Parkinsonian Motor Impairment Research Articles

Large-scale functional network connectivity mediates the association between nigral neuromelanin hypopigmentation and motor impairment in Parkinson's disease.

Neuromelanin hypopigmentation within substantia nigra pars compacta (SNc) reflects the loss of pigmented neurons, which in turn contributes to the dysfunction of the nigrostriatal and striato-cortical pathways in Parkinson's disease (PD). Our study aims to investigate the relationships between SN degeneration manifested by neuromelanin reduction, functional connectivity (FC) among large-scale brain networks, and motor impairment in PD. This study included 68 idiopathic PD patients and 32 age-, sex- and education level-matched healthy controls who underwent neuromelanin-sensitive magnetic resonance imaging (MRI), functional MRI, and motor assessments. SN integrity was measured using the subregional contrast-to-noise ratio calculated from neuromelanin-sensitive MRI. Resting-state FC maps were obtained based on the independent component analysis. Subsequently, we performed partial correlation and mediation analyses in SN degeneration, network disruption, and motor impairment for PD patients. We found significantly decreased neuromelanin within SN and widely altered inter-network FCs, mainly involved in the basal ganglia (BG), sensorimotor and frontoparietal networks in PD. In addition, decreased neuromelanin content was negatively correlated with the dorsal sensorimotor network (dSMN)-medial visual network connection (P = 0.012) and dSMN-BG connection (P = 0.004). Importantly, the effect of SN neuromelanin hypopigmentation on motor symptom severity in PD is partially mediated by the increased connectivity strength between BG and dSMN (indirect effect = - 1.358, 95% CI: - 2.997, - 0.147). Our results advanced our understanding of the interactions between neuromelanin hypopigmentation in SN and altered FCs of functional networks in PD and suggested the potential of multimodal metrics for early diagnosis and monitoring the response to therapies.

GABAA Receptor Benzodiazepine Binding Sites and Motor Impairments in Parkinson's Disease.

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABAAR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson's disease (PD). Little is known about how regional GABAAR availability affects motor symptoms. We investigated the relationship between regional availability of GABAAR benzodiazepine binding sites and motor impairments in PD. Methods: A total of 11 Patients with PD (males; mean age 69.0 ± 4.6 years; Hoehn and Yahr stages 2-3) underwent [11C]flumazenil GABAAR benzodiazepine binding site and [11C]dihydrotetrabenazine vesicular monoamine transporter type-2 (VMAT2) PET imaging and clinical assessment. Stepwise regression analysis was used to predict regional cerebral correlates of the four cardinal UPDRS motor scores using cortical, striatal, thalamic, and cerebellar flumazenil binding estimates. Thalamic GABAAR availability was selectively associated with axial motor scores (R2 = 0.55, F = 11.0, β = -6.4, p = 0.0009). Multi-ligand analysis demonstrated significant axial motor predictor effects by both thalamic GABAAR availability (R2 = 0.47, β = -5.2, F = 7.2, p = 0.028) and striatal VMAT2 binding (R2 = 0.30, β = -3.9, F = 9.1, p = 0.019; total model: R2 = 0.77, F = 11.9, p = 0.0056). Post hoc analysis demonstrated that thalamic [11C]methyl-4-piperidinyl propionate cholinesterase PET and K1 flow delivery findings were not significant confounders. Findings suggest that reduced thalamic GABAAR availability correlates with worsened axial motor impairments in PD, independent of nigrostriatal degeneration. These findings may augur novel non-dopaminergic approaches to treating axial motor impairments in PD.

Cholinergic centro-cingulate network in Parkinson disease and normal aging.

