The effect of subthalamic nucleus deep brain stimulation and dopaminergic treatment on dual-task manual dexterity in Parkinson's disease.

BACKGROUND AND PURPOSE: Dual-task manual dexterity is required to perform activities of daily living and is affected by cognitive functions. This study aimed to investigate the effects of two main treatment options, subthalamic nucleus deep brain stimulation (STN-DBS) and dopaminergic treatment (DT), on dual-task manual dexterity and cognitive functions of people with Parkinson's disease (PwPD). METHODS: Twenty-one PwPD were assessed in four different conditions as medication "on-off" and STN-DBS "on-off" in random order. Motor symptoms were measured with the Movement Disorder Society-Unified Parkinson Disease Rating Scale, motor section (MDS-UPDRS-III). Single and dual-task manual dexterity was assessed with the Nine-Hole Peg Test (NHPT) and cognitive functions were assessed with the Stroop Test (ST) and the Trail Making Test (TMT). RESULTS: Both DT and STN-DBS enhanced MDS-UPDRS-III, and the combination of DT and STN-DBS provided further improvement. Only STN-DBS enhanced dominant hand single-task NHPT scores. Non-dominant single-task NHPT scores and dual-task NHPT scores improved with both treatments alone; however, STN-DBS resulted in more improvement than DT. Dual-task interference, ST, and TMT scores improved with both treatments alone; however, combining DT and STN-DBS did not provide more improvement. CONCLUSION: DT, STN-DBS, and combining both treatments have different effects on motor symptoms, single and dual-task manual dexterity, dual-task interference, and cognitive functions. These results indicate that DT and STN-DBS may affect motor and cognitive functions via different mechanisms. Effects of DT and STN-DBS on manual dexterity may depend on the degree of cognitive involvement in manual dexterity tasks.

Modulatory Effects of Levodopa on Cerebellar Connectivity in Parkinson's Disease.

Levodopa has been the mainstay of symptomatic therapy for Parkinson's disease (PD) for the last five decades. However, it is associated with the development of motor fluctuations and dyskinesia, in particular after several years of treatment. The aim of this study was to shed light on the acute brain functional reorganization in response to a single levodopa dose. Functional magnetic resonance imaging (fMRI) was performed after an overnight withdrawal of dopaminergic treatment and 1 h after a single dose of 250 mg levodopa in a group of 24 PD patients. Eigenvector centrality was calculated in both treatment states using resting-state fMRI. This offers a new data-driven and parameter-free approach, similar to Google's PageRank algorithm, revealing brain connectivity alterations due to the effect of levodopa treatment. In all PD patients, levodopa treatment led to an improvement of clinical symptoms as measured with the Unified Parkinson's Disease Rating Scale motor score (UPDRS-III). This therapeutic effect was accompanied with a major connectivity increase between cerebellar brain regions and subcortical areas of the motor system such as the thalamus, putamen, globus pallidus, and brainstem. The degree of interconnectedness of cerebellar regions correlated with the improvement of clinical symptoms due to the administration of levodopa. We observed significant functional cerebellar connectivity reorganization immediately after a single levodopa dose in PD patients. Enhanced general connectivity (eigenvector centrality) was associated with better motor performance as assessed by UPDRS-III score. This underlines the importance of considering cerebellar networks as therapeutic targets in PD.

Regulation of Protein Synthesis and Apoptosis in Lymphocytes of Parkinson Patients: The Effect of Dopaminergic Treatment.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of the dopaminergic neurons in the substantia nigra, presumably due to increased apoptosis. In previous studies, we showed altered expression of proteins involved in mammalian target of rapamycin (mTOR) antiapoptotic and double-stranded RNA-dependent protein kinase (PKR) apoptotic pathways of translational control in experimental cellular and animal models of PD. RESULTS: In this work, our results showed clear modifications in the expression of kinases involved in mTOR and PKR apoptosis pathways, in lymphocytes of PD patients treated or not with anti-PD treatment (levodopa), which confirmed the role played by apoptosis in the pathogenesis of this disease and the positive effect of treatment with medication on this parameter. Others proteins involved in apo-ptosis were also evaluated in lymphocytes of patients as the expression of the peripheral benzodiazepine receptor and caspase-3. CONCLUSION: Translational control is altered in PD and hence its evaluation in peripheral blood mononuclear cells may serve as an early marker of apoptosis and indicate the efficacy of the dopaminergic treatment.

