical improvements, particularly in regions supplied by the posterior cerebellar artery or posterior inferior cerebellar artery. The absence of operative mortality and minimal transient morbidities underscored the procedure's safety. CONCLUSIONS: Microneurosurgery for vertebral artery anomalies in refractory VBI patients, particularly those with concomitant parkinsonian-like syndromes, has demonstrated potential in symptom remission and medication reduction.

Behavioural recovery on simple and complex tasks by means of cell replacement therapy in unilateral 6-hydroxydopamine-lesioned mice.

Before cell replacement therapies can enter the clinic, it is imperative to test the therapeutic benefits in well-described animal models. In the present study, we aimed to investigate the effects of 6-hydroxydopamine lesions to the medial forebrain bundle and subsequent grafting of embryonic day (E)12.5 ventral mesencephalon into the denervated striatum in C57/Bl6 mice on a battery of simple motor tests (drug-induced rotation, rotarod, and corridor) and the lateralised choice reaction time task conducted in the mouse nine-hole box. Histological analysis confirmed effective lesions and good graft survival. The lesion induced marked deficits in the choice reaction time task, the rotarod test, and corridor test, and these deficits were partially but significantly alleviated in the grafted mice. Although the lesions induced significant rotation following injections of amphetamine and apomorphine, respectively, the grafts did not, suprisingly, alleviate the rotation deficit. This study shows the ability of ventral mesencephalic tissue to ameliorate some of the lesion-induced deficits, and the power of operant testing in detecting small but significant improvements. The behavioural tests presented are useful drug-free approaches for evaluating cell-based therapies.

PTEN deletion enhances survival, neurite outgrowth and function of dopamine neuron grafts to MitoPark mice.

Clinical trials in Parkinson's disease have shown that transplants of embryonic mesencephalic dopamine neurons form new functional connections within the host striatum, but the therapeutic benefits have been highly variable. One obstacle has been poor survival and integration of grafted dopamine neurons. Activation of Akt, a serine/threonine kinase that promotes cell survival and growth, increases the ability of neurons to survive after injury and to regenerate lost neuronal connections. Because the lipid phosphatase, phosphatase and tensin homolog (PTEN) inhibits Akt, we generated a mouse with conditional knock-out of PTEN in dopamine neurons, leading to constitutive expression of Akt in these neurons. Ventral mesencephalic tissue from dopamine phosphatase and tensin homologue knock-out or control animals was then transplanted bilaterally into the dopamine depleted striata of MitoPark mice that express a parkinsonian phenotype because of severe respiratory chain dysfunction in dopamine neurons. After transplantation into MitoPark mice, PTEN-deficient dopamine neurons were less susceptible to cell death, and exhibited a more extensive pattern of fibre outgrowth compared to control grafts. Voltammetric measurements demonstrated that dopamine release and reuptake were significantly increased in the striata of animals receiving dopamine PTEN knock-out transplants. These animals also displayed enhanced spontaneous and drug-induced locomotor activity, relative to control transplanted MitoPark mice. Our results suggest that disinhibition of the Akt-signalling pathway may provide a valuable strategy to enhance survival, function and integration of grafted dopamine neurons within the host striatum and, more generally, to improve survival and integration of different forms of neural grafts.

A novel strategy for intrastriatal dopaminergic cell transplantation: sequential "nest" grafting influences survival and behavioral recovery in a rat model of Parkinson's disease.

Neural transplantation in experimental parkinsonism (PD) is limited by poor survival of grafted embryonic dopaminergic (DA) cells. In this proof-of-principle study we hypothesized that a first regular initial graft may create a "dopaminergic" environment similar to the perinatal substantia nigra and consequently stimulate a subsequent graft. Therefore, we grafted ventral mesencephalic neurons sequentially at different time intervals into the same target localization. Rats with a unilateral lesion of the dopamine neurons produced by injections of 6-hydroxydopamine (6-OHDA) received E14 ventral mesencephalon derived grafts into the DA-depleted striatum. In the control group we grafted all 6 deposits on the first day (d0). The other 4 groups received four graft deposits distributed over 2 implantation tracts followed by a second engraftment injected into the same site 3, 6, 14 and 21 days later. Quantitative assessment of the survival of tyrosine hydroxylase-immunoreactive neurons and graft volume revealed best results for those DA grafts implanted 6 days after the first one. In the present study, a model of short-interval sequential transplantation into the same target-site, so called "nest" grafts were established in the 6-OHDA rat model of PD which might become a useful tool to further elucidate the close neurotrophic and neurotopic interactions between the immediate graft vicinity and the cell suspension graft. In addition, we could show that the optimal milieu was established around the sixth day after the initial transplantation. This may also help to further optimize current transplantation strategies to restore the DA system in patients with PD.

