Parkinsonian Motor Research Articles

Parkinson's Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson's Disease Progression.

Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge. To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones. Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression. Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p < 0.0001), greater MDS-UPDRS total scores (p < 0.0001), higher GDS-15 depression scores (p = 0.0341), lower dopamine transporter binding (p = 0.0043), and lower CSF total α-synuclein levels (p = 0.0030). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639). Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.

P01-03: Building an Excess Calcium-centric Adverse Outcome Pathway for Parkinsonian Motor Symptoms Related to Pesticides

P01-03: Building an Excess Calcium-centric Adverse Outcome Pathway for Parkinsonian Motor Symptoms Related to Pesticides

Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism.

Degeneration of midbrain dopaminergic (DA) neurons alters the connectivity and functionality of the basal ganglia-thalamocortical circuits in Parkinson's disease (PD). Particularly, the aberrant outputs of the primary motor cortex (M1) contribute to parkinsonian motor deficits. However, cortical adaptations at cellular and synaptic levels in parkinsonism remain poorly understood. Using multidisciplinary approaches, we found that DA degeneration induces cell subtype- and input-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. At molecular level, we identified that N-methyl-d-aspartate (NMDA) receptors play a key role in mediating the reduced thalamocortical excitation to PT neurons. At circuit level, we showed that the reduced thalamocortical transmission in parkinsonian mice can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that cell subtype- and synapse-specific adaptations in M1 contribute to altered cortical outputs in parkinsonism and are important aspects of PD pathophysiology.

The Parkinson's disease waiting room of the future: measurements, not magazines.

Utilizing technology to precisely quantify Parkinson's disease motor symptoms has evolved over the past 50 years from single point in time assessments using traditional biomechanical approaches to continuous monitoring of performance with wearables. Despite advances in the precision, usability, availability and affordability of technology, the "gold standard" for assessing Parkinson's motor symptoms continues to be a subjective clinical assessment as none of these technologies have been fully integrated into routine clinical care of Parkinson's disease patients. To facilitate the integration of technology into routine clinical care, the Develop with Clinical Intent (DCI) model was created. The DCI model takes a unique approach to the development and integration of technology into clinical practice by focusing on the clinical problem to be solved by technology rather than focusing on the technology and then contemplating how it could be integrated into clinical care. The DCI model was successfully used to develop the Parkinson's disease Waiting Room of the Future (WROTF) within the Center for Neurological Restoration at the Cleveland Clinic. Within the WROTF, Parkinson's disease patients complete the self-directed PD-Optimize application on an iPad. The PD-Optimize platform contains cognitive and motor assessments to quantify PD symptoms that are difficult and time-consuming to evaluate clinically. PD-Optimize is completed by the patient prior to their medical appointment and the results are immediately integrated into the electronic health record for discussion with the movement disorder neurologist. Insights from the clinical use of PD-Optimize has spurred the development of a virtual reality technology to evaluate instrumental activities of daily living in PD patients. This new technology will undergo rigorous assessment and validation as dictated by the DCI model. The DCI model is intended to serve as a health enablement roadmap to formalize and accelerate the process of bringing the advantages of cutting-edge technology to those who could benefit the most: the patient.

Suppression of beta oscillations by delayed feedback in a cortex-basal ganglia-thalamus-pedunculopontine nucleus neural loop model.

Excessive neural synchronization of neural populations in the beta (β) frequency range (12-35 Hz) is intimately related to the symptoms of hypokinesia in Parkinson's disease (PD). Studies have shown that delayed feedback stimulation strategies can interrupt excessive neural synchronization and effectively alleviate symptoms associated with PD dyskinesia. Work on optimizing delayed feedback algorithms continues to progress, yet it remains challenging to further improve the inhibitory effect with reduced energy expenditure. Therefore, we first established a neural mass model of the cortex-basal ganglia-thalamus-pedunculopontine nucleus (CBGTh-PPN) closed-loop system, which can reflect the internal properties of cortical and basal ganglia neurons and their intrinsic connections with thalamic and pedunculopontine nucleus neurons. Second, the inhibitory effects of three delayed feedback schemes based on the external globus pallidum (GPe) on β oscillations were investigated separately and compared with those based on the subthalamic nucleus (STN) only. Our results show that all four delayed feedback schemes achieve effective suppression of pathological β oscillations when using the linear delayed feedback algorithm. The comparison revealed that the three GPe-based delayed feedback stimulation strategies were able to have a greater range of oscillation suppression with reduced energy consumption, thus improving control performance effectively, suggesting that they may be more effective for the relief of Parkinson's motor symptoms in practical applications.

