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Objectives: Despite the large amount of literature examining the potential influence of subthalamic nucleus deep brain stimulation (STN-DBS) on psychiatric symptoms and cognitive disorders, only a few studies have focused on its effect on personality. We investigated the correlation between total electrical energy delivered (TEED) and the occurrence of depressive traits in patients with Parkinson disease (PD) after one year of DBS. Materials and Methods: Our study involved 20 patients with PD (12 women, mean [±SD] age 57.60 ± 7.63 years) who underwent bilateral STN-DBS, whose personality characteristics were assessed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), according to the core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD) procedure. Results: We found that despite a marked improvement in motor functions and quality of life after 12 months, patients showed a significant increase in MMPI-2 subscales for depression (D scale and Depression scale) and in other content component scales (low self-esteem, work interference, and negative treatment indicators). Interestingly, only the TEED on the right side was inversely correlated with the changes in scale D (rs = −0.681, p = 0.007), whereas depressive traits did not correlate with disease duration, levodopa equivalent daily dose (LEDD) reduction, patient's age, or severity of motor symptoms. Conclusions: Our preliminary observations indicate that despite the excellent motor outcome and general improvement in quality of life, DBS treatment can result in patients poorly adjusting to their personal, familiar, and socio-professional life. Different influences and multiple factors (such as TEED, intra/postsurgical procedure, coping mechanisms, and outcome expectations) may affect depressive traits. Further advances are expected to improve stimulation methods.

INTRODUCTION: Patients with advanced Parkinson disease (PD) often experience problems with mobility, including walking under single- (ST) and dual-tasking (DT) conditions. The effects of deep brain stimulation in the subthalamic nucleus (DBS) versus dopaminergic medication (Med) on these conditions are not well investigated. MATERIALS AND METHODS: We used two ST and two DT-gait paradigms to evaluate the effect of DBS and dopaminergic medication on gait parameters in 14 PD patients (mean age 66 ± 8 years) under DBS(OFF)/Med(ON), DBS(ON)/Med(OFF), and DBS(ON)/Med(ON) conditions. They performed standardized 20-meter walks with convenient and fast speed. To test DT capabilities, they performed a checking-boxes and a subtraction task during fast-paced walking. Quantitative gait analysis was performed using a tri-axial accelerometer (Dynaport, McRoberts, The Netherlands). Dual-task costs (DTC) of gait parameters and secondary task performance were compared intraindividually between DBS(OFF)/Med(ON) vs DBS(ON)/Med(ON), and DBS(ON)/Med(OFF) vs DBS(ON)/Med(ON) to estimate responsiveness. RESULTS: Dopaminergic medication increased gait speed and cadence at convenient speed. It increased cadence and decreased number of steps at fast speed, and improved DTC of cadence during the checking boxes and DTC of cadence and number of steps during the subtraction tasks. DBS only improved DTC of cadence during the checking boxes and DTC of gait speed during the subtraction task. CONCLUSION: Dopaminergic medication showed larger additional effects on temporal gait parameters under ST and DT conditions in advanced PD than DBS. These results, after confirmation in independent studies, should be considered in the medical management of advanced PD patients with gait and DT deficits.

Neurophysiological studies exploring involuntary attention have reported that electroencephalographic (EEG) measures can indicate impaired neural processing from initial stages of Parkinson's disease (PD). Since involuntary attention is regulated by right hemisphere networks and PD generally initiates its motor symptomatology unilaterally, whether involuntary attention is impaired depending on the onset side of PD remains unknown.We compared the neurophysiological correlates of involuntary attention among a PD group with left-side onset (L-PD), a PD group with right-side onset (R-PD) symptomatology, and a healthy control group (HC). All participants performed an auditory involuntary attention task while a digital EEG was recorded.Our main finding was a reduction both in the P3a amplitude and evoked delta-theta phase alignment in the L-PD group compared to the HC. Further, there was a significant correlation between P3a amplitude and disease duration in the R-PD, but not in the L-PD group. Behaviorally, both clinical groups, and in particular L-PD, showed reduced orientation towards novel stimuli, and no reduction of distraction effects during the experiment.Our results indicate that involuntary attention is differentially impaired in patients with left side onset of symptoms. Involuntary attention impairment might be present from initial stages of left onset PD and become progressively compromised in patients with right onset PD.The onset side of symptomatology should be considered for attentional impairment in PD.

Onset of neuropsychiatric symptoms in older adults may represent prodromal manifestations of neurodegenerative disorders. The association between the onset of somatic symptom and related disorders (SSRD) and the subsequent development of neurodegenerative disorders remains unclear. A critical review of studies describing the association between SSRD and neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and Lewy body dementia was performed.To critically review studies describing the association between SSRD and neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and Lewy body dementia.A systematic review of Web of Science Core databases was carried out from inception of databases up to May 2021 to identify observational studies pertaining to both SSRD and neurodegenerative disorders. Data was extracted and compiled regarding subjects enrolled, age at onset of the SSRD and at onset of the neurodegenerative disorders, and specific SSRD manifestations and underlying neuropathologies reported.Thirteen articles were included. Of the 123 identified subjects with SSRD at baseline, 34.1% developed a neurodegenerative disorder, with 80.9% of these being a Lewy body spectrum disorder. The interval between onset of SSRD manifestations and subsequent development of a neurodegenerative disorder was less than 3 years for half of the cases. Of the 1,494 subjects with a neurodegenerative disorder at baseline retrieved, SSRD manifestations were reported in 33.4% of Lewy body spectrum disorders cases. Onset of SSRD manifestations antedated or was concomitant to the diagnosis of the Lewy body spectrum disorder in 65.6% of cases.While limited, current evidence suggests a possible association between late-onset SSRD and the subsequent development of neurodegenerative disorders, notably Lewy body spectrum disorders.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder accompanied by mild cognitive impairment (MCI) as a crucial nonmotor manifestation. Event-related oscillations (EROs) are suggested to reflect cognitive status associated with subcortical structures in neurodegenerative conditions. In this study, 36 individuals with PD-MCI and 32 PD-CN were compared with 60 healthy control (HC) participants using visual EROs by measures of event-related spectral perturbation and inter-trial coherence, along with subcortical gray matter volumes based on the FIRST algorithm. Cross-correlations among electrophysiological, neuropsychological, and structural parameters were investigated exploratively. Both PD-MCI and PD-CN patients had diminished delta and alpha phase-locking than HC, however, electrophysiological abnormalities were more pronounced in PD-MCI over frontal, central, parietal, and temporal locations in almost all frequency bands, accompanied by bilateral thalamus, hippocampus, and right putamen atrophy. PD-CN had lower hippocampal volumes than HC, without exhibiting any subcortical differences from PD-MCI. Lastly, EROs showed low-to-high correlations with structural and neuropsychological measures. These findings may highlight the complex interplay between electrophysiological, neuropsychological, and structural parameters in detected abnormalities of PD-CN and PD-MCI. Dokuz Eylül Üniversitesi

