Dysfunction In Parkinson's Disease Research Articles

TNFRSF10B is involved in motor dysfunction in Parkinson's disease by regulating exosomal α-synuclein secretion from microglia

A-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson’s disease (PD), a neurodegenerative disease with no effective treatment. Therefore, there has been a strong drive to clarify the pathology of PD associated with α-syn. Several mechanisms have been proposed to unravel the pathological cascade of this disease, and most of them share a particular similarity: cell-to-cell communication through exosomes (EXO). Here, we show that tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) promotes the secretion of α-syn-containing EXO by microglia, resulting in motor dysfunction in PD. Upregulation of TNFRSF10B predicted severer condition in PD patients. In response to α-syn preformed fibrils (PFF), the expression of TNFRSF10B was increased in microglia. PFF-treated microglia exhibited a pro-inflammatory phenotype and caused neuronal damage by secreting α-syn-containing EXO. TNFRSF10B downregulation in microglia inhibited the secretion of α-syn-containing EXO and the release of pro-inflammatory factors, and ameliorated neuronal injury. PFF induced motor dysfunction in mice, which was ameliorated by inhibiting TNFRSF10B to suppress microglia-mediated α-syn communication or by directly depleting microglia. Taken together, these results indicate that TNFRSF10B promotes neuronal injury and motor dysfunction by delivery of α-syn-containing EXO and highlight the TNFRSF10B knockdown as a potential therapeutic target in PD.

Deep Learning Using Images of the Retina for Assessment of Severity of Neurological Dysfunction in Parkinson Disease

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Ophthalmology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Ophthalmology journal

Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in Parkinson’s disease models

Whole-exome sequencing of Parkinson's disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the tyrosine nonreceptor kinase-2 (TNK2) gene. Although this kinase had a previously demonstrated activity in preventing the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2-associated dysfunction in PD remains unresolved. We postulated the dopaminergic neurodegeneration resulting from patient-associated variants in TNK2 were a consequence of aberrant or prolonged TNK2 overactivity, the latter being a failure in TNK2 degradation by an E3 ubiquitin ligase, neuronal precursor cell-expressed developmentally down-regulated-4 (NEDD4). Interestingly, systemic RNA interference protein-3 (SID-3) is the sole TNK2 ortholog in the nematode Caenorhabditis elegans, where it is an established effector of epigenetic gene silencing mediated through the dsRNA-transporter, SID-1. We hypothesized that TNK2/SID-3 represents a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Use of a TNK2 inhibitor (AIM-100) or a NEDD4 activator [N-aryl benzimidazole 2 (NAB2)] in bioassays for either dopamine- or dsRNA-uptake into worm dopaminergic neurons revealed that sid-3 mutants displayed robust neuroprotection from 6-hydroxydopamine (6-OHDA) exposures, as did AIM-100 or NAB2-treated wild-type animals. Furthermore, NEDD4 activation by NAB2 in rat primary neurons correlated to a reduction in TNK2 levels and the attenuation of 6-OHDA neurotoxicity. CRISPR-edited nematodes engineered to endogenously express SID-3 variants analogous to TNK2 PD-associated SNPs exhibited enhanced susceptibility to dopaminergic neurodegeneration and circumvented the RNAi resistance characteristic of SID-3 dysfunction. This research exemplifies a molecular etiology for PD whereby dopaminergic and epigenetic signaling are coordinately regulated to confer susceptibility or resilience to neurodegeneration.

Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting 1%-2% of the population over the age of 65. As the population ages, it is anticipated that the burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves the quality of life of many PD patients, there are no treatments that can slow down, halt, or reverse disease progression. Because the loss of a specific cell type, midbrain dopamine neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is considered a promising target for cell replacement therapy. Indeed, numerous preclinical and clinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells remains fraught with controversy due to fundamental ethical, practical, and clinical limitations. Groundbreaking work on human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, coupled with extensive basic research in the stem cell field offers promising potential for hPSC-based cell replacement to become a realistic treatment regimen for PD once several major issues can be successfully addressed. In this review, we will discuss the prospects and challenges of hPSC-based cell therapy for PD.