Neural metabolite changes in corpus striatum after rat multipotent mesenchymal stem cells transplanted in hemiparkinsonian rats by magnetic resonance spectroscopy.

OBJECTIVE: To investigate the biochemical changes in striatum after rat bone marrow mesenchymal stem cells (MSCs) were transplanted into hemiparkinsonian rats and to further confirm the therapeutic effects of rat MSCs for Parkinson's disease (PD). METHODS: 5-bromo-2-deoxyuridine (BrdU)-labeled MSCs were transplanted into the corpus striatum of the 6-hydroxydopamine (6-OHDA)-injected side of six PD model rats. Before and 8 weeks after MSC transplantation, ethological changes in PD rats were assessed. The expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum were measured using immunohistochemical methods. The differentiation of MSCs was detected by double immunofluorescence techniques. The concentrations of neural metabolites of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were measured by ¹H-magnetic resonance spectroscopy (MRS). Relative concentrations of NAA/Cr and Cho/Cr were calculated. RESULTS: The behavior of PD rats in rotarod tests improved, and there were statistical differences in TH-positive cells in SN and TH-positive terminals in striatum after the transplantation of BrdU-labeled MSCs. Transplanted MSCs differentiated into MAP-2-positive neurons. Especially compared with pre-MSC transplantation, the neural metabolite NAA/Cr ratio of the 6-OHDA-injected side of the striatum increased (P < 0.05) and the Cho/Cr ratio decreased (P < 0.05). CONCLUSION: MSCs transplantation apparently improves neuronal function in the striatum of PD rats.

Intrathecal application of autologous bone marrow cell preparations in Parkinsonian syndromes.

BACKGROUND: A growing number of patients is treated with intrathecal application of autologous bone marrow cells (aBMCs), but clinical data are completely lacking in movement disorders. We provide first clinical data on efficacy and safety of this highly experimental treatment approach in parkinsonian syndromes. METHODS: Retrospective data collection from patients with parkinsonism who spontaneously sought cell treatment. The application procedure was neither recommended nor performed by the authors. RESULTS: We report 17 patients with parkinsonian syndromes (Parkinson's disease [PD], n = 7; multiple system atrophy [MSA], n = 7; various, n = 3) who received intrathecal application of aBMCs. We did not observe any changes in motor function, activities of daily living, global clinical impression, or antiparkinsonian medication after a median observation period of 10 months. Two patients reported a worsening of parkinsonian symptoms, but the intervention was otherwise safe and well-tolerated. CONCLUSIONS: Intrathecal application of aBMCs in uncontrolled conditions produces no clinical benefit in parkinsonian syndromes.

Transfer of host-derived α synuclein to grafted dopaminergic neurons in rat.

Multiple laboratories have recently demonstrated that long-term dopaminergic transplants form Lewy bodies in patients with Parkinson's disease. Debate has arisen as to whether these Lewy bodies form from the transfer of α synuclein from the host to the graft or whether they form from intrinsic responses of the graft from being placed into what was, or became, an inflammatory focus. To test whether the former hypothesis was possible, we grafted fetal rat ventral mesencephalon into the dopamine depleted striatum of rats that had previously received 6-hydroxydopamine lesions. One month after the transplant, rats received viral over expression of human α synuclein (AAV2/6-α synuclein) or green fluorescent protein (AAV2/6-GFP) into the striatum rostral to the grafts. Care was taken to make sure that the AAV injections were sufficiently distal to the graft so no cells would be directly transfected. All rats were sacrificed five weeks after the virus injections. Double label immunohistochemistry combined with confocal microscopy revealed that a small number of grafted tyrosine hydroxylase (TH) neurons (5.7% ± 1.5% (mean ± SEM) of grafted dopamine cells) expressed host derived α synuclein but none of the grafted cells expressed host-derived GFP. The α synuclein in a few of these cells was misfolded and failed to be digested with proteinase K. These data indicate that it is possible for host derived α synuclein to transfer to grafted neurons supporting the concept that this is one possible mechanism by which grafted dopamine neurons form Lewy bodies in Parkinson's disease patients.

Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice.

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease, and the most common movement disorder. Drug treatment and deep brain stimulation can ameliorate symptoms, but the progressive degeneration of dopaminergic neurons in the substantia nigra eventually leads to severe motor dysfunction. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum and reactivate functional circuits. We have generated substrate-adherent embryonic stem cell-derived neural aggregates overexpressing the neural cell adhesion molecule L1, because it has shown beneficial functions after central nervous system injury. L1 enhances neurite outgrowth and neuronal migration, differentiation and survival as well as myelination. In a previous study, L1 was shown to enhance functional recovery in a mouse model of Huntington's disease. In another study, a new differentiation protocol for murine embryonic stem cells was established allowing the transplantation of stem cell-derived neural aggregates consisting of differentiated neurons and radial glial cells into the lesioned brain. In the present study, this embryonic stem cell line was engineered to overexpress L1 constitutively at all stages of differentiation and used to generate stem cell-derived neural aggregates. These were monitored in their effects on stem cell survival and differentiation, rescue of endogenous dopaminergic neurons and ability to influence functional recovery after transplantation in an animal model of Parkinson's disease. Female C57BL/6J mice (2 months old) were treated with the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneally to deplete dopaminergic neurons selectively, followed by unilateral transplantation of stem cell-derived neural aggregates into the striatum. Mice grafted with L1 overexpressing stem cell-derived neural aggregates showed better functional recovery when compared to mice transplanted with wild-type stem cell-derived neural aggregates and vehicle-injected mice. Morphological analysis revealed increased numbers and migration of surviving transplanted cells, as well as increased numbers of dopaminergic neurons, leading to enhanced levels of dopamine in the striatum ipsilateral to the grafted side in L1 overexpressing stem cell-derived neural aggregates, when compared to wild-type stem cell-derived neural aggregates. The striatal levels of gamma-aminobutyric acid were not affected by L1 overexpressing stem cell-derived neural aggregates. Furthermore, L1 overexpressing, but not wild-type stem cell-derived neural aggregates, enhanced survival of endogenous host dopaminergic neurons after transplantation adjacent to the substantia nigra pars compacta. Thus, L1 overexpressing stem cell-derived neural aggregates enhance survival and migration of transplanted cells, differentiation into dopaminergic neurons, survival of endogenous dopaminergic neurons, and functional recovery after syngeneic transplantation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

Effects of GDF5 overexpression on embryonic rat dopaminergic neurones in vitro and in vivo.

Transplantation of embryonic dopaminergic neurones has shown promise for the treatment of Parkinson's disease (PD), but this approach is limited by the poor survival of the transplanted cells. Exogenous dopaminergic neurotrophic factors such as growth/differentiation factor 5 (GDF5) have been found to enhance the survival of transplanted dopaminergic neurones. However, this approach is limited by the rapid degradation of such factors in vivo; thus, methods for long-term delivery of these factors are under investigation. The present study shows, using optimised lipid-mediated transfection procedures, that overexpression of GDF5 significantly improves the survival of dopaminergic neurones in cultures of embryonic day (E) 13 rat ventral mesencephalon (VM) and protects them against 6-hydroxydopamine (6-OHDA)-induced toxicity. In another experiment, E13 VM cells were transfected with GDF5 after 1 day in vitro (DIV), then transplanted into 6-OHDA-lesioned adult rat striata after 2 DIV. The survival of these E13 VM dopaminergic neurones after transfection and transplantation was as least as high as that of freshly dissected E14 VM dopaminergic neurones, demonstrating that transfection was not detrimental to these cells. Furthermore, GDF5-overexpressing E13 VM transplants significantly reduced amphetamine-induced rotational asymmetry in the lesioned rats. This study shows that lipid-mediated transfection in vitro prior to transplantation is a valid approach for the introduction of neurotrophic proteins such as GDF5, as well as lending further support to the potential use of GDF5 in neuroprotective therapy for PD.