Decreased cholinergic binding within the recently identified centro-cingulate brain network robustly has been shown to robustly correlate with the severity of cognitive impairment in Parkinson disease (PD). This network with key hubs within the cingulum, operculum and peri-central cortical regions also correlates with elements of parkinsonian motor impairments, including postural instability and gait difficulties, such as falls or freezing. MRI neuroimaging studies have shown that the anterior midcingulate cortex is a key node for cognitive aspects of movement generation, i.e., intentional motor control. Recent evidence also suggests a novel aspect of organization of primary motor cortex, describing "effector" regions for fine movement control intercalated with interlinked "inter-effector" regions devoted to whole-body control. A distinguishing feature of inter-effector regions is tight linkage to the cingular and opercular regions. Such inter-effector regions have been proposed to be part of a greater somato-cognitive action network necessary for integration of goals and movement. Recent evidence also points to vulnerabilities of cholinergic nerve terminals in the centro-cingulate network in older non-PD adults. These features of normal aging underscore that cortical cholinergic terminal losses in age-associated neurodegenerative disorders are likely not exclusively the result of disease-specific etiologies but also related to otherwise normal aging. Practical implications of this overlap are that addressing disease-specific and general aging etiologies involved in neurodegeneration, may be of benefit in age-associated neurodegenerative disorders where significant cholinergic systems degeneration is present.

Retinal Changes in Parkinson's Disease: A Non-invasive Biomarker for Early Diagnosis.

Parkinson's disease (PD) is caused due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to the depletion of dopamine in the body. The lack of dopamine is mainly due to aggregation of misfolded α-synuclein which causes motor impairment in PD. Dopamine is also required for normal retinal function and the light-dark vision cycle. Misfolded α-synuclein present in inner retinal layers causes vision-associated problems in PD patients. Hence, individuals with PD also experience structural and functional changes in the retina. Mutation in LRRK2, PARK2, PARK7, PINK1, or SNCA genes and mitochondria dysfunction also play a role in the pathophysiology of PD. In this review, we discussed the different etiologies which lead to PD and future prospects of employing non-invasive techniques and retinal changes to diagnose the onset of PD earlier.

Molecular Targets Underlying the Neuroprotective Effects of Boswellic Acid: A Systematic Review.

Neurodegenerative procedures include a large spectrum of disorders with diverse pathological features and clinical manifestations, such as Alzheimer's Disease (AD), Parkinson's disease (PD), Multiple sclerosis, and Amyotrophic lateral sclerosis (ALS). Neurodegenerative diseases (NDs) are indicated by progressive loss of neurons and cognitive function, which is associated with free radical formation, extra and intercellular accumulation of misfolded proteins, oxidative stress, mitochondrial and neurotrophins dysfunction, bioenergetic impairment, inflammation, and apoptotic cell death. Boswellic acid is a pentacyclic triterpene molecule of plant origin that has been applied for treating several inflammatory disorders. Numerous studies have also investigated its' therapeutic potential against multiple NDs. In this article, we aim to review the neuroprotective effects of boswellic acid on NDs and the related mechanisms of action. The databases of PubMed, Google Scholar, Web of Sciences, and Scopus were searched to find studies that reported the effects of boswellic acid on NDs without time limits. Review articles, letters, editorials, unpublished data, and articles not published in the English language were not included in the study. Overall, 17 studies were included in the present study (8 NDs in general, 5 AD, 3 PD, and 1 ALS). According to the reports, boswellic acid exerts anti-inflammatory, antioxidant, antiapoptotic, and neuromodulatory effects against NDs. Boswellic acid decreases Tau phosphorylation and amyloid-β (Aβ) generation in AD. This substance also protects nigrostriatal dopaminergic neurons and improves motor impairments in PD and modulates neurotransmitters, decreases the demyelination region, and improves behavioral functions in ALS. Due to the significant effects of boswellic acid in NDs, more clinical studies are necessary to evaluate the pharmacokinetics of this substance because it seems that boswellic acid can be used as a complementary or alternative treatment in patients with NDs.

Bradykinesia and rigidity modulated by functional connectivity between the primary motor cortex and globus pallidus in Parkinson's disease.