Re-emergent tremor in Parkinson's disease: the effect of dopaminergic treatment.

BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) with resting tremor may be affected by a tremor that appears after a varying latency while a posture is maintained, a phenomenon referred to as re-emergent tremor (RET). The aim of the study was to evaluate the occurrence and clinical features of RET in patients with PD tested off and on treatment, and to compare the effect of dopaminergic treatment on RET with the effect on resting and action tremor. METHODS: We consecutively enrolled 100 patients with PD. Patients were clinically evaluated 24 h after withdrawal of therapy (off-treatment phase) and 60 min after therapy administration (on-treatment phase). We collected the demographic and clinical data of patients with PD. The severity of the disease was assessed by means of the Hoehn and Yahr scale and Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III. We evaluated the latency, severity and body side affected both off and on treatment in patients with RET. RESULTS: Re-emergent tremor was present in 24% of the patients with PD off treatment and in 19% of the patients on treatment. Dopaminergic treatment reduced the clinical severity of RET. Dopaminergic treatment increased the number of patients with unilateral RET and reduced the number of those who had bilateral RET. RET and resting tremor responded similarly to dopaminergic treatment, whereas action tremor was less responsive. Patients with RET had milder motor symptoms than patients without RET both off and on treatment. CONCLUSIONS: Dopaminergic treatment modified RET occurrence, severity and body distribution. Dopaminergic depletion plays a role in the pathophysiology of RET.

Rate of augmentation and risk factors with long-term follow-up in Japanese patients with restless legs syndrome.

OBJECTIVES: Preventing augmentation is the critical clinical issue for RLS treatment. As for augmentation in Asian RLS patients, there have been only four studies and the follow-up durations of these studies were not long. We investigated Japanese RLS patients with longer duration of treatment in a clinical setting. METHODS: This study is a retrospective assessment of 42 RLS patients with follow-up durations of longer than 18 months (78.4 ± 29.2, range 19-139) at two urban sleep centers in Osaka, Japan from May 2004 to April 2014. RESULTS: The mean age of first visit was 63.5 ± 14.1 years old and the estimated age of RLS onset was 47.9 ± 16.5 years old. Twenty-eight out of 42 patients were female. At initial evaluation, the mean International Restless Legs Scale score (IRLS score) was 22.0 ± 5.9. Thirty-one of 42 had already visited other clinics before coming to our sleep centers, and the number of clinics visited was 1.3 ± 0.6. Augmentation developed in two patients (4.8%), and the dosage of dopamine equivalent in patients with and without augmentation was 12.5 and 18.8 mg vs. 15.8 ± 17.7 mg. In the two RLS patients with augmentation, ferritin was 113.1 and 114.1 ng/mL, respectively, and the number of clinics before coming to our sleep centers was both three. CONCLUSIONS: The augmentation rate of Japanese RLS patients from our study is low compared with previous Western and Asian studies. It might be attributable to racial difference, lower dosage of dopaminergic treatment, and the level of ferritin.

A dynamic brain network decomposition method discovers effective brain hemodynamic sub-networks for Parkinson's disease.