The use of the anti-parkinsonian drug trihexyphenidyl (THP) to treat patients with Parkinson's disease (PD), particularly those with tremor-dominant PD (tdPD), has been well documented. Despite growing concerns about THP causing cognitive decline in tdPD patients, the underlying neural correlates remain unclear. Therefore, we investigated the effects of THP on prefrontal executive function and spontaneous neural activity in patients with tdPD by utilizing functional near-infrared spectroscopy (fNIRS).We recruited 30 patients with tdPD, including 15 patients receiving THP and 15 patients not receiving THP. We performed comprehensive neuropsychological and clinical assessments to evaluate each patient's cognitive function, mental status, and clinical symptoms. We measured brain activation elicited from the verbal fluency task (VFT) and changes in amplitude of low-frequency fluctuations (ALFF) at rest to investigate executive function and spontaneous neural activity, respectively. In addition, we examined the relationship between altered activation during task and resting state and neuropsychological and clinical data.Compared with tdPD patients not taking THP, tdPD patients taking THP showed no differences on neuropsychological tests. However, there was insufficient activity of the dorsolateral prefrontal cortex (DLPFC) during VFT and reduced ALFF values for the DLPFC, ventrolateral prefrontal cortex (VLPFC), and the orbitofrontal cortex (OFC) related to the frontoparietal network (FPN) at rest. Furthermore, ALFF values of the VLPFC were positively correlated with scores of multiple cognitive domain functions.These findings suggest that THP treatment may lead to prefrontal dysfunction in tdPD patients, attenuating brain activation in executive function and cognition-related spontaneous neural activity.

Independently, veterans and individuals with Parkinson's Disease (PD) are at increased risk for suicide. To our knowledge, the risk of suicide among veterans with PD has yet to be evaluated. This study aimed to examine the associations between PD and risk of suicide, as well as suicide means among those using Veteran Health Administration (VHA) services.Retrospective cohort study of individuals who used VHA services between 1/1/2001-12/31/2019. Cox proportional hazard models were used to estimate the hazard of suicide for those with PD relative to those without. A nested-case control study was carried out among the suicide decedents where logistic regression was used to assess the relationship between PD and suicide by firearms versus suicide by any other means.The unadjusted hazard of death by suicide for those with a PD diagnosis, relative to those without, was 1.51 (95% CI: 1.32-1.72, p 0.0001), and was still significant after controlling for age/gender, and psychiatric/chronic physical health diagnoses (HR: 1.50; 95% CI: 1.32-1.72, p 0.0001; HR:1.21, 95% CI:1.06-1.38, p = 0.006, respectively). Compared to the non-PD cohort, the PD group also had higher rates of mood, anxiety, and psychotic disorders. There was no significant difference between the method of suicide for those with PD versus those without PD (p = 0.60). Most suicide deaths among both cohorts were firearm-related (PD = 78.9%, No-PD = 80.3%).PD is associated with an elevated risk for suicide. Based on the high rate of deaths by firearm, increased efforts to facilitate lethal means safety among veterans is warranted.

Turning in gait digital parameters may be useful in measuring disease progression in Parkinson's disease (PD), however challenges remain over algorithm validation in real-world settings. The influence of clinician observation on turning outcomes is poorly understood. Our objective is to describe a unique in-home video dataset and explore the use of turning parameters as biomarkers in PD.11 participants with PD, 11 control participants stayed in a home-like setting living freely for 5 days (with two sessions of clinical assessment), during which high-resolution video was captured. Clinicians watched the videos, identified turns and documented turning parameters.From 85 hours of video 3869 turns were evaluated, averaging at 22.7 turns per hour per person. 6 participants had significantly different numbers of turning steps and/or turn duration between "ON" and "OFF" medication states. Positive Spearman correlations were seen between the Movement Disorders Society-sponsored revision of the Unified Parkinson's Disease Rating Scale III score with a) number of turning steps (rho = 0.893, p 0.001), and b) duration of turn (rho = 0.744, p = 0.009) "OFF" medications. A positive correlation was seen "ON" medications between number of turning steps and clinical rating scale score (rho = 0.618, p = 0.048). Both cohorts took more steps and shorter durations of turn during observed clinical assessments than when free-living.This study shows proof of concept that real-world free-living turn duration and number of turning steps recorded can distinguish between PD medication states and correlate with gold-standard clinical rating scale scores. It illustrates a methodology for ecological validation of real-world digital outcomes.

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease caused by a combination of genetic and environmental risk factors. The serum metabolome refers to a set of small-molecules which are an important determinant of cellular health. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 376 metabolites which were population matched with 2 GWAS studies of AD. For each metabolite we performed 2-sample MR (2SMR) using an inverse variance weighted (IVW) estimate for significance testing. After Bonferroni multiple testing correction one metabolite was causally linked to AD in both GWAS: serum urate. This result was supported by robust 2SMR measures and sensitivity analyses. We applied 2SMR to test for a causal relationship between serum urate and other neurodegenerative diseases: Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS). In ALS but not PD we identified a nominally significant link between serum urate and disease-risk, although in this case increased serum urate was protective. We conclude that serum urate is a modulator of risk for neurodegeneration. Our work has implications for the design of preventative interventions.

Apathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine levels is correlated with apathetic symptoms. We aimed to ascertain the role of lateralization in the neuropathogenesis of apathy in PD.Twenty-six apathetic PD patients (PD-A), twenty-seven nonapathetic PD patients (PD-NA), and twenty-three healthy controls (HCs) were recruited. All subjects underwent T1-weighted and resting state functional MRI scanning during OFF medication state. Voxel-mirrored Homotopic Connectivity (VMHC) and asymmetry voxel-based morphometry (asymmetry VBM) analysis were applied to detect the synchrony of homotopic connections between hemispheres and grey matter asymmetry index.Compared with both PD-NA and HCs groups, the PD-A group showed excessively decreased z-VMHC values in the nucleus accumbens (NAcc) and putamen. Additionally, both PD subgroups exhibited decreased z-VMHC values in the cerebellum lobule VIII compared with controls. However, no corresponding alteration in grey matter asymmetry index was found. Further, a negative correlation between the z-VMHC values of the NAcc and the Apathy Scale (AS) was confirmed in the PD-A group. Meanwhile, the same relationship was also confirmed between the putamen and AS. Notably, ROC curve analyses uncovered that the z-VMHC values of the NAcc and putamen could be a potential neuroimaging feature discerning apathetic PD patient, respectively.This is a cross-sectional study.Our findings demonstrated that the asymmetric functional connectivity in the mesocorticolimbic and nigrostriatal systems might induce the pathophysiological mechanisms of apathy in PD.