The mechanisms underlying motor fluctuations in patients with Parkinson's disease (PD) are currently unclear. Regional brain stimulation reported the changing of motor symptoms, but the correlation with functional connectivity (FC) in the brain network is not fully understood. Hence, our study aimed to explore the relationship between motor symptom severity and FC using resting-state functional magnetic resonance imaging (rsfMRI) in the "on" and "off" states of PD. In 26 patients with sporadic PD, FC was assessed using rsfMRI, and clinical severity was analyzed using the motor part of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS Part III) in the on and off states. Correlations between FC values and MDS-UPDRS Part III scores were assessed using Pearson's correlation coefficient. The correlation between FC and motor symptoms differed in the on and off states. FC between the ipsilateral precentral gyrus (PreCG) and globus pallidus (GP) correlated with the total MDS-UPDRS Part III scores and those for bradykinesia/rigidity in the off state. Lateralization analysis indicated that FC between the PreCG and GP correlated with the contralateral total MDS-UPDRS Part III scores and those for bradykinesia/rigidity in the off state. Aberrant FC in cortico-striatal circuits correlated with the severity of motor symptoms in PD. Cortico-striatal hyperconnectivity, particularly in motor pathways involving PreCG and GP, is related to motor impairments in PD. These findings may facilitate our understanding of the mechanisms underlying motor symptoms in PD and aid in developing treatment strategies such as brain stimulation for motor impairment.

How can I assess my patients with Parkinson's disease during a busy clinic day?

BackgroundThe evaluation of motor impairment in Parkinson's disease (PD) is mainly assessed with the motor subdomain of the Unified Parkinson's Disease Rating scale (UPDRS part III) and, lately, with the MDS-UPDRS part III. To optimize efforts and special needs during specific circumstances in clinical practice, we sought to identify the most sensitive items to assess motor impairment in PD. MethodsWe included the COPPADIS-PD cohort and collected the UPDRS part III at baseline (V0), 12 months (V1), and 24 months (V2). Factor analysis and effect size using Cohen's d formula were performed in the Off and On states at V0, V1, and V2. ResultsWe included 667 patients with PD, mean age of 62.59 ± 8.91 years, 410 (60.2%) males, with a median HY stage of 2.00 (1.00; 4.00) at baseline. Over time, the most discriminating items were postural stability and body bradykinesia (“arise from chair” and “gait”) in the Off state, right and left upper extremity bradykinesia ("finger tap", "hand movements" and "prono/supination") in the On state. Body bradykinesia and right-left finger tapping were the items with the largest effect size (0.93, 0.84, 0.83, respectively) to assess motor improvement after receiving antiparkinsonian medications over time. ConclusionUnder specific circumstances, selecting a few items of the UPDRS part III, including postural stability, body bradykinesia, and upper extremity bradykinesia, could be used to create a quick clinical judgment of motor status and improvement in PD.

An Apple a Day to Keep the Parkinson's Disease Doctor Away?

It is challenging to reliably assess the motor features of Parkinson's disease in real-time. This has motivated the search for new digital outcomes that can objectively and remotely measure the severity of parkinsonian motor impairments over an extended period of time. The United States Food and Drug Administration (FDA) has recently granted a 510(k) clearance to the Rune Labs Kinematics System, an ambulatory, smartwatch-based monitoring system to remotely track tremor and dyskinesias in persons with Parkinson's disease. The FDA clearance means that this new digital approach can be regarded as being safe for use in daily practice, with acceptable correlations to clinically based measures. However, the immediate implications for clinicians are limited, because it remains to be demonstrated whether the digital signals correlate well to clinically meaningful outcomes at patient level. The impact on research is also restricted for now, as more validation studies are needed before this new digital approach can be used as primary or secondary endpoint in clinical trials. ANN NEUROL 2023;93:681-685.

Whole-Head Functional Near-Infrared Spectroscopy as an Ecological Monitoring Tool for Assessing Cortical Activity in Parkinson's Disease Patients at Different Stages.