QEEG Signatures are Associated with Nonmotor Dysfunctions in Parkinson's Disease and Atypical Parkinsonism: An Integrative Analysis.

Parkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), share similar nonmotor symptoms. Quantitative electroencephalography (QEEG) can be used to examine the nonmotor symptoms. This study aimed to characterize the patterns of QEEG and functional connectivity (FC) that differentiate PD from PSP or MSA, and explore the correlation between the differential QEEG indices and nonmotor dysfunctions in PD and AP. We enrolled 52 patients with PD, 31 with MSA, 22 with PSP, and 50 age-matched health controls to compare QEEG indices among specific brain regions. One-way analysis of variance was applied to assess QEEG indices between groups; Spearman's correlations were used to examine the relationship between QEEG indices and nonmotor symptoms scale (NMSS) and mini-mental state examination (MMSE). FCs using weighted phase lag index were compared between patients with PD and those with MSA/PSP. Patients with PSP revealed higher scores on the NMSS and lower MMSE scores than those with PD and MSA, with similar disease duration. The delta and theta powers revealed a significant increase in PSP, followed by PD and MSA. Patients with PD presented a significantly lower slow-to-fast ratio than those with PSP in the frontal region, while patients with PD presented significantly higher EEG-slowing indices than patients with MSA. The frontal slow-to-fast ratio showed a negative correlation with MMSE scores in patients with PD and PSP, and a positive correlation with NMSS in the perception and mood domain in patients with PSP but not in those with PD. Compared to PD, MSA presented enhanced FC in theta and delta bands in the posterior region, while PSP revealed decreased FC in the delta band within the frontal-temporal cortex. These findings suggest that QEEG might be a useful tool for evaluating the nonmotor dysfunctions in PD and AP. Our QEEG results suggested that with similar disease duration, the cortical neurodegenerative process was likely exacerbated in patients with PSP, followed by those with PD, and lastly in patients with MSA.

Noninvasive neuroimaging provides evidence for deterioration of the glymphatic system in Parkinson's disease relative to essential tremor

IntroductionGrowing evidence has demonstrated dysfunction of the glymphatic system in α-synucleinopathy and related diseases. In this study, we aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and MRI-visible enlarged perivascular spaces (EPVS) to evaluate glymphatic system function quantitatively and qualitatively and its relationship to clinical scores of disease severity in Parkinson's disease (PD) and essential tremor (ET). MethodsOverall, 124 patients with PD, 74 with ET, and 106 healthy controls (HC) were enrolled. Two trained neurologists performed quantitative calculations of ALPS on DTI and visual ratings of EPVS on T2-weighted images in the centrum semiovale (CSO), basal ganglia (BG), midbrain, and cerebellum. ResultsThe ALPS index was lower in patients with PD than in patients with ET (p < 0.001) and HC (p < 0.001). Similarly, patients with PD showed a more severe EPVS burden in the CSO, BG, and midbrain compared to ET and HC. Moreover, the ALPS index was negatively correlated with disease severity in the PD subgroups; however, it did not differ within the ET subgroup. No differences in ALPS or EPVS were observed between the ET and HC groups. ConclusionIn conclusion, DTI-ALPS and EPVS both provide neuroimaging evidence of glymphatic system dysfunction in PD, which further supports that PD is an α-synucleinopathy disease, while ET is a cerebellar dysfunction-related disease.

The impact of cerebral small vessel disease burden and its imaging markers on gait, postural control, and cognition in Parkinson's disease.

This study aimed to investigate how cerebral small vessel disease (CSVD) burden and its imaging markers are related to alterations in different gait parameters in Parkinson's disease (PD) and whether they affect attention, information processing speed, and executive function when global mental status is relatively intact. Sixty-five PD patients were divided into the low CSVD burden group (n = 43) and the high CSVD burden group (n = 22). All patients underwent brain magnetic resonance imaging scans, clinical scale evaluations, and neuropsychological tests, as well as quantitative evaluation of gait and postural control. Multivariable linear regression models were conducted to investigate associations between CSVD burden and PD symptoms. Between-group analysis showed that the high CSVD group had worse attention, executive dysfunction, information processing speed, gait, balance, and postural control than the low CSVD group. Regression analysis revealed that greater CSVD burden was associated with poor attention, impaired executive function, and slow gait speed; white matter hyperintensity was associated with slow gait speed, decreased cadence, increased stride time, and increased stance phase time; the presence of lacune was associated only with poor attention and impaired executive function; enlarged perivascular space in the basal ganglia was associated with gait speed. CSVD burden may worsen gait, postural control, attention, and executive function in patients with PD, and different imaging markers play different roles. Early management of vascular risks and treatment of vascular diseases provide an alternate way to mitigate some motor and cognitive dysfunction in PD.