Transient exposure to rotenone causes degeneration and progressive parkinsonian motor deficits, neuroinflammation, and synucleinopathy

Individuals with Parkinson’s disease (PD) typically receive a diagnosis once they have developed motor symptoms, at which point there is already significant loss of substantia nigra dopamine neurons, α-synuclein accumulation in surviving neurons, and neuroinflammation. Consequently, the point of clinical presentation may be too late to initiate disease-modifying therapy. In contrast to this clinical reality, animal models often involve acute neurodegeneration and potential therapies are tested concurrently or shortly after the pathogenic insult has begun rather than later when diagnostic clinical symptoms emerge. Therefore, we sought to develop a model that reflects the clinical situation more accurately. Middle-aged rats (7–9 months-old) received a single daily intraperitoneal injection of rotenone for 5 consecutive days and were observed over the next 8–9 months. Rotenone-treated rats showed transient motor slowing and postural instability during exposure but recovered within 9 days of rotenone cessation. Rats remained without behavioral deficits for 3–4 months, then developed progressive motor abnormalities over the ensuing months. As motor abnormalities began to emerge 3 months after rotenone exposure, there was significant loss of nigral dopaminergic neurons and significant microglial activation. There was delayed accumulation of α-synuclein in neurons of the substantia nigra and frontal cortex, which was maximal at 9 months post-rotenone. In summary, a brief temporally-remote exposure to rotenone causes delayed and progressive behavioral and neuropathological changes similar to Parkinson’s disease. This model mimics the human clinical situation, in which pathogenesis is well-established by the time diagnostic motor deficits appear. As such, this model may provide a more relevant experimental system in which to test disease-modifying therapeutics.

Jumping to conclusions bias, psychosis and impulsivity in early stages of Parkinson’s disease

ObjectivesThe aim was to explore the correlations between Jumping to Conclusions (JtC) tendency and neuropsychiatric features in patients with early Parkinson’s disease (PD).BackgroundAccording to few reports, PD patients with impulsive–compulsive behaviors (ICBs) are prone to working memory difficulties including JtC bias. The correlation of psychotic features and JtC tendency remains still unclear.MethodsHealthy controls and patients within 3 years of PD onset were recruited. Participants were examined for psychotic symptoms using a 10 question PD-specific psychosis severity scale. JtC was measured by a probalistic reasoning scenario (beads task). In PD group, medication use, motor and non-motor symptoms were documented. Impulsivity was evaluated using the Questionnaire for Impulsive–Compulsive Disorders in PD (QUIP).ResultsThe prevalence of JtC bias was 9% (6/70) in healthy individuals, compared to 32% (22/68) of PD group [p = 0.001]. No association was detected between the presence of JtC tendency and PD-associated psychosis (p = 0.216). Patients with JtC had shorter duration of PD, more tremor-dominant PD subtype and higher QUIP scores, regardless of the dopaminergic therapy (p = 0.043, p = 0.015, p = 0.007, respectively). A trend towards attention and inhibition control deficit was noticed in JtC patients.ConclusionsWe found a high prevalence of JtC bias in early, cognitively intact PD population and a potential link between subthreshold ICBs and poor performance on beads task. Additional studies are needed to confirm our results and elaborate on the mechanisms that correlate impulsivity with JtC tendency, which are likely to be different from those mediating psychotic features in early PD.