Functional near-infrared spectroscopy (fNIRS) is increasingly employed as an ecological neuroimaging technique in assessing age-related chronic neurological disorders, such as Parkinson's disease (PD), mainly providing a cross-sectional characterization of clinical phenotypes in ecological settings. Current fNIRS studies in PD have investigated the effects of motor and non-motor impairment on cortical activity during gait and postural stability tasks, but no study has employed fNIRS as an ecological neuroimaging tool to assess PD at different stages. Therefore, in this work, we sought to investigate the cortical activity of PD patients during a motor grasping task and its relationship with both the staging of the pathology and its clinical variables. This study considered 39 PD patients (age 69.0 ± 7.64, 38 right-handed), subdivided into two groups at different stages by the Hoehn and Yahr (HY) scale: early PD (ePD; N = 13, HY = [1; 1.5]) and moderate PD (mPD; N = 26, HY = [2; 2.5; 3]). We employed a whole-head fNIRS system with 102 measurement channels to monitor brain activity. Group-level activation maps and region of interest (ROI) analysis were computed for ePD, mPD, and ePD vs. mPD contrasts. A ROI-based correlation analysis was also performed with respect to contrasted subject-level fNIRS data, focusing on age, a Cognitive Reserve Index questionnaire (CRIQ), disease duration, the Unified Parkinson's Disease Rating Scale (UPDRS), and performances in the Stroop Color and Word (SCW) test. We observed group differences in age, disease duration, and the UPDRS, while no significant differences were found for CRIQ or SCW scores. Group-level activation maps revealed that the ePD group presented higher activation in motor and occipital areas than the mPD group, while the inverse trend was found in frontal areas. Significant correlations with CRIQ, disease duration, the UPDRS, and the SCW were mostly found in non-motor areas. The results are in line with current fNIRS and functional and anatomical MRI scientific literature suggesting that non-motor areas-primarily the prefrontal cortex area-provide a compensation mechanism for PD motor impairment. fNIRS may serve as a viable support for the longitudinal assessment of therapeutic and rehabilitation procedures, and define new prodromal, low-cost, and ecological biomarkers of disease progression.

Preserved Motility after Neonatal Dopaminergic Lesion Relates to Hyperexcitability of Direct Pathway Medium Spiny Neurons.

In Parkinson's disease patients and rodent models, dopaminergic neuron loss (DAN) results in severe motor disabilities. In contrast, general motility is preserved after early postnatal DAN loss in rodents. Here we used mice of both sexes to show that the preserved motility observed after early DAN loss depends on functional changes taking place in medium spiny neurons (MSN) of the dorsomedial striatum (DMS) that belong to the direct pathway (dMSN). Previous animal model studies showed that adult loss of dopaminergic input depresses dMSN response to cortical input, which likely contributes to Parkinson's disease motor impairments. However, the response of DMS-dMSN to their preferred medial PFC input is preserved after neonatal DAN loss as shown by in vivo studies. Moreover, their response to inputs from adjacent cortical areas is increased, resulting in reduced cortical inputs selectivity. Additional ex vivo studies show that membrane excitability increases in dMSN. Furthermore, chemogenetic inhibition of DMS-dMSN has a more marked inhibitory effect on general motility in lesioned mice than in their control littermates, indicating that expression of normal levels of locomotion and general motility depend on dMSN activity after early DAN loss. Contrastingly, DMS-dMSN inhibition did not ameliorate a characteristic phenotype of the DAN-lesioned animals in a marble burying task demanding higher behavioral control. Thus, increased dMSN excitability likely promoting changes in corticostriatal functional connectivity may contribute to the distinctive behavioral phenotype emerging after developmental DAN loss, with implications for our understanding of the age-dependent effects of forebrain dopamine depletion and neurodevelopment disorders.SIGNIFICANCE STATEMENT The loss of striatal dopamine in the adult brain leads to life-threatening motor impairments. However, general motility remains largely unaffected after its early postnatal loss. Here, we show that the high responsiveness to cortical input of striatal neurons belonging to the direct basal ganglia pathway, crucial for proper motor functioning, is preserved after early dopamine neuron loss, in parallel with an increase in these cells' membrane excitability. Chemogenetic inhibition studies show that the preserved motility depends on this direct pathway hyperexcitability/hyperconnectivity, while other phenotypes characteristic of this condition remained unaltered despite the dMSN inhibition. This insight has implications for our understanding of the mechanism underlying the behavioral impairments observed in neuropsychiatric conditions linked to early dopaminergic hypofunction.

Video-Based Automated Assessment of Movement Parameters Consistent with MDS-UPDRS III in Parkinson's Disease.

Among motor symptoms of Parkinson's disease (PD), including rigidity and resting tremor, bradykinesia is a mandatory feature to define the parkinsonian syndrome. MDS-UPDRS III is the worldwide reference scale to evaluate the parkinsonian motor impairment, especially bradykinesia. However, MDS-UPDRS III is an agent-based score making reproducible measurements and follow-up challenging. Using a deep learning approach, we developed a tool to compute an objective score of bradykinesia based on the guidelines of the gold-standard MDS-UPDRS III. We adapted and applied two deep learning algorithms to detect a two-dimensional (2D) skeleton of the hand composed of 21 predefined points, and transposed it into a three-dimensional (3D) skeleton for a large database of videos of parkinsonian patients performing MDS-UPDRS III protocols acquired in the Movement Disorder unit of Avicenne University Hospital. We developed a 2D and 3D automated analysis tool to study the evolution of several key parameters during the protocol repetitions of the MDS-UPDRS III. Scores from 2D automated analysis showed a significant correlation with gold-standard ratings of MDS-UPDRS III, measured with coefficients of determination for the tapping (0.609) and hand movements (0.701) protocols using decision tree algorithms. The individual correlations of the different parameters measured with MDS-UPDRS III scores carry meaningful information and are consistent with MDS-UPDRS III guidelines. We developed a deep learning-based tool to precisely analyze movement parameters allowing to reliably score bradykinesia for parkinsonian patients in a MDS-UPDRS manner.

Corticospinal Suppression Underlying Intact Movement Preparation Fades in Parkinson's Disease.

In Parkinson's disease (PD), neurophysiological abnormalities within the primary motor cortex (M1) have been shown to contribute to bradykinesia, but exact modalities are still uncertain. We propose that such motor slowness could involve alterations in mechanisms underlying movement preparation, especially the suppression of corticospinal excitability-called "preparatory suppression"-which is considered to propel movement execution by increasing motor neural gain in healthy individuals. On two consecutive days, 29 PD patients (on and off medication) and 29 matched healthy controls (HCs) underwent transcranial magnetic stimulation over M1, eliciting motor-evoked potentials (MEPs) in targeted hand muscles, while they were either at rest or preparing a left- or right-hand response in an instructed-delay choice reaction time task. Preparatory suppression was assessed by expressing MEP amplitudes during movement preparation relative to rest. Contrary to HCs, PD patients showed a lack of preparatory suppression when the side of the responding hand was analyzed, especially when the latter was the most affected one. This deficit, which did not depend on dopamine medication, increased with disease duration and also tended to correlate with motor impairment, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (both total and bradykinesia scores). Our novel findings indicate that preparatory suppression fades in PD, in parallel with worsening motor symptoms, including bradykinesia. Such results suggest that an alteration in this marker of intact movement preparation could indeed cause motor slowness and support its use in future studies on the relation between M1 alterations and motor impairment in PD. © 2022 International Parkinson and Movement Disorder Society.

Cumulative additional information does not improve the neuromuscular control during postural responses to perturbations in postural instability/gait disorders subtype of Parkinson's disease.

Postural response impairments in postural instability and gait disorders (PIGD) subtype patients may be attributed to Parkinson's disease (PD)-deterioration in central-set (programing/modulating of central outputs during motor responses). Although additional information improves some PD motor impairments, an unanswered question is whether additional information can benefit postural response in PIGD subtype. To analyze the effect of cumulative additional information on postural responses after perturbation in PIGD and neurologically healthy older adults (CG). Perturbations were applied in 16 PIGD and 19 CG by the support-base translation. Participants performed 3 blocks of 5 trials without additional information (B1-B3, Day 1) and 5 trials of each cumulative additional information (C1-C4, Day 2): information about perturbation (C1), visual (C2), verbal (C3), and somatosensory information (C4). Electromyography and center of pressure (CoP) parameters were analyzed by ANOVAs with Group (PIGD×CG) and Block (B1×B2×B3) and with Group (PIGD×CG) and Condition (B3×C1×C2×C3×C4). PIGD decreased the range of CoP in B3 while CG decreased both range of CoP and the integral of antagonist's muscle activity (iEMG) in B2. Also, PIGD decreased the recovery time in C4 while CG increased the iEMG of agonist's muscle in C2 and antagonist's muscle in all conditions except C2. Additional information provided before postural control assessment influences the postural response in PIGD and CG differently. PIGD demonstrated inflexibility of central-set in modulating the neuromuscular control regardless of additional information. CG presents a flexible system evidenced by the increase of agonist muscle iEMG when provided visual information.

Development and validation of an instrument for measuring parkinsonian motor impairment: TRAPS-D.

Parkinson's disease is incurable, idiopathic, degenerative, and progressive, and affects about 1% of the elderly population. Multidisciplinary clinical treatment is the best and most adopted therapeutic option, while surgical treatment is used in less than 15% of those affected. In practice, there is a lack of reliable and validated scales for measuring motor impairment, and monitoring and screening for surgical indications. To develop and validate an instrument for measuring parkinsonian motor impairment in candidates for neurosurgical treatment. The development and validation methods followed published guidelines. The first part was the choice of domains that would make up the construct: cardinal signs of disease (tremor, rigidity (stiffness), posture/balance/gait, hypokinesia/akinesia, and speech), along with pain and dyskinesia. A multi-professional working group prepared an initial pilot instrument. Ten renowned specialists evaluated, judged, and suggested modifications to the instrument. The second phase was the evaluation of the content of each domain and the respective ability to classify commitment intensity. The third phase was the correction of the main flaws detected and new submission to the board. The instrument was applied to 41 candidates for neurosurgical treatment in two situations: with and without medication RESULTS: The final form received 100% agreement from the judges. Its average time for application was 8min. It was very responsive (p = 0.001, Wilcoxon) in different situations (On-Off). TRASP-D is a valid instrument for measuring motor impairment in patients with Parkinson's disease who are candidates for neurosurgical treatment. It allows measurement in multiple domains with reliability and sensitivity.

Development of an \u03b1-synuclein knockdown peptide and evaluation of its efficacy in Parkinson\u2019s disease models

Convincing evidence supports the premise that reducing α-synuclein levels may be an effective therapy for Parkinson’s disease (PD); however, there has been lack of a clinically applicable α-synuclein reducing therapeutic strategy. This study was undertaken to develop a blood-brain barrier and plasma membrane-permeable α-synuclein knockdown peptide, Tat-βsyn-degron, that may have therapeutic potential. The peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in animals. Tat-βsyn-degron decreased α-synuclein aggregates and microglial activation in an α-synuclein pre-formed fibril model of spreading synucleinopathy in transgenic mice overexpressing human A53T α-synuclein. Moreover, Tat-βsyn-degron reduced α-synuclein levels and significantly decreased the parkinsonian toxin-induced neuronal damage and motor impairment in a mouse toxicity model of PD. These results show the promising efficacy of Tat-βsyn-degron in two different animal models of PD and suggest its potential use as an effective PD therapeutic that directly targets the disease-causing process.

Loss of nigral excitation of cholinergic interneurons contributes to parkinsonian motor impairments

Progressive loss of dopamine inputs in Parkinson's disease leads to imbalances in coordinated signaling of dopamine and acetylcholine (ACh) in the striatum, which is thought to contribute to parkinsonian motor symptoms. As reciprocal interactions between dopamine inputs and cholinergic interneurons (ChIs) control striatal dopamine and ACh transmission, we examined how partial dopamine depletion in an early-stage mouse model for Parkinson's disease alters nigral regulation of cholinergic activity. We found region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability that differ between the dorsomedial (DMS) and dorsolateral (DLS) striatum. Specifically, we found that dopamine depletion downregulates metabotropic glutamate receptors (mGluR1) on DLS ChIs at synapses where dopamine inputs co-release glutamate, abolishing the ability of dopamine inputs to drive burst firing. This loss underlies parkinsonian motor impairments, as viral rescue of mGluR1 signaling in DLS ChIs was sufficient to restore circuit function and attenuate motor deficits in early-stage parkinsonian mice.

Reserpine-Induced Progressive Parkinsonism in Mice Predisposed and Non-Predisposed to Depressive-Like Behavior

Parkinson’s disease (PD) is a progressive degenerative condition that mainly affects the elderly. The disease comprises motor symptoms such as tremors at rest, loss of voluntary movement, decreased muscle strength, propensity to lean forward and acceleration of the walking pace. These signs are related to the degeneration of the nigrostriatal dopaminergic pathway. Patients also have non-motor symptoms, among which sleep alterations, cognitive deficits, fatigue, pain and depression stand out. Although depression has been described as the most prevalent non-motor symptom, it is not clear whether this mood disorder is due to PD or patients would already have a greater predisposition. The present study evaluated the relationship between the predisposition to depressive-like behavior and the development of motor alterations in a progressive pharmacological model of PD in mice. Mice were classified into groups of depressive-like propensities and submitted to the pharmacological model. Reserpine was administrated at 0.1 mg/kg on alternate days for 40 days. The catalepsy and oral movement tests were used to evaluate motor alterations, the sucrose preference test was used to evaluate anhedonia, and the open field test was applied to evaluate general activity. Reserpine promoted parkinsonian motor impairments, and there were no differences between animals from different depressive-like behavior profiles. Thus, it was not possible to find a relationship between parkinsonism and the propensity to depression based on the basal sucrose preference test. More studies with other evaluations of depressive-like behavior are needed to confirm the results found in our study.

A novel dopamine D3R agonist SK609 with norepinephrine transporter inhibition promotes improvement in cognitive task performance in rodent and non-human primate models of Parkinson's disease

Mild cognitive impairment is present in a number of neurodegenerative disorders including Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) often manifests as deficits in executive functioning, attention, and spatial and working memory. Clinical studies have suggested that the development of mild cognitive impairment may be an early symptom of PD and may even precede the onset of motor impairment by several years. Dysfunction in several neurotransmitter systems, including dopamine (DA), norepinephrine (NE), may be involved in PD-MCI, making it difficult to treat pharmacologically. In addition, many agents used to treat motor impairment in PD may exacerbate cognitive impairment. Thus, there is a significant unmet need to develop therapeutics that can treat both motor and cognitive impairments in PD. We have recently developed SK609, a selective, G-protein biased signaling agonist of dopamine D3 receptors. SK609 was successfully used to treat motor impairment and reduce levodopa-induced dyskinesia in a rodent model of PD. Further characterization of SK609 suggested that it is a selective norepinephrine transporter (NET) inhibitor with the ability to increase both DA and NE levels in the prefrontal cortex. Pharmacokinetic analysis of SK609 under systemic administration demonstrated 98% oral bioavailability and high brain distribution in striatum, hippocampus and prefrontal cortex. To evaluate the effects of SK609 on cognitive deficits of potential relevance to PD-MCI, we used unilateral 6-hydroxydopamine (6-OHDA) lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus macaques, with deficits in performance in a sustained attention and an object retrieval task, respectively. SK609 dose dependently improved the performance of 6-OHDA-lesioned rats, with peak performance achieved using a 4 mg/kg dose. This improvement was predominantly due to a significant reduction in the number of misses and false alarm errors, contributing to an increase in sustained attention. In MPTP-lesioned monkeys, this same dose also improved performance in an object retrieval task, significantly reducing cognitive errors (barrier reaches) and motor errors (fine motor dexterity problems). These data demonstrate that SK609 with its unique pharmacological effects on modulating both DA and NE can ameliorate cognitive impairment in PD models and may provide a therapeutic option to treat both motor and cognitive impairment in PD patients.