The study examined how clinically measured walking capacity contributes to real-world walking performance in persons with Parkinson's disease (PD).Cross-sectional baseline data (n = 82) from a PD clinical trial were analyzed. The 6-Minute Walk Test (6MWT) and 10-Meter Walk Test (10MWT) were used to generate capacity metrics of walking endurance and fast gait speed, respectively. An activity monitor worn for seven days was used to generate performance metrics of mean daily steps and weekly moderate intensity walking minutes. Univariate linear regression analyses were used to examine associations between each capacity and performance measure in the full sample and less and more active subgroups.Walking capacity significantly contributed to daily steps in the full sample (endurance: RWalking capacity contributed to, but explained a relatively small portion of the variance in, real-world walking performance. The contribution was somewhat greater in less active individuals. The study adds support to the idea that clinically measured walking capacity may have limited benefit for understanding real-world walking performance in PD. Factors beyond walking capacity may better account for actual walking behavior.

and objective: Tremor is a disabling symptom of PD that usually responds poorly to available standard pharmacological agents. This study aimed to assess the effect of Zonisamide 25 mg on tremor in tremor-dominant PD patients as compared to placebo.This was a randomized, placebo-controlled, double-blind study. Parkinson's disease patients were allocated either to the intervention group (standard treatment along with Zonisamide 25 mg add-on) or the placebo group (standard treatment along with placebo). Baseline Unified Parkinson's Disease Rating Scale (UPDRS) and Tremor Research Group Essential Tremor Rating Scale (TETRAS) scores, as well as accelerometric tremor analysis were done and follow-up assessments of the same were done after 12 weeks of intervention. Percentage change from baseline in the UPDRS tremor score was the primary outcome whereas percentage change from baseline of total UPDRS score, UPDRS rigidity and bradykinesia scores, TETRAS score, and accelerometric tremor analysis values were the secondary outcomes.There was no significant difference in the percentage change from baseline UPDRS tremor scores between the two groups (placebo: 8.33 [-19.89-23.86] vs drug: 26.14 [-35.58 to -16.07], p-value: 0.164, CI: 0.157-0.171). Best-case analysis for missing values showed a significant improvement in the drug group, compared to the placebo group (p-value:0.001, CI:0.001 -0.001).Zonisamide at a dose of 25 mg per day did not improve tremor in tremor-dominant PD patients, however, a positive trend was seen as compared to Placebo in the UPDRS tremor score. Larger studies are required to confirm this finding.

Fatigue is one of the most common and debilitating non-motor symptoms in patients with Parkinson's disease (PD), which could manifest during the early stage of the disease and persist through the disease course. However, the treatment options for fatigue remain limited for patients with PD.Using seed-based resting-state functional magnetic resonance imaging, we explored the fatigue-related functional deficiencies in the anterior caudate nucleus, anterior putamen, and posterior putamen in a cohort of early-stage drug-naïve patients with PD. Thirty-eight patients with PD, 19 with and 19 without fatigue, and 31 matched healthy controls were selected. The fatigue status was defined based on the score obtained from the fatigue severity scale (FSS).Patients with PD with fatigue exhibited a decreased connectivity in the cerebellar-striatal, cortico-striatal, and mesolimbic-striatal loops. No increased functional connectivity was observed. The abnormal connections of the dorsal striatum subdivisions overlapped to extensive brain regions, including the cerebellum, inferior frontal gyrus, inferior temporal gyrus, lingual gyrus, rolandic operculum, insular, and hippocampus.Our findings revealed that the widespread functional deficiency in the striatal-cerebellar-cerebral cortical network may be critical to the pathology underlying fatigue in the early-stage PD. The key feature of fatigue-related connectivity was observed between the caudate nucleus and the cerebellum, which could serve as a potential biomarker or treatment target for fatigue in early-stage patients with PD in future studies.

To explore the potential clinical effects of renin-angiotensin system blocker (RASB, angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)) in patients from the Parkinson's Progress Marker Initiative (PPMI) study database.One hundred and seven untreated, newly diagnosed PD patients with hypertension, from the PPMI were included. We measured cognitive performance, biomarkers in CSF, and magnetic resonance imaging (MRI) during the five follow-up years for patients exposed or not to renal-angiotensin system blockers. Sixteen PD patients with hypertension underwent [18F]florbetaben positron emission tomography (PET) scanning. SUVRs of region of interest (ROI) were calculated and compared within different groups.Treatment with ARBs but not ACEIs improved global cognitive function evaluated by MoCA score in PD patients with hypertension compared to other hypertensive medicines up to 5 years follow up. Specifically, ARBs improved visuospatial, memory, executive abilities, processing speed attention test scores in PD. There was no significant impact of ARBs on α-syn, tau, Aβ in CSF. RASBs reduced [18F] florbetaben uptake in cortex and subcortex nuclei in the brain.These results show potential protective effect with ARBs in cognitive impairment of parkinson's disease with hypertension.

Anxiety that occurs in association with on-off dopamine medication fluctuations is a major cause of distress, dysfunction, and lower quality of life in people with Parkinson's disease (PD). However, the association between anxiety and on-off fluctuations is poorly understood and it is difficult to predict which patients will suffer from this atypical form of anxiety. To understand whether fluctuating anxiety in PD exists as part of an endophenotype that is associated with other signs or symptoms, we prospectively assessed the change in anxiety and a battery of clinical variables when transitioning from the off-dopamine medication state to the on state in 200 people with PD. We performed latent profile analysis with observed variables as latent profile indicators measuring the on-off-state difference in anxiety, depression, motor function, daily functioning, and the wearing off questionnaire 19 item scale (WOQ-19) in order to model unobserved (i.e., latent) profiles. A two-class model produced the best fit. The majority of participants, 69%, were categorized as having a 'typical on-off response' compared to a second profile constituting 31% of the sample who experienced a worsening in anxiety in the off state that was three times that of other participants. This profile referred to as "anxious fluctuators" had a Hamilton Anxiety Rating Scale change between the off and on medication state of 10.22(32.85) compared to 3.27 (7.62), higher depression scores, greater disability and was less likely to improve on select WOQ-19 items when in the on-state. Anxious fluctuators were more likely to be male and have a family history of anxiety disorder. Given the adverse impact of this profile we believe it may be important to distinguish patients with a typical on-off response from those with this more problematic course of fluctuations.

Fibril formation of α-synuclein is linked with Parkinson's disease. The intrinsically disordered nature of α-syn provides extensive conformational plasticity and becomes difficult to characterize its transition pathway from native monomeric to disease-associated fibril form. We implemented different simulation methods such as steered dynamics-umbrella sampling, and replica-exchange and conventional MD simulations to access various conformational states of α-syn. Nineteen distinct intermediate structures were identified by free energy landscape and cluster analysis. They were then sorted based on secondary structure and solvent exposure of fibril-core residues to illustrate the fibril dissociation pathway. The analysis showed that following the initial dissociation of the polypeptide chain from the fibril, α-syn might form either compact-conformations by long-range interactions or extended-conformations stabilized by local interactions. This leads α-syn to adapt two different pathways. The secondary structure, solvation, contact distance, interaction energies and backbone dihedrals of thirty-two selected residues were analyzed for all the 19 intermediates. The results suggested that formation of β-turns, reorganization of salt bridges, and dihedral changes in the hydrophobic regions are the major driving forces for helix-fibril transition. Structural features of the intermediates also correlated with the earlier experimental and computational studies. The study provides critical information on the fibrillation pathway of α-syn.

Parkinson's disease (PD) is a motor disorder charactertised by altered neural activity throughout the basal ganglia-thalamocortical circuit. Electrical deep brain stimulation (DBS) is efficacious in alleviating motor symptoms, but has several notable side-effects, most likely reflecting the non-specific nature of electrical stimulation and/or the brain regions targeted. We determined whether specific optogenetic activation of glutamatergic motor thalamus (Mthal) neurons alleviated forelimb akinesia in a chronic rat model of PD. Parkinsonian rats (unilateral 6-hydroxydopamine injection) were injected with an adeno-associated viral vector (AAV5-CaMKII-Chrimson-GFP) to transduce glutamatergic Mthal neurons with the red-shifted Chrimson opsin. Optogenetic stimulation with orange light at 15 Hz tonic and a physiological pattern, previously recorded from a Mthal neuron in a control rat, significantly increased forelimb use in the reaching test (p 0.01). Orange light theta burst stimulation, 15 Hz and control reaching patterns significantly reduced akinesia (p 0.0001) assessed by the step test. In contrast, forelimb use in the cylinder test was unaffected by orange light stimulation with any pattern. Blue light (control) stimulation failed to alter behaviours. Activation of Chrimson using complex patterns in the Mthal may be an alternative treatment to recover movement in PD. These vector and opsin changes are important steps towards translating optogenetic stimulation to humans.