Real‐world sleep in Parkinson’s disease predicts cognitive dysfunction.

AbstractBackgroundSleep dysfunction is signature of Alzheimer’s disease and Parkinson’s disease (PD), and can signify incipient disease, disease risk, and worsen symptoms over time. How real‐world sleep dysfunction relates to patient self‐report of sleep and clinical cognitive dysfunction is poorly understood, partly because self ‐report is impaired in patients with cognitive decline. We monitored real‐world sleep with wearable actigraphy devices in patients with PD to test the hypothesis that objective patterns of sleep dysfunction are associated with worse cognitive performance.MethodTwenty‐nine participants with idiopathic PD (age = 67.44 ± 5.79, 20 males) completed the Montreal Cognitive Assessment (MoCA) and Epworth Sleepiness Scale (ESS) to capture clinical cognitive decline and self‐reported daytime sleepiness. Sleep was monitored for 4‐weeks using wrist‐worn ActiGraphs. Sub‐scores and total scores of MoCA were compared with Total Sleep Time (TST), Sleep Efficiency (SE), Wakefulness After Sleep Onset (WASO), and Sleep Fragmentation Index (SFI) measured by actigraphy, as well as ESS total using a Pearson correlation.ResultWorse sleep fragmentation (SFI), the percentage of awakenings and movements during sleep, predicted worse cognitive impairment overall (MoCA score: r = ‐0.38, p &lt; .05) and delayed recall (r = ‐0.44, p &lt; .05). Reduced sleep time (TST) and worse sleep quality (SE, WASO) did not worsen patient cognitive impairment. Patient self‐report of sleepiness (ESS) did not associate with worse cognitive outcomes.ConclusionThis pilot analysis identifies sleep fragmentation as a key risk factor for cognitive dysfunction in PD. Patient self‐report of sleep may not reliably reflect chronic sleep disruption and related cognitive dysfunction. Results underscore that objective measures of real‐world dysfunction can help inform clinical care and intervention for patients at risk for cognitive decline and dementia.

Changes in the Neuronal Architecture of the Hippocampus in a 6-Hydroxydopamine-Lesioned Rat Model of Parkinson Disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder in which dopaminergic (DAergic) systems are destroyed (particularly in the nigrostriatal system), causing both motor and nonmotor symptoms. Hippocampal neuroplasticity is altered in PD animal models, resulting in nonmotor dysfunctions. However, little is known about the precise mechanism underlying the hippocampal dysfunctions in PD. Striatal 6-hydroxydopamine (6-OHDA) infusions were performed unilaterally in adult Sprague Dawley rats. Both motor and nonmotor symptoms alongside the expression of tyrosine hydroxylase (TH) in the substantia nigra and striatum were confirmed in 6-OHDA-lesioned rats. The neuronal architecture in the hippocampus was analyzed by Golgi staining. During the 7-8 weeks after infusion, the 6-OHDA-lesioned rats exhibited motor and nonmotor dysfunctions (especially anxiety/depression-like behaviors). Rats with unilateral 6-OHDA infusion displayed reduced TH+ immunoreactivity in the ipsilateral nigrostriatal pathway of the brain. Golgi staining revealed that striatal 6-OHDA infusion significantly decreased the dendritic complexity (i.e., number of crossing dendrites, total dendritic length, and branch points) in the ipsilateral hippocampal conus ammonis 1 (CA1) apical/basal and dentate gyrus (DG) subregions. Additionally, the dendritic spine density and morphology were significantly altered in the CA1 apical/basal and DG subregions following striatal 6-OHDA infusion. However, alteration of microglial and astrocytic distributions did not occur in the hippocampus following striatal 6-OHDA infusion. The present study provides anatomical evidence that the structural plasticity in the hippocampus is altered in the late phase following striatal 6-OHDA infusion in rats, possibly as a result of the prolonged suppression of the DAergic system, and independent of neuroinflammation.