Motor progression phenotypes in early-stage Parkinson’s Disease: A clinical prediction model and the role of glymphatic system imaging biomarkers

BackgroundSubstantial heterogeneity of motor symptoms in Parkinson’s disease (PD) poses a challenge to disease prediction. ObjectivesThe aim of this study was to construct a nomogram model that can distinguish different longitudinal trajectories of motor symptom changes in early-stage PD patients. MethodsData on 90 patients with 5-years of follow-up were collected from the Parkinson’s Progression Marker Initiative (PPMI) cohort. We used a latent class mixed modeling (LCMM) to identify distinct progression patterns of motor symptoms, and backward stepwise logistic regression with baseline information was conducted to identify the potential predictors for motor trajectory and to develop a nomogram. The performance of the nomogram model was then evaluated using the optimism-corrected C-index for internal validation, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for discrimination, the calibration curve for predictive accuracy, and decision curve analysis (DCA) for its clinical value. ResultsWe identified two trajectories for motor progression patterns. The first, Class 1 (Motor deteriorated group), was characterized by sustained, continuously worsening motor symptoms, and the second, Class 2 (Motor stable group), had stable motor symptoms throughout the follow-up period. The best combination of 7 baseline variables was identified and assembled into the nomogram: Scopa-AUT [odds ratio (OR), 1.11; p = 0.091], Letter number sequencing (LNS) (OR, 0.76; p = 0.068), the asymmetry index of putamen (OR, 0.95; p = 0.034), mean caudate uptake (OR, 0.14; p = 0.086), CSF pTau/α-synuclein (OR, 0.00; p = 0.011), CSF tTau/Aβ (OR, 25434806; p = 0.025), and the index for diffusion tensor image analysis along the perivascular space (ALPS-index) (OR, 0.02; p = 0.030). The nomogram achieved good discrimination, with an original AUC of 0.901 (95% CI, 0.813–0.989), and the bias-corrected concordance index (C-index) with 1,000 bootstraps was 0.834. The calibration curve and DCA also suggested both the high accuracy and clinical usefulness of the nomogram, respectively. ConclusionsThis study proposes an effective nomogram to predict different motor progression patterns in early-stage PD. Furthermore, the imaging biomarker indicating glymphatic function could be an independent predictive factor for PD motor progression.

Genome-wide Analysis of Motor Progression in Parkinson Disease.

The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets. We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores. We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (β = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode). Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.

Distinct amyloid-dependent patterns of nigra dopamine depletion in Lewy body diseases.

Concomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies. We enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status. There was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone. This study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Striatal Dopamine Transporter Uptake, Parkinsonism, and Cognition in Alzheimer's Disease.

The correlates of motor parkinsonism in Alzheimer's disease (AD) remains controversial. We evaluated the effects of nigrostriatal dopaminergic degeneration on parkinsonism and cognition in biomarker-validated patients with AD. This study recruited 116 patients with AD who underwent dual-phase 18 F-N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane PET, 18 F-Florbetaben PET, 3-Tesla brain MRI, Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests. The mean cortical thickness in the frontal, temporal, parietal, and occipital cortices, and the dopamine transporter (DAT) uptake in the caudate, anterior/posterior putamen, and substantia nigra were quantified. We investigated the relationship between DAT uptake, mean lobar cortical thickness, UPDRS motor score, and cognition using general linear models (GLMs) after controlling for age, sex, education, intracranial volume, and deep and periventricular white matter hyperintensities. A path analysis was performed for the UPDRS motor score with the same covariates. Path analysis and multivariable GLM for UPDRS motor score showed that lower caudate DAT uptake was directly associated with a higher UPDRS motor score, whereas caudate DAT uptake confounded the association between mean frontal/parietal thickness and UPDRS motor score. Multivariable GLMs for cognitive scores showed that lower caudate DAT uptake was associated with visuospatial/executive dysfunction independent of mean frontal or parietal thickness. Nigrostriatal dopaminergic dysfunction is associated with parkinsonism and visuospatial/executive dysfunction in patients with AD.