The human phenomenon of loneliness has been increasing in prominence across societies, with precipitous increase since COVID-19, and individuals with Parkinson's disease are not unscathed. Loneliness is of clinical relevance as it is cross-sectionally related to, and longitudinally precedes, mortality and other health risks, including worse motor, cognitive, and behavioral-psychological functioning. Relatively few studies have evaluated loneliness, or associated social experiences, in the context of Parkinson's, but the existing data is provocative. The authors advocate for clinicians' awareness and researchers' investigational focus.

Non-invasive brain stimulation (NIBS), especially repetitive transcranial magnetic stimulation (rTMS), is a promising therapeutic tool for managing the psychiatric symptoms of Parkinson's disease (PD). This meta-analysis aims to assess the effect of NIBS on psychiatric symptoms in patients with PD.Several electronic databases were systematically searched for relevant literature from inception to October 18, 2021. The therapeutic effects of NIBS were evaluated using a random-effects meta-analysis based on the standard mean difference (SMD) and multivariable-adjusted effect estimates and subgroup analyses. Publication bias and sensitivity analyses were used to explore the sources of heterogeneity.Finally, 57 and 15 studies with 4,010 participants were obtained from the meta-analysis and systematic review, respectively. Significant differences were found between NIBS and sham-stimulation/placebo participants for depression (SMD = -0.75, 95 % confidence interval [CI]: -0.99 to -0.50, INIBS can be considered an effective non-pharmacological option for treating PD depression; moreover, rTMS combined with antidepressants was demonstrated to be a useful tool against depression and anxiety in PD.

Freezing of gait (FOG) is a devastating symptom that develops in patients with advanced Parkinson's disease (PD) and is often unresponsive to pharmacological treatment. Recent research suggests that FOG may result from dysfunctional plantar peripheral sensory systems. The impact of combined plantar pressure and vibratory stimulation over vibratory or pressure alone on FOG remains unexplored.PD patients with FOG were randomised into four groups and treated with combined vibratory and pressure stimulation, vibratory stimulation alone, pressure stimulation alone, or controls (no stimulation). Vibratory stimulation targeted both Achilles' tendons. Simultaneous bilateral pressure stimulation was applied to the first hallux, first metatarsal bone, and the sole. The primary outcome included normalized percent changes in percent FOG measured both pre- and immediately post-stimulation. Other outcomes including clinical rating scale, response to questionnaires, number and duration of freezing episodes, and spatiotemporal gait parameters at pre- and freezing episodes were also explored.Sixty PD patients participated in the study. Patients who were treated with combined vibratory and pressure stimulation responded with significant decreases in normalized percent changes of percent FOG (62.75 ± 25.54%, p 0.001) compared with those treated with vibration alone (11.38 ± 8.29%, p 0.001), pressure alone (15.15 ± 16.18%, p 0.001), or controls (8.59 ± 16.85%, p 0.001).Our study demonstrated the benefit of combined vibratory and pressure stimulation on FOG suggesting that this strategy might be developed as a novel treatment modality for PD patients with FOG.

It is well-known that α-synuclein (Syn) protein aggregation is implicated in the pathogenesis of Parkinson's disease. There is an increased evidence that large protein aggregates populate very early the subsaturated solutions of several aggregate-prone proteins, including Syn. The role of these early large protein aggregates and the reaction processes that they involve remain elusive. Amyloid protein's fluorophores (aromatic residues) can retrieve information regarding the amyloid protein's aggregation, by monitoring their fluorescence intensity. By excitation of Syn tyrosine residues in a low ionic strength medium (0.01 M tris-HCl) and collecting the time resolved fluorescence (stopped-flow analysis) it was possible to discriminate a time window of the first ca. 2 s, corresponding to the prevalent dissociation of early large Syn aggregates formed. Lowering even further the media ionic strength, such as Syn in water and Syn in solution containing 1,4-dioxane (pH ≈ 6.5), the above referred time window of the first ca. 2 s was abolished. It should be expected that Syn aggregation mainly occurred. In fact, Syn aggregation is initially delayed by the addition of a structure-induced agent (1,4-dioxane) in a stepwise mechanism. This study retrieves that very early the large Syn aggregates formed are unstructured and, in low ionic strength media (0.01 M), they restructure in the dissociation process and intertwined the occurrence of its aggregation. In lower ionic strength media (0.01 M), the large Syn aggregates dissociation is abolished and its aggregation is initially delayed, conferring to these protein aggregates restructuring in a stepwise mechanism.

This meta-analysis aimed to evaluate the effect of pioglitazone on Parkinson's disease (PD) in diabetes patients.A study search was carried out in PubMed, Embase, and Web of Science databases from inception to July 22, 2021. The Newcastle-Ottawa scale was used to evaluate the quality of the eligible studies. The risk ratio (RR) and 95% confidence intervals (CI) were used as effect size indicators in this meta-analysis to evaluate the risk association between pioglitazone and PD. The Cochran's Q and IThree studies were eligible for this meta-analysis. Compared with diabetes patients who did not use pioglitazone, there was a significant reduction in the risk of PD (RR of 0.87 [95 % CI 0.62-0.99, P = 0.039]) in pioglitazone users. No significant difference in PD risk was noted in diabetes patients taking 438 dose-duration-days (DDDs) of pioglitazone or lower compared with those who did not. When the DDD of pioglitazone was 438, the RR was 0.85 (95 % CI [0.72-1.00], P = 0.05). When the DDD of pioglitazone was 438, the risk of PD in patients with diabetes was significantly decreased (P 0.05) and showed an approximate linear correlation trend.Pioglitazone administration in PD in diabetes patients is significantly associated with a decrease in the risk of PD.

Language disorders in Parkinson's Disease (PD) following bilateral subthalamic Nucleus Deep Brain Stimulation (STN-DBS) are common.To assess STN-DBS impact on language and observe clinical and anatomical predictors of poor outcome.We prospectively included PD patients undergoing STN-DBS. We performed a neuropsychological evaluation focusing on language before (V0), 3 days after (V1), and 3 months after (V2) surgery. Patients performed all assessments in ON drug condition, V1 with the stimulation turned OFF to evaluate the lesion effect, and V2 with the stimulation turned ON to evaluate the stimulation effect. Electrodes and active contact locations were determined with MRI-Atlas fusion. The stimulation parameters and the total electrical energy delivered (TEED) were recorded for each patient.18 PD patients consecutively operated were included. We identified a decline in phonemic verbal fluency (VFP) at V1 and V2 (p = 0.023 and 0.032 respectively), as well as in semantic verbal fluency (VFS) (p = 0.025 and 0.019, respectively). There was a significant slowdown in the verbs naming test (p = 0.048). No other language alteration was recorded. There was no correlation between demographic or clinical factors and verbal fluency (VF) evolution. Active contact location within substantia nigra was associated with VFP worsening (p = 0.047), while elevated TEED on the left-sided electrode was associated with VFS decline (p = 0.021).VF was significantly altered following STN-DBS. Location outside the dorsolateral sensorimotor STN, and high stimulation power appeared to promote this decline. Other language domains remained stable.

Free water fraction (FWF) is considered a metric of microstructural integrity and may be useful in predicting cognitive decline in idiopathic Parkinson's Disease (PD). We sought to determine if higher FWF within the dorsal portion of the caudate nucleus and basal nucleus of Meynert, two regions associated with cognitive decline in PD, predict change in cognition over a two-year span. Due to the existence of cognitive and neurophysiological subgroups within PD, we statistically categorized participants based on FWF in these regions.At baseline, participants completed a research cognitive protocol followed by MRI structural and diffusion metrics. We used k-means cluster analysis with average FWF values from bilateral basal nucleus of Meynert and dorsal caudate to create data-driven FWF clusters for baseline. Two-year reliable change indices were calculated for metrics of language, visuospatial, memory, cognitive flexibility, and reasoning domains. Reliable change scores were compared between the clusters and non-PD peers.Baseline participants included 174 participants (112 PD, 62 non-PD). Cluster analysis yielded three clusters: low FWF in both regions of interest (ROIs), high FWF in both ROIs, and moderate FWF in both ROIs. Reliable change analyses were completed on 93 participants (67 PD, 26 non-PD). After controlling for age and education, the High FWF cluster declined more than non-PD peers in every domain except memory.Individuals with high FWF in regions associated with cognitive decline in PD show significant decline across several cognitive domains compared to non-PD peers. Future research should include FWF in additional cortical regions.

Gingival mesenchymal stem cells (GMSCs) demonstrate high proliferation, trilineage differentiation and immunomodulatory properties. Parkinson disease (PD) is the second most common type of neurodegenerative disease. This study aimed to explore the effect and mechanism of GMSC-based therapy in 6-hydroxydopamine-induced PD rats.RNA sequencing and quantitative proteomics technology was used to validate the neuroprotective role of GMSCs therapeutic in 6-Hydroxydopamine -induced PD model in vitro and in vivo. Western blotting, immunofluorescence and real-time quantitative PCR verified the molecular mechanism of GMSCs treatment.Intravenous injection of GMSCs improved rotation and forelimb misalignment behavior, enhanced the anti-apoptotic B-cell lymphoma 2/B-cell lymphoma 2-associated X axis, protected tyrosine hydroxylase neurons, decreased the activation of astrocytes and reduced the astrocyte marker glial fibrillary acidic protein and microglia marker ionized calcium-binding adaptor molecule 1 in the substantia nigra and striatum of PD rats. The authors found that GMSCs upregulated nerve regeneration-related molecules and inhibited metabolic disorders and the activation of signal transducer and activator of transcription 3. GMSCs showed a strong ability to protect neurons and reduce mitochondrial membrane potential damage and reactive oxygen species accumulation. The safety of GMSC transplantation was confirmed by the lack of tumor formation following subcutaneous transplantation into nude mice for up to 8 weeks.The authors' research helps to explain the mechanism of GMSC-based therapeutic strategies and promote potential clinical application in Parkinson disease.

Parkinson's disease (PD) is a common neurodegenerative disease. The main pathological feature is the degeneration and loss of dopaminergic neurons in the substantia nigra, which leads to the significant decrease of dopamine content in the striatum. Our recent studies have shown that scorpion venom heat-resistant synthetic peptide (SVHRSP) have protective effects on neuroinflammation. In this study, using C. elegans induced by 6-hydroxydopamine (6-OHDA) as neurodegenerative model, we investigated the effect of SVHRSP on dopaminergic neurons neurotoxicity. Our results implied that SVHRSP treatment could improve the motor capacity in 6-OHDA-induced C. elegans and improve dopaminergic neuron mediated food sensitivity behavior. After SVHRSP treatment, dopaminergic neuron degeneration induced by 6-OHDA was significantly prevented along with a decreased α-synuclein aggregation and restored lipid deposition in C. elegans induced by 6-OHDA. We also observed the reduced levels of reactive oxygen species (ROS) after SVHRSP treatment in model-building C. elegans. In addition, the genes related to apoptosis, oxidative stress, like ctl-1, egl-1and cat-2 in C. elegans induced by 6-OHDA upregulated after treatment with SVHRSP. In conclusion, SVHRSP may impose anti-PD effect through its neuroprotective action on dopaminergic neurons. This study elucidates the effect and related mechanism of SVHRSP on PD and provides evidences for the therapeutic treatment of PD.

Parkinson's disease (PD) is a neurological disorder. Recently, celastrol (Cel) has been reported to have neuroprotective properties. We investigated the protective effects of Cel on PD in a cell model with 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells and further addressed the underlying protective mechanisms of Cel.PC12 cells were treated with 6-OHDA, and Cel was added to the medium at various concentrations. The CCK-8 assay, Hoechst/PI staining, and flow cytometry analysis were performed to detect cellular viability and apoptosis. Mitochondrial membrane potential (MMP) was examined by JC-1 staining. ROS level was quantified by ROS staining. The effects of Cel on the expression of miR-146a and PI3K/Akt/mTOR pathway were then clarified using real-time PCR and Western blotting. Moreover, a miR-146a mimic was synthesized and transfected into PC12 cells to further determine the mechanisms of Cel's neuronal protection against 6-OHDA-induced neurotoxicity.Cel greatly improved cell viability and lessened apoptosis. Flow cytometry showed that Cel especially inhibited early apoptosis. Cel also obviously restored the MMP and decreased ROS level destroyed by 6-OHDA. Moreover, 6-OHDA increased the expression of miR-146a and decreased pAkt/mTOR protein levels, whereas Cel reversed these changes. In particular, miR-146a targeted and inhibited the expression of PI3K, an upstream molecule of Akt/mTOR. Transfection of 6-OHDA-treated neurons with miR-146a mimic notably attenuated Cel's protective effects.There were no animal experiments in our study.Cel exerts neuroprotective activity against 6-OHDA-caused neurotoxicity by regulating miR-146a/PI3K/Akt/mTOR pathway, which provides a potential application of Cel for treating neurodegenerative diseases.

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in 'average' healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson's disease patients. Current knowledge on gastrointestinal conditions in these patients was incorporated into model development. Relevant in vivo pharmacokinetic data and patient-specific in vitro release data from a novel in vitro test setup were integrated into patient-specific physiologically-based pharmacokinetic models. AUC, c

The mechanism of Pisa syndrome in Parkinson's disease (PD) is unclear. We aimed to analyze the spatial perception of patients with PD with Pisa syndrome using virtual reality.In total, 16 patients with Pisa syndrome, 16 age-matched patients without Pisa syndrome, and 16 age-matched controls were included. They viewed the virtual room gradually tilting to different 8 directions randomized across trials. The 75% discrimination threshold angle and the mean tilting discrimination angle for each direction were evaluated. Participants' lateral trunk deviation was measured using Kinect. Neuropsychological status was evaluated, using the Mini-Mental Status Examination (MMSE), the Japanese version of the Montreal-Cognitive Assessment, Frontal Assessment Battery, and the color-word interference task of the Stroop test. Visuospatial abilities were assessed using Benton Judgement of Line Orientation, and vestibular function was evaluated using Subjective Visual Vertical (SVV).The 75% discrimination threshold in the tilting discrimination angle was larger in all directions for those in the Pisa syndrome group compared to patients in the without Pisa syndrome group and those in the control group. There were significant differences between the three groups for Front-Right, Right, and Back. Patients with Pisa syndrome showed a significantly worse performance in these tests compared with controls and tended to have worse SVV performance compared with patients without Pisa syndrome.The present findings support the hypothesis of visuo-spatial disability and/or attentional impairment in patients with Pisa syndrome.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting millions each year. Most PD cases (∼90%) are sporadic, resulting from the age-dependent accumulation of pathogenic effects. One key pathological hallmark of PD progression is the accumulation of alpha-synuclein (α-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2+/+ and Nrf2-/- mice overexpressing human α-syn (PD model), we show that loss of NRF2 increases markers of ferroptosis across PD-relevant brain regions. Increased ferroptosis was associated with an age- and genotype-dependent increase in α-syn pathology and behavioral deficits. Finally, we demonstrate that α-syn overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to α-syn suppression of NRF2 at the protein level. Altogether, these results indicate that NRF2 is a critical anti-ferroptotic mediator of neuronal survival, and that the vicious cycle of α-syn overexpression and NRF2 suppression, leading to enhanced neuronal ferroptotic cell death, could represent a targetable and currently untapped means of preventing PD onset and progression.

To explore possible forms of domestic violence suffered by men with Parkinson's disease (PD).A qualitative study was conducted through face-to face interviews, followed by a conceptual content analysis. Forms of violence were predetermined as code categories according to a classification of mistreatment and a lack within Maslow's hierarchy of needs. Data triangulation was performed by two researchers using the "long table" method according to Kruegeramp; Casey.Eleven men with PD were interviewed to identify experienced forms of domestic violence. Since PD, the men felt neglected by their partners, lived in the fear of the partner's reactions, described a mutual sexual and physical distance, suffered from mockeries, humiliations, physical violence, and had a feeling of abandon while facing and managing PD.Domestic violence against men with PD exists and should be screened during communication with healthcare professionals.Domestic violence has different faces and is not always identified by the victims themselves. Spouses with profiles at risk for domestic violence against men with PD should be identified. Domestic violence can be triggered by female gender, alcoholism, anxiety and depression, a low educational level, low interest in and low knowledge about PD.

Early diagnosis of Parkinson's disease (PD) could significantly improve outcomes for patients and future disease-modifying treatments. Several studies have revealed that α-synuclein levels in peripheral erythrocytes are associated with PD, but the diagnostic value in early PD is still unknown.This study included both cross-sectional and longitudinal design. The subjects included 45 patients with early PD and 79 age-matched healthy controls. Participants were re-examined with repeated blood collection and clinical assessments after 3 years. The electrochemiluminescence assay was used to measure total and oligomeric α-synuclein levels respectively. The diagnostic value of erythrocytic α-synuclein for early PD was determined by receiver operator characteristic (ROC) curve. Correlations between RBC α-synuclein levels and changes over 3 years in clinical characteristic scores were further investigated with a linear regression.Total and oligomeric α-synuclein levels in erythrocyte were significantly increased in early PD groups compared with control group (Total α-synuclein, p 0.001; Oligomer, p 0.001). Levels of total and oligomeric α-synuclein in erythrocytes were correlated with MDS-UPDRS III scores in early PD (Total α-synuclein, p = 0.008; Oligomer, p = 0.037). After adjusting for age, gender and dopaminergic medication, an association was found between higher erythrocytic oligomeric α-synuclein levels at baseline and greater increase in MDS-UPDRS III scores over 3 years (p = 0.007).Our study suggests that total and oligomeric α-synuclein in erythrocyte were elevated even in the initial motor stage of PD. Higher erythrocytic oligomeric α-synuclein levels at baseline predicts a faster clinical decline over time in patients with early PD.

Sirtuin 1 (SIRT1) is an NAD

BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD) and often leads to dementia, with no effective treatment. Aging studies suggest that physical activity (PA) intensity has a positive impact on cognition and enhanced functional connectivity may underlie these benefits. However, less is known in PD. This cross-sectional study examined the relationship between PA intensity, cognitive performance, and resting state functional connectivity in PD and whether PA intensity influences the relationship between functional connectivity and cognitive performance. METHODS: 96 individuals with mild-moderate PD completed a comprehensive neuropsychological battery. Intensity of PA was objectively captured over a seven-day period using a wearable device (ActiGraph). Time spent in light and moderate intensity PA was determined based on standardized actigraphy cut points. Resting-state fMRI was assessed in a subset of 50 individuals to examine brain-wide functional connectivity. RESULTS: Moderate intensityPA (MIPA), but not light PA, was associated with better global cognition, visuospatial function, memory, and executive function. Individuals who met the WHO recommendation of ≥150 min/week of MIPA demonstrated better global cognition, executive function, and visuospatial function. Resting-state functional connectivity associated with MIPA included a combination of brainstem, hippocampus, and regions in the frontal, cingulate, and parietal cortices, which showed higher connectivity across the brain in those achieving the WHO MIPA recommendation. Meeting this recommendation positively moderated the associations between identified functional connectivity and global cognition, visuospatial function, and language. CONCLUSION: Encouraging MIPA, particularly the WHO recommendation of ≥150 min of MIPA/week, may represent an important prescription for PD cognition.

Contains fulltext : 287492.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Unplanned hospital admissions associated with Parkinson's disease could be partly attributable to comorbidities. METHODS: We studied nationwide claims databases and registries. Persons with newly diagnosed Parkinson's disease were identified based on the first Parkinson's disease-related reimbursement claim by a medical specialist. Comorbidities were classified based on the Charlson Comorbidity Index. We studied hospitalization admissions because of falls, psychiatric diseases, pneumonia and urinary tract infections, PD-related hospitalizations-not otherwise specified. The association between comorbidities and time-to-hospitalization was estimated using Cox proportional hazard modelling. To better understand pathways leading to hospitalizations, we performed multiple analyses on causes for hospitalizations. RESULTS: We identified 18 586 people with newly diagnosed Parkinson's disease. The hazard of hospitalization was increased in persons with peptic ulcer disease (HR 2.20, p = 0.009), chronic obstructive pulmonary disease (HR 1.61, p

Previous studies have assessed antipsychotic use after Parkinson's disease (PD) diagnosis, but incident antipsychotic use before PD diagnosis is unknown. The objective is to study the incidence of antipsychotic use among community-dwelling persons with and without PD 10 years before and after the PD diagnosis.The study was based on the nationwide register-based FINPARK-study including 20,994 persons with PD (diagnosed 1996-2015) and 142,944 comparison persons who had not used antipsychotics during one-year washout before the follow-up. PD was diagnosed according to the United Kingdom's Parkinson's disease Society Brain Bank's criteria. Antipsychotic initiations in six-month time-windows was assessed.26.9% (n = 5,654) of people with PD initiated antipsychotics in comparison to 9.7% (n = 13,887) of people without PD during the entire follow-up. The incidence rate increased in people with PD approximately four years before the PD diagnosis. The most commonly initiated antipsychotic was quetiapine (n = 3,642, 64.4%) in persons with PD and risperidone (n = 5,232, 37.7%) in comparison persons. The initiation rates were higher in persons with PD before (6.5 and 3.0/1000 person-years for persons with and without PD, respectively, incidence rate ratio 2.18, 95%CI 2.03-2.33) and after the index date (43.3 and 11.7/1000 person-years for persons with and without PD, respectively, IRR 3.70, 95%CI 3.57-3.83).Persons with PD have symptoms treated with antipsychotics both before and after diagnosis. Psychotic symptoms may be challenging to recognize as prodromal symptoms since they can occur years before the motor symptoms and thus, they cannot be clinically associated with the diagnosis of PD.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. The pathophysiology of this disease is the formation of the Lewy body, mostly consisting of alpha-synuclein and dysfunctional mitochondria. There are two common PD-associated genes, Pink1 (encoding a mitochondrial ser/thr kinase) and Parkin (encoding cytosolic E3-ubiquitin ligase), involved in the mitochondrial quality control pathway. They assist in removing damaged mitochondria via selective autophagy (mitophagy) which if unchecked, results in the formation of protein aggregates in the cytoplasm. The role of Rab11, a small Ras-like GTPase associated with recycling endosomes, in PD is still unclear. In the present study, we used the PD model of Drosophila melanogaster and found that Rab11 has a crucial role in the regulation of mitochondrial quality control and endo-lysosomal pathways in association with Parkin and Pink1 and Rab11 acting downstream of Parkin. Additionally, overexpression of Rab11 in parkin mutant rescued the mitochondrial impairment, suggesting the therapeutic potential of Rab11 in PD pathogenesis.

To investigate whether varying practice context during gait training could reduce context dependency and facilitate transfer of improved gait performance to a new context.A single-blind, parallel-group randomized controlled trial.Medical university rehabilitation settings.Forty-nine participants with Parkinson disease were recruited and randomized into the constant (CONS) or varied (VARI) context group.All participants received 12 sessions of treadmill and over-ground gait training. The CONS group was trained in a constant environmental context throughout the study, whereas the VARI group received training in 2 different contexts in an alternating order.The primary outcome was gait performance, including velocity, cadence, and stride length. The participants were assessed in the original training context as well as in a novel context at posttest to determine the influence of changed environmental context on gait performance.Though both groups improved significantly after training, the CONS group showed greater improvement in stride length than the VARI group when assessed in the original practice context. However, the CONS group showed a decreased velocity and stride length in the novel context, whereas the VARI group maintained their performance.Varying practice context could facilitate transfer of improved gait performance to a novel context.

The anterior-superior movement of the hyoid bone plays a significant role in securing the airway and smooth passage of food through the cricopharyngeal muscle. The hyoid bone can be detected easily with instruments such as the videofluoroscopic swallow study (VFSS) and ultrasonography (US), which have made quantitative kinematic analysis possible. Dysphagia is a critical issue in different diseases, including stroke, Parkinson's disease (PD), head and neck cancer, and amyotrophic lateral sclerosis (ALS), and the data obtained on these diseases from swallowing kinematic analysis has been accumulating. In this review article, we aimed to present the distinct features of kinematic analysis of hyoid movement in stroke, PD, head and neck cancer, and ALS. We also present the possible relationship between altered hyoid kinematics and dysphagia.

The prevalence of swallowing disorders in Parkinson's disease (PD) is relatively high. Different physiotherapy interventions for swallowing disorders are available but there is a lack of evidence-based medicine for their effectiveness in PD.The purpose of this systematic review was to investigate the effects of different physiotherapy interventions on dysphagia in PD.This systematic review was conducted according to PRISMA guidelines. We methodically searched databases including PubMed, PEDro, Cochrane Library, Embase, and Web of Science. Studies of any language published up to March 2022 were searched. Randomized controlled trials (RCTs) of non-pharmacological treatment for dysphagia in PD were selected in strict accordance with our exclusion and inclusion criteria.In total, we identified and included 10 RCTs in patients with PD undergoing dysphagia. This review involved seven rehabilitation treatments, including acupuncture, expiratory muscle strength training (EMST), repetitive transcranial magnetic stimulation (rTMS), video-assisted swallowing therapy (VAST), electrical stimulation, and speech and language therapy (SLT).For physiotherapy treatments, including acupuncture, EMST, high-frequency rTMS and VAST may be effective treatments for dysphagia in patients with PD. However, there was not enough evidence that electrical stimulation has therapeutic effects on dysphagia in patients with PD.

The efficient production of dopaminergic neurons via the direct conversion of other cell types is of interest as a potential therapeutic approach for Parkinson's disease. This study aimed to investigate the use of elongated porous gold nanorods (AuNpRs) as an enhancer of cell fate conversion. We observed that AuNpRs promoted the direct conversion of fibroblasts into dopaminergic neurons in vivo and in vitro. The extent of conversion of fibroblasts into dopaminergic neurons depended on the porosity of AuNpRs, as determined by their aspect ratio. The mechanism underlying these results involves specific AuNpR-induced transcriptional changes that altered the expression of antioxidant-related molecules. The generation of dopaminergic neurons via the direct conversion method will open a new avenue for developing a therapeutic platform for Parkinson's disease treatment. STATEMENT OF SIGNIFICANCE: In this study, we applied modified gold nanoporous materials (AuNpRs) to the direct lineage reprogramming of dopaminergic neurons. The cell reprogramming process is energy-intensive, resulting in an excess of oxidative stress. AuNpRs facilitated the direct conversion of dopaminergic neurons by ameliorating oxidative stress during the reprogramming process. We have found this mechanistic clue from high throughput studies in this research work.

In the present study, real-time quaking-induced conversion (RT-QuIC) assay was used to evaluate pathologic alpha-synuclein (AS) seeding activity in formalin-fixed paraffin-embedded (FFPE) tissue from the gastrointestinal (GI) tract of Parkinson's disease (PD) patients.This study was conducted in two parts: Part I. a preliminary autopsy study that included four autopsy-confirmed patients with synucleinopathy (2 PD, 1 dementia with Lewy bodies [DLB], and 1 multiple system atrophy [MSA]) and two normal autopsy controls. Frozen and FFPE tissues of the brain were obtained. Part II. a clinical case-control study that included 20 clinically diagnosed PD patients and matched controls. Surgically resected FFPE tissues from the upper and lower GI tracts were used. The RT-QuIC assay was performed to evaluate pathologic seed amplification using frozen or FFPE tissues. The presence or absence of AS aggregation was confirmed by conventional phosphorylated AS (pAS) immunohistochemistry (IHC).In Part I, RT-QuIC assay showed pathologic AS amplification in frozen and FFPE brain tissues of PD and DLB patients, and FFPE stomach tissue of PD patients but not in the MSA patient and controls. In Part II, pathologic seeding activity was found in 10% (2/20) of the stomach tissues of clinical PD patients but in none of the matched controls. IHC showed pAS-positive staining in 55% of patients (11/20) and 15% of controls (3/20).The present study results showed that the RT-QuIC assay using FFPE tissue of the GI tract was inadequate as a biomarker in PD.

We investigated the electrophysiological relationships in the cortico-basal ganglia network on a sub-centimeter scale to increase our understanding of neural functional relationships in Parkinson's disease (PD).Data was intraoperatively recorded from 2 sources in the human brain-a microelectrode in the subthalamic nucleus (STN) and a micro-electrocorticography grid on the motor association cortex-during bilateral deep brain stimulation (DBS) electrode placement. STN neurons and local field potential (LFP) were defined as functionally connected when the 99.7% confidence intervals of the action potential (AP)-aligned average LFP and control did not overlap.APs from STN neurons were functionally connected to the STN LFP for 18/46 STN neurons. This functional connection was observed between STN neuron APs and cortical LFP for 25/46 STN neurons. The cortical patterns of electrophysiological functional connectivity differed for each neuron.A subset of single neurons in the STN exhibited functional connectivity with electrophysiological activity in the STN and at a distance with the motor association cortex surveyed on a sub-centimeter spatial scale. These connections show a per neuron differential topography on the cortex.The cortico-basal ganglia circuit is organized on a sub-centimeter scale, and plays an important role in the mechanisms of PD and DBS.

Almost half of the nigral neurons are already lost during the preclinical period of Parkinson's disease (PD), and then the speed of neuronal loss is slowly attenuated during the subsequent progression. We sought to establish long-term temporal trajectory models for the dopaminergic input to the striatal subregions and a 4D-temporal trajectory model for the dopamine transporter positron emission tomography (PET).We selected 83 patients in PD spectrum who underwent dopamine transporter PET scan twice and 71 age-matched healthy controls. We created temporal trajectories of specific binding ratios of the striatal subregions by integrating function between baseline values and their annual change rates and also created 4D-temporal trajectory model by applying the same method for each striatal voxel. Using the PET data of additional 100 PD patients, we estimated an individual time point in the 4D-temporal trajectory model for the validation.Degenerative loss of striatal dopaminergic input first appeared in the posterior dorsal putamen in the more affected side at 14.4 years before the clinical onset, and subsequently in the posterior ventral and anterior putamen, and finally in the caudate. The time delay between the initiation of dopaminergic loss in the more and less affected posterior dorsal putamen was 6.1 years. The estimated individual time points within the entire disease course were correlated with the motor severity.Our temporal trajectory model demonstrated a sequential loss of dopaminergic input in the striatal subregions in PD and may be beneficial for the evaluation of individual status of disease progression.

Background: Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with no cure, presenting a challenging diagnosis and management. However, despite a significant number of criteria and guidelines have been proposed to improve the diagnosis of PD and to determine the PD stage, the gold standard for diagnosis and symptoms monitoring of PD is still mainly based on clinical evaluation, which includes several subjective factors. The use of machine learning (ML) algorithms in spatial-temporal gait parameters is an interesting advance with easy interpretation and objective factors that may assist in PD diagnostic and follow up. Research question: This article studies ML algorithms for: i) distinguish people with PD vs. matched-healthy individuals; and ii) to discriminate PD stages, based on selected spatial-temporal parameters, including variability and asymmetry. Methods: Gait data acquired from 63 people with PD with different levels of PD motor symptoms severity, and 63 matched-control group individuals, during self-selected walking speed, was study in the experiments. Results: In the PD diagnosis, a classification accuracy of 84.6 %, with a precision of 0.923 and a recall of 0.800, was achieved by the Naive Bayes algorithm. We found four significant gait features in PD diagnosis: step length, velocity and width, and step width variability. As to the PD stage identification, the Random Forest outperformed the other studied ML algorithms, by reaching an Area Under the ROC curve of 0.786. We found two relevant gait features in identifying the PD stage: stride width variability and step double support time variability. Significance: The results showed that the studied ML algorithms have potential both to PD diagnosis and stage identification by analysing gait parameters.

Combining multiple Parkinson's disease (PD) relevant cellular phenotypes might increase the accuracy of midbrain dopaminergic neuron (mDAN) in vitro models. We differentiated patient-derived induced pluripotent stem cells (iPSCs) with a LRRK2 G2019S mutation, isogenic control, and genetically unrelated iPSCs into mDANs. Using automated fluorescence microscopy in 384-well-plate format, we identified elevated levels of α-synuclein (αSyn) and serine 129 phosphorylation, reduced dendritic complexity, and mitochondrial dysfunction. Next, we measured additional image-based phenotypes and used machine learning (ML) to accurately classify mDANs according to their genotype. Additionally, we show that chemical compound treatments, targeting LRRK2 kinase activity or αSyn levels, are detectable when using ML classification based on multiple image-based phenotypes. We validated our approach using a second isogenic patient-derived SNCA gene triplication mDAN model which overexpresses αSyn. This phenotyping and classification strategy improves the practical exploitability of mDANs for disease modeling and the identification of novel LRRK2-associated drug targets.

Advanced Parkinson's disease is characterized by motor and non-motor fluctuations to oral dopamine replacement therapy. The BALANCE study evaluated the clinical practice in Germany and Switzerland, when patients eligible for levodopa/carbidopa intestinal gel (LCIG) therapy decided to either switch to LCIG or to stay on optimized standard of care (SoC) oral therapy as a non-randomized regular clinical decision.In this non-interventional, multicenter, prospective observational study, patients were recruited between 2015 and 2020. We obtained comprehensive baseline characteristics in both groups. As primary endpoint, we evaluated whether LCIG led to higher quality-of-life (QoL) improvement than SoC after 12 months. As secondary endpoints, we studied several motor and non-motor outcomes.About half of the 137 patients decided for LCIG treatment (n = 73, 53.5%). Those were agedgt;70 years more often, had more advanced disease stage, higher burden of motor and neuropsychiatric symptoms, and cognitive impairment including dementia compared to SoC. QoL change after 12 months did not differ between groups (P = 0.286). The LCIG group improved in secondary outcomes, including the UPDRS III in ON, UPDRS IV, Unified Dyskinesia Rating Scale, and Non-Motor Symptoms Scale. Clinical Global Impression-Improvement scale improved in 78.0% and 19.5% of patients receiving LCIG and SoC, respectively. Caregiver burden remained stable in LCIG but worsened with SoC.In current practice, patients and physicians delayed LCIG treatment and started substantially beyond the established indication criteria. This practice bears the risk to produce inferior results compared to the results from existing high-level evidence.

Decreased plasma levels of plasmalogens in neurodegenerative diseases have been watched with interest. We previously reported the decreases of erythrocyte ethanolamine plasmalogen (PlsPE) of blood not only in Alzheimer's disease (AD) and Parkinson's disease (PD), but also in coronary artery disease (CAD). In the present study, by using the same high-performance liquid chromatography (HPLC) method, we investigated the pattern of changes in the phospholipid composition of erythrocyte membrane in AD, PD and CAD compared with healthy individuals. The common patten of changes among them was as follows: The decrease of erythrocyte PlsPE was accompanied by a decrease of phosphatidylcholine although phosphatidylethanolamine remained unchanged. The decreases of PlsPE and phosphatidylcholine were replaced by an increase of sphingomyelin (SM) in the total phospholipids. The dissociated change between PlsPE and phosphatidylethanolamine (PE) may be caused by the differences in molecular structure or in location in the cell membrane. Such special changes provide another piece of biochemical evidence that these different diseases are caused by identical pathological mechanism, suggesting potential biomarkers for these chronic diseases due to aging.

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 13-35 Hz ("beta band") oscillatory dynamics in the manifestation of Parkinson's disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulses with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequency-specific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.