NMDA receptors are altered in the substantia nigra pars reticulata and their blockade ameliorates motor deficits in experimental parkinsonism

In Parkinson's disease (PD) reduced levels of dopamine (DA) in the striatum lead to an abnormal circuit activity of the basal ganglia and an increased output through the substantia nigra pars reticulata (SNr) and the globus pallidus internal part. Synaptic inputs to the SNr shape its activity, however, the properties of glutamatergic synaptic transmission in this output nucleus of the basal ganglia in control and DA-depleted conditions are not fully elucidated. Using whole-cell patch-clamp recordings and pharmacological tools, we examined alterations in glutamatergic synaptic transmission in the SNr of a mouse model of PD, i.e. mice with unilateral 6-OHDA lesion of DA neurons in the substantia nigra pars compacta, as compared to control mice. We found that AMPA receptor (AMPAR)-mediated spontaneous and evoked excitatory postsynaptic currents (sEPSCs and eEPSCs) were not altered. The AMPA/NMDA ratio was significantly decreased in 6-OHDA-lesioned mice, suggesting an increased synaptic function of NMDA receptors (NMDARs) in DA-depleted mice. The decay kinetics of NMDAR-eEPSCs were faster in 6-OHDA-lesioned mice, indicating a possible change in the subunit composition of synaptic NMDARs. In control mice NMDAR-eEPSCs were mediated by diheteromeric NMDARs made of GluN2A, GluN2B and GluN2D. In 6-OHDA-lesioned mice the function of diheteromeric NMDARs containing either GluN2B or GluN2D was dramatically decreased, whereas the function of diheteromeric NMDARs made of GluN2A was preserved. Microinjections of an NMDAR antagonist into the SNr of 6-OHDA-lesioned mice resulted in significant improvements in spontaneous locomotion. This study identifies novel alterations occurring at excitatory synapses in the basal ganglia output nucleus following DA depletion. An increased synaptic NMDAR function, due to an altered subunit composition, might contribute to hyperactivation of SNr neurons in the DA depleted state and to motor impairments in PD.

CSF NFL in a Longitudinally Assessed PD Cohort: Age Effects and Cognitive Trajectories.

Neurofilament light protein is an unspecific biofluid marker that reflects the extent of neuronal/axonal damage and thereby offers the chance monitor disease severity and progression. The objective of this study was to investigate cerebrospinal fluid (CSF) levels of neurofilament light protein in Parkinson's disease (PD) patients with clinical trajectories of motor and cognitive function longitudinally. CSF neurofilament light protein levels were assessed in 371 PDsporadic , 126 genetic PD patients (91 PDGBA , 8 PDLRRK2 , 21 PDPRKN/PINK1/DJ1_heterozygous , 6 PDPRKN/PINK1/DJ1_homozygous ), and 71 healthy controls. Participants were followed up longitudinally for up to 8 years. At baseline, mean CSF neurofilament light protein levels were highest in PD patients with cognitive impairment (Montreal Cognitive Assessment score ≤ 25; 1207 pg/mL) but also higher in PD patients with normal cognitive function (757 pg/mL) compared with healthy controls (593 pg/mL; P ≤ 0.001). In healthy controls and in PD patients older age was associated with higher CSF levels of neurofilament light protein (P ≤ 0.001). In PD patients, male gender, older age at onset, longer disease duration, higher Hoehn and Yahr stages, higher UPDRS-III scores, and lower Montreal Cognitive Assessment scores were associated with higher CSF levels of neurofilament light protein (P < 0.01). In patients who developed cognitive impairment during study, CSF neurofilament light protein levels prior to conversion to cognitive impairment were not significantly different compared with CSF neurofilament light protein levels of patients who remained cognitively normal. Increased CSF levels of neurofilament light protein are associated with cognitive decline and motor impairment in PD. However, this increase seems not a very early event and does not mark the conversion to cognitive impairment beforehand. Therefore, the predictive value needs to be discussed critically. © 2020 International Parkinson and Movement Disorder Society.