Machine learning can predict mild cognitive impairment in Parkinson's disease.

Clinical markers of cognitive decline in Parkinson's disease (PD) encompass several mental non-motor symptoms such as hallucinations, apathy, anxiety, and depression. Furthermore, freezing of gait (FOG) and specific gait alterations have been associated with cognitive dysfunction in PD. Finally, although low cerebrospinal fluid levels of amyloid-β42 have been found to predict cognitive decline in PD, hitherto PET imaging of amyloid-β (Aβ) failed to consistently demonstrate the association between Aβ plaques deposition and mild cognitive impairment in PD (PD-MCI). Finding significant features associated with PD-MCI through a machine learning approach. Patients were assessed with an extensive clinical and neuropsychological examination. Clinical evaluation included the assessment of mental non-motor symptoms and FOG using the specific items of the MDS-UPDRS I and II. Based on the neuropsychological examination, patients were classified as subjects without and with MCI (noPD-MCI, PD-MCI). All patients were evaluated using a motion analysis system. A subgroup of PD patients also underwent amyloid PET imaging. PD-MCI and noPD-MCI subjects were compared with a univariate statistical analysis on demographic data, clinical features, gait analysis variables, and amyloid PET data. Then, machine learning analysis was performed two times: Model 1 was implemented with age, clinical variables (hallucinations/psychosis, depression, anxiety, apathy, sleep problems, FOG), and gait features, while Model 2, including only the subgroup performing PET, was implemented with PET variables combined with the top five features of the former model. Seventy-five PD patients were enrolled (33 PD-MCI and 42 noPD-MCI). PD-MCI vs. noPD-MCI resulted in older and showed worse gait patterns, mainly characterized by increased dynamic instability and reduced step length; when comparing amyloid PET data, the two groups did not differ. Regarding the machine learning analyses, evaluation metrics were satisfactory for Model 1 overcoming 80% for accuracy and specificity, whereas they were disappointing for Model 2. This study demonstrates that machine learning implemented with specific clinical features and gait variables exhibits high accuracy in predicting PD-MCI, whereas amyloid PET imaging is not able to increase prediction. Additionally, our results prompt that a data mining approach on certain gait parameters might represent a reliable surrogate biomarker of PD-MCI.

Regional cortical hypoperfusion and atrophy correlate with striatal dopaminergic loss in Parkinson's disease: a study using arterial spin labeling MR perfusion.

To investigate the relationship of the striatal dopamine transporter density to changes in the gray matter (GM) volume and cerebral perfusion in patients with Parkinson's disease (PD). We evaluated the regional cerebral blood flow (CBF) and GM volume, concurrently measured using arterial spin labeling and T1-weighted magnetic resonance imaging, respectively, as well as the striatal specific binding ratio (SBR) in 123I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) single-photon emission computed tomography in 30 non-demented patients with PD (15 men and 15 women; mean age, 67.2 ± 8.8years; mean Hoehn-Yahr stage, 2.2 ± 0.9). Voxel-wise regression analyses using statistical parametric mapping (SPM) were performed to explore the brain regions that showed correlations of the striatal SBR to the GM volume and CBF, respectively, with a height threshold of p < 0.0005 at the voxel level and p < 0.05 family-wise error-corrected at the cluster level. SPM analysis showed a significant positive correlation between the SBR and GM volume in the inferior frontal gyrus (IFG). Whereas, a positive correlation between the SBR and CBF was widely found in the frontotemporal and parietotemporal regions, including the IFG. Notably, the opercular part of the IFG showed significant correlations in both SPM analyses of the GM volume (r2 = 0.90, p < 0.0001) and CBF (r2 = 0.88, p < 0.0001). The voxel-wise analyses revealed the brain regions, mainly the IFG, that showed hypoperfusion and atrophy related to dopaminergic loss, which suggests that the progression of dopaminergic neurodegeneration leads to regional cortical dysfunction in PD.