Objective.Dopaminergic treatment is effective for Parkinson's disease (PD). Nevertheless, the conventional treatment assessment mainly focuses on human-administered behavior examination while the underlying functional improvements have not been well explored. This paper aims to investigate brain functional variations of PD patients after dopaminergic therapy.Approach.This paper proposed a dynamic brain network decomposition method and discovered brain hemodynamic sub-networks that well characterized the efficacy of dopaminergic treatment in PD. Firstly, a clinical walking procedure with functional near-infrared spectroscopy was developed, and brain activations during the procedure from fifty PD patients under the OFF and ON states (without and with dopaminergic medication) were captured. Then, dynamic brain networks were constructed with sliding-window analysis of phase lag index and integrated time-varying functional networks across all patients. Afterwards, an aggregated network decomposition algorithm was formulated based on aggregated effectiveness optimization of functional networks in spanning network topology and cross-validation network variations, and utilized to unveil effective brain hemodynamic sub-networks for PD patients. Further, dynamic sub-network features were constructed to characterize the brain flexibility and dynamics according to the temporal switching and activation variations of discovered sub-networks, and their correlations with differential treatment-induced gait alterations were analyzed.Results.The results demonstrated that PD patients exhibited significantly enhanced flexibility after dopaminergic therapy within a sub-network related to the improvement of motor functions. Other sub-networks were significantly correlated with trunk-related axial symptoms and exhibited no significant treatment-induced dynamic interactions.Significance.The proposed method promises a quantified and objective approach for dopaminergic treatment evaluation. Moreover, the findings suggest that the gait of PD patients comprises distinct motor domains, and the corresponding neural controls are selectively responsive to dopaminergic treatment.

Immunomodulatory effect and clinical outcome in Parkinson's disease patients on levodopa-pramipexole combo therapy: A two-year prospective study.

Parkinson's disease (PD), the second most frequent neurodegenerative disease, has been linked to increased central and peripheral inflammation. Although the response of the immune system to dopaminergic treatment remains to be fully understood, dopaminergic agonists are known to exhibit immunoregulatory properties which may, at least in part, explain their therapeutic effect in PD. This highlights the need of analyzing immune parameters in longitudinal studies on PD patients receiving specific therapeutic regimes. In this work, PD patients were included in a two-year prospective study comparing the effect of levodopa alone and a levodopa/pramipexole combo therapy on several regulatory and pro-inflammatory immune cell populations. We demonstrated that PD patients show decreased circulating levels of several important regulatory subpopulations, as determined by flow cytometry. Notably, when administered alone, levodopa decreased the levels of functional Bregs and SLAMF1+ tolerogenic DCs and increased the levels of total and HLA-DR+ classical monocytes, while the pramipexole/levodopa combo may promote Treg- and tolerogenic DC-mediated regulatory responses. These results suggest that a regime based on levodopa alone may promote a pro-inflammatory-type response in PD patients, but when combined with pramipexole, it promotes a clinically beneficial regulatory-type environment.

Therapeutic strategies for Parkinson's disease: promising agents in early clinical development.

INTRODUCTION: To date, no drug has demonstrated clinically indisputable neuroprotective efficacy in Parkinson's disease (PD). We also have no effective symptomatic treatment for disabling symptoms such as balance problems, and dementia, and we need to improve the efficacy and safety profile of drugs currently used in the management of motor complications. AREAS COVERED: We examine the agents which appear to have most therapeutic promise based on concepts, feasibility in a reasonable time frame, and available clinical data and place an emphasis on disease-modifying treatments. PUBMED and Clinicaltrials.gov databases were searched for Phase I and II randomized trials for symptomatic or disease-modifying treatments considering only studies that began since 2010 or that were completed after 2015, up to 30 April 2020. EXPERT OPINION: Encouraging progress has been made in our understanding of molecular pathways. We find passive immunization approaches against α-synuclein, LRRK2 kinase inhibitors, and treatment that can increase GCase activity, which have shown some efficacy on both GBA-mutated and non-mutated PD patients. The recognition of non-dopaminergic impairment and the prominent role of non-motor symptoms have prompted the development of trials on compounds that could tackle different neurotransmitter systems. Future approaches will encompass more personalized medicine strategies based on molecular signatures and non-motor phenotypes.

Differential effects of deep brain stimulation and levodopa on brain activity in Parkinson's disease.