Time perception reflects individual differences in motor and non-motor symptoms of Parkinson's disease

Decreasing dopaminergic function is at the core of Parkinson's disease (PD) motor symptoms and changes in dopaminergic action are associated with many comorbid non-motor symptoms in PD. Notably, dopaminergic signaling in the striatum has been shown to play a critical role in the perception of time. We hypothesize that patients with PD perceive time differently and in accordance with their specific comorbid non-motor symptoms and clinical state. This means that individual differences in clinical symptoms may be reflected in individual differences in timing behavior. To test this hypothesis, we recruited patients with PD and compared individual differences in patients' clinical state with their ability to judge intervals of time ranging from 500 ms to 1100 ms while on and off their prescribed dopaminergic medications. We show that medication state (on vs. off medications) did not affect timing behavior, but individual differences in timing behavior are able to predict individual differences in comorbid non-motor symptoms, duration of PD diagnosis, and prescribed dopaminergic medications. We show that comorbid impulse control disorder is associated with temporal overestimation; depression is associated with decreased temporal accuracy; and increased PD duration and prescribed levodopa monotherapy are associated with reduced temporal precision and accuracy. Observed differences in time perception are consistent with hypothesized dopaminergic mechanisms thought to underlie the respective motor and non-motor symptoms in PD. In future work, time perception tasks may augment clinical diagnosis strategies, or help disentangle the neural and cognitive mechanisms underlying PD motor and non-motor symptom etiology.

Identification and quantitative assessment of motor complications in Parkinson's disease using the Parkinson's KinetiGraph™.

Effective management and therapies for the motor complications of Parkinson's disease (PD) require appropriate clinical evaluation. The Parkinson's KinetiGraph™ (PKG) is a wearable biosensor system that can record the motion characteristics of PD objectively and remotely. The study aims to investigate the value of PKG in identifying and quantitatively assessing motor complications including motor fluctuations and dyskinesia in the Chinese PD population, as well as the correlation with the clinical scale assessments. Eighty-four subjects with PD were recruited and continuously wore the PKG for 7 days. Reports with 7-day output data were provided by the manufacturer, including the fluctuation scores (FS) and dyskinesia scores (DKS). Specialists in movement disorders used the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-IV (MDS-UPDRS IV), the wearing-off questionnaire 9 (WOQ-9), and the unified dyskinesia rating scale (UDysRS) for the clinical assessment of motor complications. Spearman correlation analyses were used to evaluate the correlation between the FS and DKS recorded by the PKG and the clinical scale assessment results. Receiver operating characteristic (ROC) curves were generated to analyze the sensitivity and specificity of the FS and DKS scores in the identification of PD motor complications. The FS was significantly positively correlated with the MDS-UPDRS IV motor fluctuation (items 4.3-4.5) scores (r = 0.645, p < 0.001). ROC curve analysis showed a maximum FS cut-off value of 7.5 to identify motor fluctuation, with a sensitivity of 74.3% and specificity of 87.8%. The DKS was significantly positively correlated with the UDysRS total score (r = 0.629, p < 0.001) and the UDysRS III score (r = 0.634, p < 0.001). ROC curve analysis showed that the maximum DKS cut-off value for the diagnosis of dyskinesia was 0.7, with a sensitivity of 83.3% and a specificity of 83.3%. The PKG assessment of motor complications in the PD population analyzed in this study has a significant correlation with the clinical scale assessment, high sensitivity, and high specificity. Compared with clinical evaluations, PKG can objectively, quantitatively, and remotely identify and assess motor complications in PD, providing a good objective recording for managing motor complications.

Differential Implications of Cerebral Hypoperfusion and Hyperperfusion in Parkinson's Disease.

Patients with Parkinson's disease (PD) exhibit widespread brain perfusion changes. This study investigated whether cerebral regions with hypoperfusion and hyperperfusion have differential effects on motor and cognitive symptoms in PD using early-phase 18 F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (18 F-FP-CIT) positron emission tomography (PET) scans. We enrolled 394 patients with newly diagnosed PD who underwent dual-phase 18 F-FP-CIT PET scans. Indices reflecting associated changes in regional cerebral hypoperfusion and hyperperfusion on early-phase 18 F-FP-CIT PET scans were calculated as PD[hypo] and PD[hyper] , respectively. The associations of PD[hypo] and PD[hyper] on motor and cognitive symptoms at baseline were assessed using multivariate linear regression. Also, Cox regression and linear mixed models were performed to investigate the effects of baseline PD[hypo] and PD[hyper] on longitudinal outcomes. There was a weak correlation between PD[hypo] and PD[hyper] (γ = -0.19, P < 0.001). PD[hypo] was associated with baseline Unified Parkinson's Disease Rating Scale Part III scores (β = -1.02, P = 0.045), rapid increases in dopaminergic medications (β = -18.02, P < 0.001), and a higher risk for developing freezing of gait (hazard ratio [HR] = 0.67, P = 0.019), whereas PD[hyper] was not associated. Regarding cognitive function, PD[hypo] was more relevant to the baseline cognitive performance levels of visuospatial, memory, and frontal/executive function than PD[hyper] . However, greater PD[hyper] was associated with future dementia conversion (HR = 1.43, P = 0.004), whereas PD[hypo] was not associated. These findings suggest that PD[hypo] and PD[hyper] may differentially affect motor and cognitive functions in patients with PD. © 2023 International Parkinson and Movement Disorder Society.