Plasma Neurofilament Light Concentration Is Associated with Diffusion-Tensor MRI-Based Measures of Neurodegeneration in Early Parkinson's Disease.

Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson's disease (PD). 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical nuclei. A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD.

Longitudinal striatal dopamine transporter binding and cerebrospinal fluid alpha-synuclein, amyloid beta, total tau, and phosphorylated tau in Parkinson's disease.

Previous studies investigated CSF levels of α-synuclein (α-syn), amyloid-β (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) with clinical progression of Parkinson's disease (PD). However, there is limited data on the association between CSF biomarkers and dopamine uptake status in PD. In the current study, we aim to investigate the longitudinal association between striatal dopaminergic neuronal loss assessed by dopamine active transporter single photon emission computerized tomography (DaTSCAN) imaging with CSF α-syn, t-tau, p-tau, and Aβ1-42. A total of 413 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. Striatal binding ratios (SBRs) of DaTSCAN images in caudate and putamen nuclei were calculated. We investigated the cross-sectional and longitudinal association between CSF biomarkers and dopamine uptake using partial correlation models adjusted for the effect of age, sex, and years of education over 24months of follow-up. The level of CSF α-syn, Aβ1-42, t-tau, and p-tau was significantly higher in HCs compared to PD groups at any time point. We found that higher CSF α-syn was associated with a higher SBR score in the left caudate at baseline (P = 0.038) and after 12months (P = 0.012) in PD patients. Moreover, SBR scores in the left caudate and CSF Aβ1-42 were positively correlated at baseline (P = 0.021), 12months (P = 0.006), and 24months (P = 0.014) in patients with PD. Our findings demonstrated that change in CSF Aβ1-42 was positively correlated with change in SBR score in the left caudate after 24months in the PD group (P = 0.043). We found that cross-sectional levels of α-syn and Aβ1-42 could reflect the degree of dopaminergic neuron loss in the left caudate nucleus. Interestingly, longitudinal changes in CSF Aβ1-42 could predict the severity of left caudal dopaminergic neuron loss throughout the disease. This suggested that Aβ pathology might precede dopaminergic loss in striatal nuclei in this case left caudate and subsequently cognitive impairment in PD patients, although future studies are needed to confirm our results and expand the understanding of the pathophysiology of cognitive dysfunction in PD.

Postural control in Parkinsonisms during a short static sway

Neurological diseases, such as Parkinsonisms, are often associated with static postural instability. Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease classified among atypical Parkinsonisms. In the earliest stages, PSP is similar to Parkinson’s disease (PD) [1]. Static postural stability is an important contributor to the balance control framework and balance impairment can be quantified with a postural sway measure [2]. The main goal of our study was to compare postural sway changes in both PSP and PD subjects, using a standing single task of 5-6 seconds, in order to prove that a shorter sway time may be useful to distinguish Parkinsonisms. We assessed fifteen individuals with early PSP and fifteen individuals with recent diagnosis of PD (De Novo PD). Stabilometric analysis was performed for the evaluation of balance through a BTS Bioengineering system. The patient was instructed to stand on the force plate with the eyes open and measures of 5-6 seconds were taken. To find differences between the groups, univariate statistical analysis on sway data was conducted, and an alpha significance level was set to p-value < 0.05. The statistical analysis showed significant differences between De Novo PD and PSP groups for Medio- Lateral (M-L) sway (p-value=0.01), M-L range (p-value=0.023) and radius (p-value=0.026); minimum oscillation from the center of gravity and area showed a statistical trend with a p-value slightly above the 0.05 (p-value=0.056 and p-value=0.061, respectively). Several studies have demonstrated that balance dysfunction in PD is directionally dependent [2,3]. In agreement with our data, patients with atypical Parkinsonism show balance impairment on M-L direction as attested by augmented M-L sway, M-L range and radius. These results indicate that a short static sway of 5-6 seconds, could provide the clinician with a reliable and non-invasive tool to distinguish PSP from PD since the earliest stages.

Ghrelin Bridges DMV Neuropathology and GI Dysfunction in the Early Stages of Parkinson's Disease.

Ghrelin contributes to the communication between the brain and gastrointestinal (GI) tract. Both decreased ghrelin levels and functional GI disorders are early events in Parkinson's disease (PD) patients and animal models. However, the reason is not clear. Here it is found that choline acetyltransferase (ChAT)‐positive neurons in the dorsal motor nucleus of the vagus nerve (DMV), are lost in PD transgenic mice. In response to the selective damaging of DMV neurons with mu p75‐SAP, a rapid reduction both in plasma total and active ghrelin levels is observed. While by contrast, chemogenetic activation of DMV cholinergic neurons can increase the plasma ghrelin levels. Impairment of cholinergic neurons is accompanied by GI disorders, including decreased stool wet weight, stool dry weight, small intestine advancing rate, and gastric emptying rate, while exogenous ghrelin treatment can partially ameliorate GI dysfunction of A53T α‐synuclein transgenic mice. Using pseudorabies virus retrograde trace method, the existence of a direct pathway from the stomach fundus to the DMV is shown. Taken together, the findings suggest that the reduction in plasma ghrelin levels in the early stages of PD may be the result of the lesion of cholinergic neurons in the DMV, thus linking neurodegeneration and GI dysfunction in PD.

Orthostatic Hypotension in Parkinson Disease: What Is New?

Orthostatic hypotension (OH) is the primary manifestation of cardiovascular autonomic dysfunction in Parkinson disease (PD) and can be a prodromal feature of the disease. We review the recent progress in the field of autonomic dysfunction in PD. Individuals with isolated neurogenic OH should be followed up frequently because they may evolve into PD, dementia with Lewy bodies, or multiple system atrophy. The prevalence of OH in PD increases with disease stages, but the role of levodopa remains unclear. Measurement of supine and standing heart rate and blood pressure allows for accurate identification of neurogenic OH in the clinic. Accurate identification of neurogenic OH in the clinic is crucial for identification of individuals who may benefit from participation in neuroprotective trials in the future. The treatment of OH in PD should be individualized and may reduce the risk of falls, cognitive impairment, and death.

Oculomotor deficits in Parkinson's disease: Increasing sensitivity using multivariate approaches.

Parkinson's disease (PD) affects several domains of neurological function, from lower-level motor programs to higher cognitive processing. As certain types of eye movements (saccades) are fast, non-fatiguing, and can be measured objectively and non-invasively, they are a promising candidate for quantifying motor and cognitive dysfunction in PD, as well as other movement disorders. In this pilot study, we evaluate the latency (reaction time), damping (resistance to oscillation), and amplitude of saccadic movements in two tasks performed by 25 PD patients with mild to moderate disease and 26 age-matched healthy controls. As well as general increases in reaction time caused by PD, the damping of saccadic eye movements was found to be task-dependent and affected by disease. Finally, we introduce a proof-of-concept multivariate model to demonstrate how information from saccadometry can be combined to infer disease status.

GSK-3β-mediated regulation of Nrf2/HO-1 signaling as a new therapeutic approach in the treatment of movement disorders.

Movement disorders are neurological conditions characterized by involuntary motor movements, such as dystonia, ataxia, chorea myoclonus, tremors, Huntington's disease (HD), and Parkinson's disease (PD). It is classified into two categories: hypokinetic and hyperkinetic movements. Globally, movement disorders are a major cause of death. The pathophysiological process is initiated by excessive ROS generation, mitochondrial dysfunction, neuroinflammation, and neurotransmitters imbalance that lead to motor dysfunction in PD and HD patients. Several endogenous targets including Nrf2 maintain oxidative balance in the body. Activation of Nrf2 signaling is regulated by the enzyme glycogen synthase kinase (GSK-3β). In the cytoplasm, inhibition of GSK-3β regulates cellular proliferation, homeostasis, and apoptotic process by stimulating the nuclear factor erythroid 2 (Nrf2) pathway which is involved in the elevation of the cellular antioxidant enzymes which controls the ROS generation. The activation of Nrf2 increases the expression of antioxidant response elements (ARE), such as (Hemeoxygenase-1) HO-1, which decreases excessive cellular stress, mitochondrial dysfunction, apoptosis, and neuronal degeneration, which is the major cause of motor dysfunction. The present review explores the GSK-3β-mediated neuroprotection in various movement disorders through the Nrf2/HO-1 antioxidant pathway. This review provides alink between GSK-3β and the Nrf2/HO-1 signaling pathway in the treatment of PD and HD. In addition to that it highlights various GSK-3β inhibitors and the Nrf2/HO-1 activators, which exert robust neuroprotection against motor disorders. Therefore, the present review will help in the discovery of new therapy for PD and HD patients.

Effects of repetitive transcranial magnetic stimulation on gait disorders and cognitive dysfunction in Parkinson's disease: A systematic review with meta-analysis.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is acknowledged to be crucial to manage freezing of gait (FOG) and cognitive impairment for patients with Parkinson's disease (PD), but its effectiveness is unclear.ObjectiveTo determine the effects of rTMS on FOG and cognitive function in people with PD and to investigate potential factors that modulate the rTMS effects.MethodsDatabases searched included PubMed, Web of Science, EMBASE, and the Cochrane Library from inception to December 31, 2021. Eligible studies include a controlled randomized clinical trial of rTMS intervention for FOG and cognitive dysfunction in PD patients. The weighted mean difference (WMD) with 95% confidence intervals (CI) were calculated with fixed‐effects models. The outcome of the study included gait and cognitive assessments.ResultsSixteen studies with a total of 419 patients were included. Fixed‐effects analysis revealed that rTMS was effective in improving freezing of gait questionnaire scores (short‐term effect: WMD = −0.925, 95% CI: −1.642 to −0.209, p = .011; long‐term effect: WMD = −2.120, 95% CI: −2.751 to −1.489, p = .000), 10‐m walking time (short‐term effect: WMD = −0.456, 95% CI: −0.793 to −0.119, p = .008; long‐term effect: WMD = −0.526, 95% CI: −0.885 to −0.167, p = .004), Timed Up‐and‐Go scores (short‐term effect: WMD = −1.064, 95% CI: −1.555 to −0.572, p = .000; long‐term effect: WMD = −1.097, 95% CI: −1.422 to −0.772, p = .000), Montreal cognitive assessment (WMD = 3.714, 95% CI: 2.567 to 4.861, p = .000), and frontal assessment battery (WMD = −0.584, 95% CI: −0.934 to −0.234, p = .001).ConclusionsRTMS showed a beneficial effect on FOG and cognitive dysfunction in parkinsonism. However, the optimal rTMS protocol has not been determined and further high‐quality studies are needed.

Pedunculopontine Nucleus Dysconnectivity Correlates With Gait Impairment in Parkinson's Disease: An Exploratory Study.

BackgroundGait impairment is a debilitating and progressive feature of Parkinson’s disease (PD). Increasing evidence suggests that gait control is partly mediated by cholinergic signaling from the pedunculopontine nucleus (PPN).ObjectiveWe investigated whether PPN structural connectivity correlated with quantitative gait measures in PD.MethodsTwenty PD patients and 15 controls underwent diffusion tensor imaging to quantify structural connectivity of the PPN. Whole brain analysis using tract-based spatial statistics and probabilistic tractography were performed using the PPN as a seed region of interest for cortical and subcortical target structures. Gait metrics were recorded in subjects’ medication ON and OFF states, and were used to determine if specific features of gait dysfunction in PD were related to PPN structural connectivity.ResultsTract-based spatial statistics revealed reduced structural connectivity involving the corpus callosum and right superior corona radiata, but did not correlate with gait measures. Abnormalities in PPN structural connectivity in PD were lateralized to the right hemisphere, with pathways involving the right caudate nucleus, amygdala, pre-supplementary motor area, and primary somatosensory cortex. Altered connectivity of the right PPN-caudate nucleus was associated with worsened cadence, stride time, and velocity while in the ON state; altered connectivity of the right PPN-amygdala was associated with reduced stride length in the OFF state.ConclusionOur exploratory analysis detects a potential correlation between gait dysfunction in PD and a characteristic pattern of connectivity deficits in the PPN network involving the right caudate nucleus and amygdala, which may be investigated in future larger studies.