Levodopa is the first-line treatment for Parkinson's disease, although the precise mechanisms mediating its efficacy remain elusive. We aimed to elucidate treatment effects of levodopa on brain activity during the execution of fine movements and to compare them with deep brain stimulation of the subthalamic nuclei. We studied 32 patients with Parkinson's disease using functional MRI during the execution of finger-tapping task, alternating epochs of movement and rest. The task was performed after withdrawal and administration of a single levodopa dose. A subgroup of patients (n = 18) repeated the experiment after electrode implantation with stimulator on and off. Investigating levodopa treatment, we found a significant interaction between both factors of treatment state (off, on) and experimental task (finger tapping, rest) in bilateral putamen, but not in other motor regions. Specifically, during the off state of levodopa medication, activity in the putamen at rest was higher than during tapping. This represents an aberrant activity pattern probably indicating the derangement of basal ganglia network activity due to the lack of dopaminergic input. Levodopa medication reverted this pattern, so that putaminal activity during finger tapping was higher than during rest, as previously described in healthy controls. Within-group comparison with deep brain stimulation underlines the specificity of our findings with levodopa treatment. Indeed, a significant interaction was observed between treatment approach (levodopa, deep brain stimulation) and treatment state (off, on) in bilateral putamen. Our functional MRI study compared for the first time the differential effects of levodopa treatment and deep brain stimulation on brain motor activity. We showed modulatory effects of levodopa on brain activity of the putamen during finger movement execution, which were not observed with deep brain stimulation.

Incentive-driven decision-making networks in de novo and drug-treated Parkinson's disease patients with impulsive-compulsive behaviors: A systematic review of neuroimaging studies.

BACKGROUND: In Parkinson's disease (PD), impulsive-compulsive behaviors (ICBs) may develop as side-effect of dopaminergic medications. Abnormal incentive-driven decision-making, which is supported by the cognitive control and motivation interaction, may represent an ICBs signature. This systematic review explored whether structural and/or functional brain differences between PD patients with vs without ICBs encompass incentive-driven decision-making networks. METHODS: Structural and functional neuroimaging studies comparing PD patients with and without ICBs, either de novo or medicated, were included. RESULTS: Thirty articles were identified. No consistent evidence of structural alteration both in de novo and medicated PD patients were found. Differences in connectivity within the default mode, the salience and the central executive networks predate ICBs development and remain stable once ICBs are fully developed. Medicated PD patients with ICBs show increased metabolism and cerebral blood flow in orbitofrontal and cingulate cortices, ventral striatum, amygdala, insula, temporal and supramarginal gyri. Abnormal ventral striatum connectivity with anterior cingulate cortex and limbic structures was reported in PD patients with ICBs. DISCUSSION: Functional brain signatures of ICBs in PD encompass areas involved in cognitive control and motivational encoding networks of the incentive-driven decision-making. Functional alterations predating ICBs may be related to abnormal synaptic plasticity in these networks.

Earlier Dopaminergic Treatment in Parkinson's Disease Is Not Associated With Improved Outcomes.

BACKGROUND: The appropriate timing of dopaminergic treatment initiation in Parkinson's disease (PD) remains a matter of debate. The primary objective of this study was to determine whether earlier initiation of treatment was associated with less worsening of total UPDRS scores over 48 months. METHODS: We performed a secondary analysis of data from the CALM-PD (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease) trial to examine the associations between years since diagnosis and 48-month changes in total and component UPDRS scores, Parkinson's Disease Quality of Life Scale (PDQUALIF) score, and the EuroQol-5D visual analogue scale (VAS) score. RESULTS: There were no associations between years since PD diagnosis and 48-month changes in total UPDRS, component UPDRS scores, PDQUALIF score, or EuroQol-5D VAS score. CONCLUSION: Earlier treatment was not associated with improved long-term outcomes in this secondary analysis. Prospective studies are required to determine the appropriate timing of initiation of dopaminergic treatment to inform clinical practice.

Clinical-Pharmacogenetic Predictive Models for Time to Occurrence of Levodopa Related Motor Complications in Parkinson's Disease.

The response to dopaminergic treatment in Parkinson's disease depends on many clinical and genetic factors. The very common motor fluctuations (MF) and dyskinesia affect approximately half of patients after 5 years of treatment with levodopa. We did an evaluation of a combined effect of 16 clinical parameters and 34 single nucleotide polymorphisms to build clinical and clinical-pharmacogenetic models for prediction of time to occurrence of motor complications and to compare their predictive abilities. In total, 220 Parkinson's disease patients were included in the analysis. Their demographic, clinical, and genotype data were obtained. The combined effect of clinical and genetic factors was assessed using The Least Absolute Shrinkage and Selection Operator penalized regression in the Cox proportional hazards model. Clinical and clinical-pharmacogenetic models were constructed. The predictive capacity of the models was evaluated with the cross-validated area under time-dependent receiver operating characteristic curve. Clinical-pharmacogenetic model included age at diagnosis (HR = 0.99), time from diagnosis to initiation of levodopa treatment (HR = 1.24), COMT rs165815 (HR = 0.90), DRD3 rs6280 (HR = 1.03), and BIRC5 rs9904341 (HR = 0.95) as predictive factors for time to occurrence of MF. Furthermore, clinical-pharmacogenetic model for prediction of time to occurrence of dyskinesia included female sex (HR = 1.07), age at diagnosis (HR = 0.97), tremor-predominant Parkinson's disease (HR = 0.88), beta-blockers (HR = 0.95), alcohol consumption (HR = 0.99), time from diagnosis to initiation of levodopa treatment (HR = 1.15), CAT rs1001179 (HR = 1.27), SOD2 rs4880 (HR = 0.95), NOS1 rs2293054 (HR = 0.99), COMT rs165815 (HR = 0.92), and SLC22A1 rs628031 (HR = 0.80). Areas under the curves for clinical and clinical-pharmacogenetic models for MF after 5 years of levodopa treatment were 0.68 and 0.70, respectively. Areas under the curves for clinical and clinical-pharmacogenetic models for dyskinesia after 5 years of levodopa treatment were 0.71 and 0.68, respectively. These results show that clinical-pharmacogenetic models do not have better ability to predict time to occurrence of motor complications in comparison to the clinical ones despite the significance of several polymorphisms. Models could be improved by a larger sample size and by additional polymorphisms, epigenetic predictors or serum biomarkers.

D3 receptor agonist efficacy in restless legs syndrome.

Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a sleep related movement disorder characterized by an irresistible urge to move the limbs frequently associated with uncomfortable sensations that usually begin or worsen during inactivity and may be relieved by movement. The pathophysiology of the disorder involves several biological system; in particular, dopaminergic pathway and iron physiology have been extensively studied. Being a chronic condition, long-term treatments are required for an adequate management and strong evidence support the employment of dopamine agonists. D3 receptor agonists are of particular interest, because they act on receptors that are widely expressed in the spinal cord with an inhibitory action on sensory system. Pramipexole, rotigotine and ropinirole act on D3 receptors, even if not selectively, and are effective in reducing sensorimotor symptoms and improving sleep quality. However, despite an initial amelioration patients frequently experience augmentation, i.e., a worsening of symptoms induced by dopamine agonists. This can be explained by the activity of D1 receptor and by the non-selectiveness of D3 agonist drugs. Higher dopamine concentrations tend to activate the excitatory D1-like receptor that are associated with increased motor activity. The development of drugs that selectively target D3 receptors will be fundamental to provide alternative therapeutic strategies and to reduce the occurrence of augmentation.

Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist.

The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated - apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension - with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson's disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson's disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies.

The Outcome of Dopamine Dysregulation Syndrome in Parkinson's Disease: A Retrospective Postmortem Study.

INTRODUCTION: We have performed a retrospective analysis of the frequency and relation to treatment of dopamine dysregulation syndrome (DDS) using the Queen Square Brain Bank (QSBB) database. METHODS: A search of the QSBB database for consecutive cases donated between 2005 and 2016 with a pathological diagnosis of Parkinson's disease was performed. RESULTS: DDS was present in 8.8% of cases, was more prevalent in males, and was associated with younger age of onset, longer disease duration, and more dopa-induced dyskinesias. Treatment approaches for DDS included: reduction of levodopa, reduction/cessation of dopamine agonist (DA), and initiation of infusion therapies. DDS had completely resolved in just over half the patients. DA peak l-dopa equivalent daily dose (LEDD) was higher in patients who failed to achieve remission. CONCLUSION: This is the first study to provide data on the course of DDS until death. Treatment strategies consisted mainly of reduction of dopaminergic treatment, and, despite the majority of patients showing some improvement, half remained symptomatic. Successful treatment was associated with a lower l-dopa dosage at death.

Cardiovascular Autonomic Dysfunction in Mild and Advanced Parkinson's Disease.

OBJECTIVE: The purpose of the present study was to investigate cardiovascular autonomic dysfunction in patients with Parkinson's disease (PD) with mild to severe stages of motor symptoms and to compare cardiovascular autonomic dysfunction between drug-naïve and dopaminergic drug-treated groups. METHODS: This study included 188 PD patients and 25 age-matched healthy controls who underwent head-up tilt-testing, 24-h ambulatory blood pressure (BP) monitoring and 24-h Holter monitoring. Autonomic function test results were evaluated among groups categorized by motor symptom severities (mild vs. moderate vs. severe) and treatment (drug-naïve or dopaminergic drug treatment). RESULTS: Orthostatic hypotension and supine hypertension were more frequent in patients with PD than in healthy controls. The frequencies of orthostatic hypotension, supine hypertension, nocturnal hypertension and non-dipping were not different among groups. Additionally, no significant differences were detected in supine BP, orthostatic BP change, nighttime BP, nocturnal BP dipping, or heart rate variabilities among groups. CONCLUSIONS: Cardiovascular autonomic dysfunction is not confined to moderate to severe PD patients, and starts early in the course of the disease in a high proportion of PD patients. In addition, dopaminergic drug treatments do not affect cardiovascular autonomic function.

Can dopamine agonists trigger tactile hallucinations in patients with Parkinson's disease?

Various hallucinations are unpleasant for patients with Parkinson's disease (PD). Hallucinations are often related to anti-parkinsonian drugs. Tactile hallucinations rarely occur in patients with PD. In contrast to other types of hallucinations, tactile hallucinations often make physicians wonder if a physical abnormality is the underlying cause. However, the relation of tactile hallucinations to anti-parkinsonian drugs remains uncertain because studies are scant. We describe three patients with PD who had tactile hallucinations that were triggered by dopamine agonists. In our patients, tactile hallucinations occurred in a clear sensorium and persisted for a prolonged time. Two patients had clear visual hallucinations such as of insects, which were associated with tactile hallucinations such as of insects tied to the body. Clear tactile sensoria were unpleasant. Dopamine agonists were initiated or the doses were increased during several periods immediately before the onset of tactile hallucinations. Although the other anti-parkinsonian drugs used, such as amantadine, zonisamide, or trihexyphenidyl, were likely to be partly responsible for the tactile hallucinations, our observations suggest that an increase in the dose of dopamine agonists can trigger tactile hallucinations.

Maladaptive plasticity in levodopa-induced dyskinesias and tardive dyskinesias: old and new insights on the effects of dopamine receptor pharmacology.

Maladaptive plasticity can be defined as behavioral loss or even development of disease symptoms resulting from aberrant plasticity changes in the human brain. Hyperkinetic movement disorders, in the neurological or psychiatric realms, have been associated with maladaptive neural plasticity that can be expressed by functional changes such as an increase in transmitter release, receptor regulation, and synaptic plasticity or anatomical modifications such as axonal regeneration, sprouting, synaptogenesis, and neurogenesis. Recent evidence from human and animal models provided support to the hypothesis that these phenomena likely depend on altered dopamine turnover induced by long-term drug treatment. However, it is still unclear how and where these altered mechanisms of cortical plasticity may be localized. This study provides an up-to-date overview of these issues together with some reflections on future studies in the field, particularly focusing on two specific disorders (levodopa-induced dyskinesias in Parkinson's disease patients and tardive dyskinesias in schizophrenic patients) where the modern neuroimaging approaches have recently provided new fundamental insights.

New pharmacological options for treating advanced Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait [FoG]) and non-motor symptoms (including psychiatric and cognitive disorders). Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission and thus improving motor symptoms. However, the currently licensed medications have several major limitations. Firstly, dopaminergic medications modulate all the key steps in dopamine transmission other than the most powerful determinant of extracellular dopamine levels: the activity of the presynaptic dopamine transporter. Secondly, other monoaminergic neurotransmission systems (ie noradrenergic, cholinergic and glutamatergic systems are altered in PD and may be involved in a variety of motor and non-motor symptoms. Thirdly, today's randomized clinical trials are primarily designed to assess the efficacy and safety of treatments for motor fluctuations and dyskinesia. Fourthly, there is a need for disease- modifying treatments (DMTs) that slow disease progression and reduce the occurrence of the very disabling disorders seen in late-stage PD. OBJECTIVE: To systematically review a number of putative pharmacological options for treating the main impairments in late-stage PD (ie gait disorders, cognitive disorders and behavioural disorders such as apathy). METHODS: We searched the PubMed database up until July 2013 with logical combinations of the following search terms: "Parkinson's disease", "gait", "cognition", "apathy", "advanced stage", "modulation", "noradrenergic", "cholinergic", "glutamatergic" and "neurotransmission". RESULTS: In patients undergoing subthalamic nucleus stimulation, the potentiation of noradrenergic and dopaminergic transmission by methylphenidate improves gait and FoG and may relieve apathy. However, the drug failed to improve cognition in this population. Potentiation of the cholinergic system by acetylcholinesterase inhibitors (which are licensed for use in dementia) may reduce pre-dementia apathy and falls. Modulation of the glutamatergic system by an N-methyl-D-aspartate receptor antagonist did not improve gait and dementia but may have reduced axial rigidity. A number of putative DMTs have been reported. DISCUSSION: Novel therapeutic strategies should seek to reduce the appearance of the very disabling disorders observed in late-stage PD. Dopamine and/or noradrenaline transporter inhibitors, anticholinesterase inhibitors, Peroxisome-proliferator-activated-receptor-agonists and iron chelators should at least be investigated as putative DMTs by applying a delayed-start clinical trial paradigm to a large population CONCLUSIONS: There is a need for more randomized clinical trials of treatments for late-stage PD.

Can 4-aminopyridine modulate dysfunctional gait networks in Parkinson's disease?

Gait dysfunction and postural instability represent a major therapeutic challenge in Parkinson's disease (PD). Gait disability in PD has been historically attributed to striato-nigral degeneration, however there is emerging evidence that multiple neurotransmitter deficits contribute to mobility impairment in PD. 4-aminopyridine (4-AP), a potent neurotransmitter modulator, has a wide range of favorable effects on gait in patients with neurological conditions including multiple sclerosis, spinal cord injury and cerebellar ataxia. In this Review we identify the neurobiological pathways involved in gait dysfunction in PD and discuss the mechanisms of action of 4-AP and its effect on gait related neuronal networks. The proposed mechanisms that may facilitate 4-AP favorable effect on gait in Parkinson's disease include 1) neurotransmitter release (dopamine, glutamate, acetylcholine and noradrenaline) 2) modulation of neuronal network oscillations and 3) increased cortical excitation. Recent clinical trials of 4-AP in neurological conditions associated with gait disorders will be highlighted and the importance of studying non-dopaminergic medications such as 4-AP in PD patients with gait impairment will be emphasized.