The Association of the Glymphatic Function with Parkinson's Disease Symptoms: Neuroimaging Evidence from Longitudinal and Cross-Sectional Studies.

Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking. In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function. Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aβ1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5. The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683.

Do motor subtypes of Parkinson’s disease impact the learning of motor tasks?

BACKGROUND:Previous studies have demonstrated that people with Parkinson's disease (PD) can acquire postural control skills even with the degeneration of motor areas responsible for consolidation of the representation regarding the learned motor skill in long-term memory. However, these findings have not considered the PD motor subtypes – tremor-dominant (TD), and postural instability and gait difficulty (PIGD). Although there is considerable heterogeneity in motor and non-motor symptoms between TD and PIGD, no study has addressed the effect of the PD subtype on learning postural control skills. AIM:We investigated the influence of PD motor subtypes on the learning of tasks with different postural control demands. METHOD:Fourteen individuals with PD (7 TD, 7 PIGD) practiced four motor tasks with high postural and cognitive demands. Participants completed 13 one-hour sessions (2x/week for 7 weeks). We considered the first and last practice sessions, pre-test and post-test, respectively. Also, we conducted one-week and one-month retention tests to assess performance persistence (motor learning). We assessed motor performance through the scores achieved on each motor task. RESULTS:Both groups demonstrated improvement in performance during the acquisition phase. However, the TD group outperformed the PIGD group in all motor tasks, despite both groups showing improvement in motor performance when comparing the results of pre-test with the post-test, and the improved performance was maintained in retention tests. The performance differences between groups are dissipated during consolidation, and they did not directly affect motor learning. INTERPRETATION: The TD and PIGD motor subtypes learned postural control tasks with different motor and cognitive demands.

Rethinking the network determinants of motor disability in Parkinson's disease.

For roughly the last 30 years, the notion that striatal dopamine (DA) depletion was the critical determinant of network pathophysiology underlying the motor symptoms of Parkinson's disease (PD) has dominated the field. While the basal ganglia circuit model underpinning this hypothesis has been of great heuristic value, the hypothesis itself has never been directly tested. Moreover, studies in the last couple of decades have made it clear that the network model underlying this hypothesis fails to incorporate key features of the basal ganglia, including the fact that DA acts throughout the basal ganglia, not just in the striatum. Underscoring this point, recent work using a progressive mouse model of PD has shown that striatal DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. Given the broad array of discoveries in the field, it is time for a new model of the network determinants of motor disability in PD.

Irritable bowel syndrome based on Rome IV diagnostic criteria associates with non-motor symptoms of Parkinson's disease

