Executive function and freezing in Parkinson's

Dopaminergic neuron degeneration is known to give rise to dendrite injury and spine loss of striatal neurons, however, changes of intrastriatal glutamatergic terminals and their synapses after 6-hydroxydopamine (6OHDA)-induced dopamine (DA)-depletion remains controversial. To confirm the effect of striatal DA-depletion on the morphology and protein levels of corticostriatal and thalamostriatal glutamatergic terminals and synapses, immunohistochemistry, immuno-electron microscope (EM), western blotting techniques were performed on Parkinson's disease rat models in this study...

OBJECTIVE: Associations between cognition and nigrostriatal dopaminergic deficits in Parkinson's disease have been documented in the literature, but are incompletely understood. Here we studied the extent to which physical activity mediates the relationship between striatal dopamine transporter availability and global cognition among patients with Parkinson's disease. METHODS: Data from 174 patients from a multi-center study were analyzed using regression-based mediation analysis...

Impulsive-compulsive behaviours like pathological gambling or hypersexuality are a frequent side effect of dopamine replacement therapy in patients with Parkinson's disease. Multiple imaging studies suggest a significant reduction of presynaptic dopamine transporters in the nucleus accumbens to be a predisposing factor, reflecting either a reduction of mesolimbic projections or, alternatively, a lower presynaptic dopamine transporter expression per se. Here, we aimed to test the hypothesis of fewer mesolimbic projections as a risk factor by using dopamine synthesis capacity as a proxy of dopaminergic terminal density...

BACKGROUND: Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID). OBJECTIVE: This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. METHODS: The pharmacokinetic profile and effects of pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID...

The pedunculopontine nucleus (PPN) shows altered electrophysiological and anatomic characteristics in Parkinson's disease (PD), but little is known about the effect of 6-hydroxydopamine (6-OHDA) lesion and levodopa (L -DOPA) therapy on the relationship between spike and local field potential (LFP) activities in the PPN and motor cortex. Aiming to investigate this, synchronous spike and LFP signals in the PPN and primary motor cortex (M1) were recorded. The spike-LFP relationship was evaluated using coherence analysis, phase-lock and spike-field coherence (SFC)...

Levodopa-induced dyskinesias (LID) negatively impact on the quality of life of patients with Parkinson's disease (PD). We assessed the risk factors for LID in a cohort of de-novo PD patients enrolled in the Parkinson's Progression Markers Initiative (PPMI). This retrospective cohort study included all PD patients enrolled in the PPMI cohort. Main outcome was the incidence rate of dyskinesia, defined as the first time the patient reported a non-zero score in the item "Time spent with dyskinesia" of the MDS-UPDRS part IV...

Levodopa-induced dyskinesia (LID) is the main side effect associated with levodopa treatment and represents the biggest challenge for Parkinson's disease therapy. While the overexpression of ΔFosB transcription factor is related to the development of LID, few studies have been undertaken on fosB gene transcriptional regulation induced by levodopa in vivo. The aim of this study is to evaluate the expression of ΔFosB mRNA and FosB mRNA in the striatum after acute, chronic, and subchronic levodopa treatment in rats with unilateral 6-OHDA-lesion in the medial forebrain bundle...

The subthalamic nucleus (STN) possesses microcircuits distinguished by subtypes of nicotinic acetylcholine receptors (nAChRs). Although dysfunction of the STN is well-known in Parkinson's disease, there is still little information about whether dopamine differentially modulates excitatory and inhibitory synaptic inputs to STN neurons expressing different nAChR subtypes. To address this issue, we performed brain slice patch-clamp recordings on STN neurons, while we pharmacologically manipulated dopaminergic inputs...

Neurodegeneration of the nigrostriatal dopaminergic system and concurrent dopamine (DA) deficiency in the basal ganglia represent core features of Parkinson's disease (PD). Despite the central role of DA in the pathogenesis of PD, dopaminergic systems outside of the midbrain have not been systematically investigated for Lewy body pathology or neurodegeneration. Dopaminergic neurons show a surprisingly rich neurobiological diversity, suggesting that there is not one general type of dopaminergic neuron, but rather a spectrum of different dopaminergic phenotypes...

OBJECTIVE: To determine the time course of hazard for motor and nonmotor milestones of Parkinson disease (PD) in the long term and to investigate whether risk scales nonlinearly with time is instrumental in identifying changes in pathological processes and evaluating disease-modifying therapies in PD. METHODS: Outpatients with PD at the Lyon University Movement Disorders Center were evaluated for 7 clinical milestones in this retrospective cohort study, encompassing 4 domains of PD progression: (1) motor (motor fluctuations, dyskinesias); (2) axial (postural instability and falls, freezing of gait); (3) neuropsychiatric (impulse control disorders, hallucinations); and (4) cognitive (dementia) complications...

BACKGROUND: Parkinson's disease (PD) is frequently associated with behavioral disorders, particularly within the spectrum of motivated behaviors such as apathy or impulsivity. Both pharmacological and neurosurgical treatments have an impact on these impairments. However, there still is controversy as to whether subthalamic nucleus deep brain stimulation (STN-DBS) can cause or reduce impulsive behaviors. OBJECTIVES: We aimed to identify the influence of functional surgery on decision-making processes in PD...

BACKGROUND: The etiology of freezing of gait in Parkinson's disease (PD) is yet to be clarified. Non-motor risk factors including cognitive impairment, sleep disturbance and mood disorders have been shown in freezing of gait. RESEARCH QUESTION: We aimed to determine the predictive value of non-motor features in freezing of gait development. METHODS: Data were obtained from the Parkinson's Progression Markers Initiative. Fifty PD patients with self-reported freezing of gait, and 50 PD patients without freezing of gait at the fourth year visit were included...

INTRODUCTION: It remains to be clarified whether penetration of the caudate nucleus increases the risk of cognitive decline in patients with Parkinson's disease (PD) undergoing deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: A retrospective analysis of pre/postoperative neuropsychological changes was performed with 46 consecutive patients with PD who underwent DBS of the STN. In particular, to evaluate the possible relationship between cognitive changes and DBS lead trajectories, repeated-measures ANCOVAs were conducted to analyze the effects of group (23 patients with vs 23 patients without penetration of the caudate nucleus) and time (T0 vs T1) for each neuropsychological test...

Methylphenidate (MPD) is a psychostimulant used for the treatment of ADHD and works by increasing the bioavailability of dopamine (DA) in the brain. As a major source of DA, the ventral tegmental area (VTA) served as the principal target in this study as we aimed to understand its role in modulating the acute and chronic MPD effect. Forty-eight male Sprague-Dawley rats were divided into control, sham, electrical lesion, and 6-OHDA lesion groups. Given the VTA's implication in the locomotive circuit, three locomotor indices-horizontal activity, number of stereotypy, and total distance-were used to measure the animals' behavioral response to the drug...

OBJECTIVE: To determine whether CSF biomarkers can be used as a predictor of freezing of gait (FOG) in Parkinson disease (PD) and to investigate the predictive value of clinical, dopamine transporter (DAT) imaging, and CSF parameters both separately and in combination. METHODS: This study using the PPMI data included 393 patients with newly diagnosed PD without FOG at baseline. We evaluated CSF for β-amyloid 1-42 (Aβ42 ), α-synuclein, total tau, phosphorylated tau181 , and the calculated ratio of Aβ42 to total tau at baseline...

This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson's disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH)...

BACKGROUND: Cognitive deficits in Parkinson's disease (PD) may result from damage in the cortex as well as in the dopaminergic, noradrenergic, and cholinergic inputs to the cortex. Cholinergic inputs to the cortex mainly originate from the basal forebrain and are clustered in several regions, called Ch1 to Ch4, that project to the hippocampus (Ch1-2), the olfactory bulb (Ch3), and the cortex and amygdala (Ch4). OBJECTIVE: We investigated changes in basal forebrain and their role in cognitive deficits in PD...

IRL790 is a novel compound with psychomotor stabilizing properties primarily targeting the dopamine D3 receptor. IRL790 is developed as an experimental treatment for levodopa-induced dyskinesia (LID), impulse control disorder, and psychosis in Parkinson's disease (PD). The primary objective was to investigate the safety and tolerability of IRL790 in PD patients with LID in a randomized controlled trial. PD patients with peak-dose dyskinesia were randomized to placebo or IRL790 treatment (1:3 ratio) for 4 weeks...

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...

Patients with Parkinson's disease may develop impulse control disorders under dopaminergic treatments. Impulse control disorders include a wide spectrum of behaviours, such as hypersexuality, pathological gambling or compulsive shopping. Yet, the neural systems engaged in specific impulse control disorders remain poorly characterized. Here, using model-based functional MRI, we aimed to determine the brain systems involved during delay-discounting of erotic rewards in hypersexual patients with Parkinson's disease (PD+HS), patients with Parkinson's disease without hypersexuality (PD - HS) and controls...