BackgroundRecent concepts suggest that the neuropathological hallmark of Parkinson's disease (PD) may in part originate from the enteric nervous system. We evaluated the frequency of functional gastrointestinal disorders in PD patients using Rome IV criteria and correlated the clinical severity of PD. MethodsPD patients and matched controls were recruited between January 2020 and December 2021. Rome IV criteria were used to diagnose constipation and irritable bowel syndrome (IBS). Severity of PD motor symptoms was evaluated using UPDRS part III scores and non-motor symptoms using Non-motor Symptoms Scale (NMSS). ResultsA total of 99 PD patients and 64 controls were enrolled. The prevalence of constipation (65.7% vs. 34.3%, P < 0.001) and IBS (18.1% vs 5%, P = 0.02) were significantly higher in PD patients than controls. The prevalence of IBS was higher in early-stage PD than advanced-stage PD (14.43% vs. 8.25%, P = 0.02), whereas constipation was more common in advanced stages (71.43% vs. 18.56%, P < 0.001). PD patients with IBS had higher NMSS total scores (P < 0.01) than those without IBS. The severity of IBS correlated with NMSS scores (r = 0.71, P < 0.001), especially subscores in domain 3 assessing mood disorders (r = 0.83, P < 0.001), but not UPDRS part III scores (r = 0.06, P = 0.45). The severity of constipation correlated with the UPDRS part III scores (r = 0.59, P < 0.001) but not the domain 3 mood subscores (r = 0.15, P = 0.07). ConclusionThe prevalence of IBS and constipation was higher in PD patients than controls and phenotypic correlation supported the occurrence of IBS with higher non-motor symptom burden, especially mood symptoms, in PD patients.

Corticostriatal beta oscillation changes associated with cognitive function in Parkinson's disease.

Cognitive impairment is the most frequent non-motor symptom in Parkinson's disease and is associated with deficits in a number of cognitive functions including working memory. However, the pathophysiology of Parkinson's disease cognitive impairment is poorly understood. Beta oscillations have previously been shown to play an important role in cognitive functions including working memory encoding. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits increases the spectral power of beta oscillations and results in Parkinson's disease motor symptoms. Analogous changes in parallel cognitive CSTC circuits involving the caudate and dorsolateral prefrontal cortex (DLPFC) may contribute to Parkinson's disease cognitive impairment. The objective of our study is to evaluate whether changes in beta oscillations in the caudate and DLPFC contribute to cognitive impairment in Parkinson's disease patients. To investigate this, we used local field potential recordings during deep brain stimulation surgery in 15 patients with Parkinson's disease. Local field potentials were recorded from DLPFC and caudate at rest and during a working memory task. We examined changes in beta oscillatory power during the working memory task as well as the relationship of beta oscillatory activity to preoperative cognitive status, as determined from neuropsychological testing results. We additionally conducted exploratory analyses on the relationship between cognitive impairment and task-based changes in spectral power in additional frequency bands. Spectral power of beta oscillations decreased in both DLPFC and caudate during working memory encoding and increased in these structures during feedback. Subjects with cognitive impairment had smaller decreases in caudate and DLPFC beta oscillatory power during encoding. In our exploratory analysis, we found that similar differences occurred in alpha frequencies in caudate and theta and alpha in DLPFC. Our findings suggest that oscillatory power changes in cognitive CSTC circuits may contribute to cognitive symptoms in patients with Parkinson's disease. These findings may inform the future development of novel neuromodulatory treatments for cognitive impairment in Parkinson's disease.

DPP-4 inhibitors and type 2 diabetes mellitus in Parkinson's disease: a mutual relationship.

Parkinson's disease (PD) usually occurs due to the degeneration of dopaminergic neurons in the substantia nigra (SN). Management of PD is restricted to symptomatic improvement. Consequently, a novel treatment for managing motor and non-motor symptoms in PD is necessary. Abundant findings support the protection of dipeptidyl peptidase 4 (DPP-4) inhibitors in PD. Consequently, this study aims to reveal the mechanism of DPP-4 inhibitors in managing PD. DPP-4 inhibitors are oral anti-diabetic agents approved for managing type 2 diabetes mellitus (T2DM). T2DM is linked with an increased chance of the occurrence of PD. Extended usage of DPP-4 inhibitors in T2DM patients may attenuate the development of PD by inhibiting inflammatory and apoptotic pathways. Thus, DPP-4 inhibitors like sitagliptin could be a promising treatment against PD neuropathology via anti-inflammatory, antioxidant, and anti-apoptotic impacts. DPP-4 inhibitors, by increasing endogenous GLP-1, can also reduce memory impairment in PD. In conclusion, the direct effects of DPP-4 inhibitors or indirect effects through increasing circulating GLP-1 levels could be an effective therapeutic strategy in treating PD patients through modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurogenesis.