Untreated Parkinson's Disease Research Articles

Long-Term Dementia Risk in Parkinson Disease.

It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point. For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years. Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.

Narrative analysis in individuals with Parkinson's disease following intensive voice treatment: secondary outcome variables from a randomized controlled trial.

Communication is often impaired in individuals with Parkinson's disease (PD), typically secondary to sensorimotor deficits impacting voice and speech. Language may also be diminished in PD, particularly for production and comprehension of verbs. Evidence exists that verb processing is influenced by motor system modulation suggesting that verb deficits in PD are underpinned by similarities in the neural representations of actions that span motor and semantic systems. Conversely, subtle differences in cognition in PD may explain difficulty in processing of complex syntactic forms, which increases cognitive demand and is linked to verb use. Here we investigated whether optimizing motor system support for vocal function (improving loudness) affects change in lexical semantic, syntactic, or informativeness aspects of spoken discourse. Picture description narratives were compared for 20 Control participants and 39 with PD, 19 of whom underwent Lee Silverman Voice Treatment (LSVT LOUD®). Treated PD narratives were also contrasted with those of untreated PD and Control participants at Baseline and after treatment. Controls differed significantly from the 39 PD participants for verbs per utterance, but this difference was largely driven by untreated PD participants who produced few utterances but with verbs, inflating their verbs per utterance. Given intervention, there was a significant increase in vocal loudness but no significant changes in language performance. These data do not support the hypothesis that targeting this speech motor system results in improved language production. Instead, the data provide evidence of considerable variability in measures of language production across groups, particularly in verbs per utterance.

Premotor cortical beta synchronization and the network neuromodulation of externally paced finger tapping in Parkinson's disease

Parkinson's disease (PD) is characterized by the disruption of repetitive, concurrent and sequential motor actions due to compromised timing-functions principally located in cortex-basal ganglia (BG) circuits. Increasing evidence suggests that motor impairments in untreated PD patients are linked to an excessive synchronization of cortex-BG activity at beta frequencies (13–30 Hz). Levodopa and subthalamic nucleus deep brain stimulation (STN-DBS) suppress pathological beta-band reverberation and improve the motor symptoms in PD. Yet a dynamic tuning of beta oscillations in BG-cortical loops is fundamental for movement-timing and synchronization, and the impact of PD therapies on sensorimotor functions relying on neural transmission in the beta frequency-range remains controversial. Here, we set out to determine the differential effects of network neuromodulation through dopaminergic medication (ON and OFF levodopa) and STN-DBS (ON-DBS, OFF-DBS) on tapping synchronization and accompanying cortical activities. To this end, we conducted a rhythmic finger-tapping study with high-density EEG-recordings in 12 PD patients before and after surgery for STN-DBS and in 12 healthy controls. STN-DBS significantly ameliorated tapping parameters as frequency, amplitude and synchrony to the given auditory rhythms. Aberrant neurophysiologic signatures of sensorimotor feedback in the beta-range were found in PD patients: their neural modulation was weaker, temporally sluggish and less distributed over the right cortex in comparison to controls. Levodopa and STN-DBS boosted the dynamics of beta-band modulation over the right hemisphere, hinting to an improved timing of movements relying on tactile feedback. The strength of the post-event beta rebound over the supplementary motor area correlated significantly with the tapping asynchrony in patients, thus indexing the sensorimotor match between the external auditory pacing signals and the performed taps. PD patients showed an excessive interhemispheric coherence in the beta-frequency range during the finger-tapping task, while under DBS-ON the cortico-cortical connectivity in the beta-band was normalized. Ultimately, therapeutic DBS significantly ameliorated the auditory-motor coupling of PD patients, enhancing the electrophysiological processing of sensorimotor feedback-information related to beta-band activity, and thus allowing a more precise cued-tapping performance.

Impaired dual-task gait in Parkinson's disease is associated with brain morphology changes.

In Parkinson's disease (PD), impaired gait and cognition affect daily activities, particularly in the more advanced stages of the disease. This study investigated the relationship between gait parameters, cognitive performance, and brain morphology in patients with early untreated PD. 64 drug-naive PD patients and 47 healthy controls (HC) participated in the study. Single- and dual-task gait (counting task) were examined using an expanded Timed Up & Go Test measured on a GaitRite walkway. Measurements included gait speed, stride length, and cadence. A brain morphometry analysis was performed on T1-weighted magnetic resonance (MR) images. In PD patients compared to HC, gait analysis revealed reduced speed (p < 0.001) and stride length (p < 0.001) in single-task gait, as well as greater dual-task cost (DTC) for speed (p = 0.007), stride length (p = 0.014) and cadence (p = 0.029). Based on the DTC measures in HC, PD patients were further divided into two subgroups with normal DTC (PD-nDTC) and abnormally increased DTC (PD-iDTC). For PD-nDTC, voxel-based morphometric correlation analysis revealed a positive correlation between a cluster in the left primary motor cortex and stride-length DTC (r = 0.57, p = 0.027). For PD-iDTC, a negative correlation was found between a cluster in the right lingual gyrus and the DTC for gait cadence (r=-0.35, pFWE = 0.018). No significant correlations were found in HC. The associations found between brain morphometry and gait performance with a concurrent cognitive task may represent the substrate for gait and cognitive impairment occurring since the early stages of PD.

Comparison of quantitative REM without atonia parameters in isolated REM sleep behavior disorder and early untreated Parkinson's disease

ObjectivesTo analyze REM sleep without atonia (RWA) metrics in patients with isolated REM sleep behavior disorder (iRBD), Parkinson's disease (PD) and healthy subjects and compare them in terms of degree of presumed brainstem damage. MethodsForty-nine iRBD patients, 62 PD patients and 38 healthy controls were included into the analysis. Detailed polysomnographic and clinical data including motor, olfactory, autonomic, and cognitive assessment were obtained in all participants and subsequently compared within groups without RBD (i.e., healthy controls, PD-RBD-) and with RBD (i.e., iRBD, PD-RBD+). SINBAR criteria were used to score RWA. ResultsTwenty-one PD patients (33.8 %) had RBD. When comparing PD-RBD-patients and controls, RWA tonic (p = 0.001) and RWA mixed (p = 0.03) were higher in PD-RBD-group. PD-RBD-patients had worse olfactory function than controls (p < 0.001); no significant difference in autonomic or cognitive function was registered. There were no significant differences in RWA parameters when comparing iRBD and PD-RBD + groups. iRBD patients had better olfactory function than PD-RBD+ (p = 0.006); no significant difference in autonomic or cognitive function was registered. PD-RBD + had worse autonomic (p = 0.006) and olfactory (p = 0.001) but not motor and cognitive function compared to PD-RBD-. ConclusionsUntreated de-novo PD patients without RBD have increased RWA metrics compared to healthy subjects indicating subclinical degeneration of brainstem nuclei responsible for RWA. iRBD patients do not differ in RWA metrics from untreated de-novo PD patients with premotor RBD suggesting a similar level of brainstem degeneration caudal to substantia nigra in both groups. Groups with RBD are associated with autonomic dysfunction.

Rate of motor progression in Parkinson's disease: a systematic review and meta-analysis.

The search for neuroprotective treatments for Parkinson's disease (PD) still relies largely on motor disability scales. A limitation of these tools is the strong influence of symptomatic dopaminergic treatment effects. Drawing on a wealth of published information, we conducted a systematic review and meta-analysis of motor progression in PD and its relationships with dopaminergic therapy. We searched Medline, Embase, and Central to identify 84 publications with adequate serial motor scores to calculate progression, expressed as an increase in the percentage of maximum disability. A random-effects model showed motor progression at 2.0% p.a. (95% CI 1.7-2.4%). There were no significant differences by baseline age, sample size, or observation period. However, untreated patients, in 8 publications, progressed at 4.5% p.a. compared to 1.6% p.a. in 76 studies containing individuals on dopaminergic drugs (p = 0.0004, q = 0.003). This was supported by research on phenoconversion in prodromal PD, where motor progression exceeded 5% p.a. in the 2 years before diagnosis. Starting levodopa improved pre-treatment disability by 40.3 ± 15.2%. Practically defined off state measurements increase faster than on scores by a modest degree (p = 0.05). This survey suggests that accurate long-term measurements of motor progression to assess disease-modifying therapies can be conducted despite the sequential commencement of dopaminergic drugs and sample attrition over time. While study designs involving prodromal or untreated PD avoid confounding effects of symptomatic treatment, different assumptions about motor progression may be needed. A defined off state with the levodopa test dose method maximizes information about the medication cycle once dopaminergic therapy has begun.

Nanoscale Magneto-mechanical-genetics of Deep Brain Neurons Reversing Motor Deficits in Parkinsonian Mice.

Here, we introduce the magneto-mechanical-genetic (MMG)-driven wireless deep brain stimulation (DBS) using magnetic nanostructures for therapeutic benefits in the mouse model of Parkinson's disease (PD). Electrical DBS of the subthalamic nucleus (STN) is an effective therapy for mitigating Parkinson's motor symptoms. However, its broader application is hampered by the requirement for implanted electrodes and the lack of anatomical and cellular specificity. Using the nanoscale magnetic force actuators (m-Torquer), which deliver torque force under rotating magnetic fields to activate pre-encoded Piezo1 ion channels on target neurons, our system enables wireless and STN-specific DBS without implants, addressing key unmet challenges in the DBS field. In both late- and early-stage PD mice, MMG-DBS significantly improved locomotor activity and motor balance by 2-fold compared to untreated PD mice. Moreover, MMG-DBS enabled sustained therapeutic effects. This approach provides a non-invasive and implant-free DBS with cellular targeting capability for the effective treatment of Parkinsonian symptoms.

Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. D&D Pharmatech-Neuraly.

The effect of dopamine replacement therapy on cortical structure in Parkinson's disease.

To explore the cortical structural reorganization in Parkinson's disease (PD) patients under chronic dopamine replacement therapy (DRT) in cross-sectional and longitudinal data and determine whether these changes were associated with clinical alterations. A total of 61 DRT-treated, 60 untreated PD patients, and 61 normal controls (NC) were retrospectively included. Structural MRI scans and neuropsychological tests were conducted. Cortical thickness and volume were extracted based on FreeSurfer and were analyzed using general linear model to find statistically significant differences among three groups. Correlation analyses were performed among significant cortical areas, medication treatment (duration and dosage), and neuropsychological tests. Longitudinal cortical structural changes of patients who initiated DRT were analyzed using linear mixed-effect model. Significant cortical atrophy was primarily observed in the prefrontal cortex in treated patients, including the cortical thickness of right pars opercularis and the volume of bilateral superior frontal cortex (SFC), left rostral anterior cingulate cortex (rACC), right lateral orbital frontal cortex, right pars orbitalis, and right rostral middle frontal cortex. A negative correlation was detected between the left SFC volume and levodopa equivalent dose (LED) (r = -0.316, p = 0.016), as well as the left rACC volume and medication duration (r = -0.329, p = 0.013). In the patient group, the left SFC volume was positively associated with digit span forward score (r = 0.335, p = 0.017). The left SFC volume reduction was longitudinally correlated with increased LED (standardized coefficient = -0.077, p = 0.001). This finding provided insights into the influence of DRT on cortical structure and highlighted the importance of drug dose titration in DRT.

Associations of Orthostatic Hypotension and Orthostatic Intolerance with Domain-Specific Cognitive Decline in Patients with Early Parkinson Disease: An 8-Year Follow-up

ObjectiveAlthough orthostatic hypotension (OH) and orthostatic intolerance (OI) are prevalent in patients with Parkinson disease (PD), it remains unclear how these conditions primarily affect the trajectory of decline in specific cognitive domains. This study aimed to explore the effects of OH and OI on longitudinal domain-specific cognitive changes in patients with PD. DesignAn 8-year follow-up of the Parkinson Progression Markers Initiative cohort study. Setting and ParticipantsA total of 403 patients with early, untreated PD and 195 matched healthy controls were included. They were classified into OH, OI, and normal groups. OH was defined according to the international consensus, and OI was defined as the presence of orthostatic symptoms without meeting the criteria for OH. MethodsThe patients underwent detailed neuropsychological testing annually for up to 8 years of follow-up. Linear mixed effects models were used to investigate the associations between OH, OI, and longitudinal cognitive changes. ResultsThe prevalence of both OH and OI in patients with PD was significantly higher than that in controls (13.4% vs 7.2%, P = .002, for OH, and 29.3% vs 14.4%, P < .001, for OI). The OH group in patients with PD showed a faster decline in Letter-Number Sequencing (LNS) (β = −0.11, 95% CI −0.20 to −0.02, t = −2.44, P = .015) and Semantic Fluency Test (SFT) (β = −0.44, 95% CI –0.81 to −0.08, t = −2.42, P = .016) scores than the normal group. Similarly, the OI group showed a steeper decline in LNS (β = −0.08, 95% CI –0.14 to −0.01, t = −2.20, P = .028) and SFT (β = −0.36, 95% CI –0.63 to −0.08, t = −2.55, P = .011) scores compared to the normal group. There were no significant longitudinal changes in the other neuropsychological test scores between the groups. Conclusions and ImplicationsBoth OH and OI may be associated with a faster decline in executive function among cognitive domains of patients with PD. These findings may highlight the potential importance of orthostatic blood pressure control in PD patients with OH and even those with orthostatic symptoms without OH.

Baseline prevalence and longitudinal assessment of autonomic dysfunction in early Parkinson's disease.

Autonomic dysfunction (AutD) is common and debilitating in Parkinson's disease (PD). Predictors of AutD are unclear, and data are limited on the biological relevance of AutD in PD. Here, we evaluated the baseline prevalence and 2-year longitudinal assessment of AutD in patients with de novo PD compared with healthy controls (HC). Moreover, we also assessed various variables that could predict longitudinal changes in AutD in early PD. Parkinson's Progression Markers Initiative (PPMI) was utilized to evaluate untreated PD participants at baseline and HC. Autonomic function was assessed using the 25-item Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) score at baseline and 2years. Clinical and biological variables were measured for their correlations with AuD for up to 2years. Two hundred and ninety PD subjects and 170 HC were enrolled and followed for 2years. SCOPA-AUT mean (SD) scores increased from baseline 8.49 ± 5.23 to 10.12 ± 5.77 at year 2 in PD subjects (p < 0.001) versus from 4.98 ± 3.34 to 5.03 ± 374 in HC (p = 0.496), with a significant difference between the groups (p < 0.001). Among them, 242 PD participants and 151 HC completed the SCOPA-AUT assessment, including sexual function. In the multivariate analysis, a higher baseline SCOPA-AUT score was associated with higher baseline MDS-UPDRS Part I scores (p < 0.001). Moreover, a longitudinal increase in autonomic function severity was associated with the white race (p = 0.010) at baseline. In contrast, there was no association with the CSF biomarkers. MDS-UPDRS Part I score may predict AuD in patients with early PD, which is correlated with nonmotor symptoms and race.

Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease

IntroductionKW-6356 is a novel selective adenosine A2A receptor antagonist/inverse agonist. We evaluated the efficacy and safety of KW-6356 as monotherapy in patients with early, untreated Parkinson's disease (PD). MethodsThis was a randomized, placebo-controlled, double-blind study conducted in Japan to investigate the efficacy and safety of once-daily KW-6356 (3 or 6 mg/day) orally administered as monotherapy for 12 weeks in patients with early PD (NCT02939391). The primary endpoint was the least squares means of change from baseline in the MDS-UPDRS Part III total score. ResultsOverall, 168 patients were randomized and treated (KW-6356 3 mg/day n = 55; 6 mg/day n = 58, placebo n = 55); Week 12 completion rates were >90% per group. LS mean [95% CI] changes from baseline to Week 12 in MDS-UPDRS Part III total scores were −5.37 [-7.25, −3.48] for 3 mg/day, −4.76 [-6.55, −2.96] for 6 mg/day and −3.14 [−4.97, −1.30] for placebo. Changes from baseline were larger for both KW-6356 groups than for the placebo group at all time points. Secondary endpoints supported the primary findings with larger changes in MDS-UPDRS Part II, Parts II + III, and Total scores in the KW-6356 groups than in the placebo group. Treatment was well-tolerated; the most common treatment-emergent adverse events with KW-6356 were constipation (n = 4 [7.3%] and n = 6 [10.3%] in the 3 and 6 mg/day groups, respectively) followed by nasopharyngitis (n = 4 [7.3%] and n = 5 [8.6%] in the 3 and 6 mg/day groups, respectively). ConclusionKW-6356 monotherapy is well tolerated and more effective than placebo in patients with early, untreated PD.

Longitudinal Assessment of Botulinum Toxin Treatment for Lateral Trunk Flexion and Pisa Syndrome in Parkinson's Disease: Real-life, Long-Term Study.

Lateral trunk flexion (LTF) and its severe form, called Pisa syndrome (PS), are highly invalidating axial postural abnormalities associated with Parkinson's disease (PD). Management strategies for LTF lack strong scientific evidence. We present a real-life, longitudinal study evaluating long-term efficacy of botulinum toxin (BoNT) injections in axial muscles to reduce LTF and PS in PD. A total of 13 PD patients with LTF > 5° received ultrasound- and electromyography-guided BoNT injections every 4 months. Seven untreated matched PD patients with LTF served as controls and their changes in posture after 18 months were compared with those of seven patients continuing BoNT over 12 months. 53.8% of patients continued the BoNT injections for at least 12 months. Various individual LTF responses were observed. Overall, BoNT-treated patients obtained a not statistically significant improvement of LTF of 17 ± 41% (p = 0.237). In comparison, the seven untreated PD patients suffered a deterioration in LTF over 12 months by 36 ± 45% (p = 0.116), showing a significantly different trajectory of posture change (p = 0.026). In conclusion, repeated BoNT injections in axial muscles showed varying effects in managing PD-associated LTF, suggesting that: (a) a relevant number of patients with LTF can benefit from BoNT; (b) long-term treatment could prevent LTF worsening; (c) an instrumented, personalized approach is important; and (d) there is a need for prospective, long-term studies.

Time to initiation of symptomatic treatment in untreated Parkinson disease in the Parkinson progression marker initiative cohort: A 10-year follow up

BackgroundInitiation of symptomatic therapy in Parkinson disease is a disease progression milestone, and its prediction is important. Previous studies were limited in duration and number of variables included in their predictive models. ObjectivesTo identify predictors of time to initiation of symptomatic therapy in patients with PD not on treatment, using a large pool of candidate variables from the Parkinson's Progression Markers Initiative dataset, analyzed at ten years. MethodsKaplan Meier survival curve was used to estimate time to initiation of symptomatic treatment. Potential predictors included 33 baseline clinical, imaging, biofluid, and genetic biomarkers. Univariate Cox regression was used for variable selection, significant predictors subsequently entering a multivariate Cox proportional hazard model, which was further reduced using the Akaike Information Criterion into a final reduced model. ResultsOf 425 participants with Parkinson's Disease, 406 initiated symptomatic therapy at last follow up. The outcome was censored for 4.5% of the sample. The risk of initiating symptomatic therapy was 65% (95%CI 60–70%) within the first year from enrollment. Predictors included dopamine transporter SPECT, the Movement Disorders Society Unified Parkinson Disease Rating Scale, and anxiety (State Trait Anxiety Inventory). ConclusionsBaseline dopamine transporter SPECT specific binding ratio was found to be the most impactful predictor for time to initiation of symptomatic therapy in this 10-year follow up analysis of the Progressive Parkinson Markers Initiative cohort, when treatment status was known for 95.5% of the sample.

Correlation analysis between 18F-fluorodeoxyglucose positron emission tomography and cognitive function in first diagnosed Parkinson's disease patients.

Evaluation of the correlation between 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and cognitive function in first-diagnosed and untreated Parkinson's disease (PD) patients. This cross-sectional study included 84 first diagnosed and untreated PD patients. The individuals were diagnosed by movement disorder experts based on the 2015 MDS Parkinson's disease diagnostic criteria. The patients also underwent 18F-FDG PET scans and clinical feature assessments including the Montreal Cognitive Assessment (MoCA) scale. Glucose metabolism rates were measured in 26 brain regions using region of interest (ROI) and pixel-wise analyses with displayed Z scores. The cognitive function was assessed by professionals using the MoCA scale, which covers five cognitive domains. Spearman's linear correlation and linear regression models were used to compare the correlations between 18F-FDG metabolism in each brain region and cognitive domain, using SPSS 25.0 software. The results indicated a positive correlation between executive function and glucose metabolism in the lateral prefrontal cortex of the left hemisphere (p = 0.041). Additionally, a positive correlation between memory function and glucose metabolism in the right precuneus (p = 0.014), right lateral occipital cortex (p = 0.017), left lateral occipital cortex (p = 0.031), left primary visual cortex (p = 0.008), and right medial temporal cortex (p = 0.046). Further regression analysis showed that for every one-point decrease in the memory score, the glucose metabolism in the right precuneus would decrease by 0.3 (B = 0.30, p = 0.005), the glucose metabolism in the left primary visual cortex would decrease by 0.25 (B = 0.25, p = 0.040), the glucose metabolism in the right lateral occipital cortex would decrease by 0.38 (B = 0.38, p = 0.012), and the glucose metabolism in the left lateral occipital cortex would decrease by 0.32 (B = 0.32, p = 0.045). This study indicated that cognitive impairment in PD patients mainly manifests as changes in executive function, visual-spatial function and memory functions, while glucose metabolism mainly decreases in the frontal and posterior cortex. Further analysis shows that executive function is related to glucose metabolism in the left lateral prefrontal cortex. On the other hand, memory ability involves changes in glucose metabolism in a more extensive brain region. This suggests that cognitive function assessment can indirectly reflect the level of glucose metabolism in the relevant brain regions.

The longitudinal progression of autonomic dysfunction in Parkinson's disease: A 7-year study.

Autonomic dysfunction, including gastrointestinal, cardiovascular, and urinary dysfunction, is often present in early Parkinson's Disease (PD). However, the knowledge of the longitudinal progression of these symptoms, and the connection between different autonomic domains, is limited. Furthermore, the relationship between the presence of autonomic symptoms in early-stage PD and olfactory dysfunction, a possible marker of central nervous system involvement, has not been fully investigated. We aimed to investigate the occurrence and progression of autonomic dysfunction in recently diagnosed (< 2 years) untreated PD patients and determine any coexistence of symptoms in individual patients. We also investigated the relationship between autonomic symptoms, olfactory dysfunction, and motor impairment. Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database. Autonomic dysfunction was measured using the Scales for Outcomes in Parkinson's Disease (SCOPA-AUT). Symptom frequency and mean scores over 7 years were determined. The simultaneous occurrence of different autonomic symptoms was also examined. Finally, the relationships between SCOPA-AUT scores, olfactory dysfunction, and motor impairment were investigated using the University of Pennsylvania Smell Identification Test (UPSIT) and the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), respectively. Follow-up data were available for 7 years for 171 PD patients and for 5 years for 136 HCs. Mean SCOPA-AUT score increased significantly from baseline to the 7-year follow-up for each autonomic domain, except for female sexual dysfunction. Most patients reported three or more autonomic symptoms. Common clusters of symptoms were composed of combinations of gastrointestinal, urinary, thermoregulatory, and sexual dysfunction. At baseline, greater SCOPA-AUT total score was associated with lower UPSIT scores (r = -0.209, p = 0.006) and with greater total MDS-UDPRS III score (r = 0.218, p = 0.004). Autonomic dysfunction, often with coexistence of autonomic manifestations, is common in early PD and progressively worsens over the first 7 years of disease, suggesting that these symptoms should be addressed with appropriate treatments early in the disease. The association between greater autonomic dysfunction and greater olfactory impairment, coupled with the association with more severe motor scores at baseline, indicates that patients who show more severe autonomic dysfunction could also have more severe involvement of the central nervous system at the time of diagnosis.

Associations of striatal dopamine transporter binding with motor and non-motor symptoms in early Parkinson's disease.

Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical practices focused on qualitatively visual interpretation of DAT imaging, whereas quantitative analyses are potentially more helpful when monitoring the progression of PD. Previous cross-sectional studies indicated certain motor and non-motor features were associated with striatal DAT binding, whereas limited data were reported in terms of the longitudinal correlation between clinical features of PD with striatal DAT binding. The purpose of our study is to clarify current and longitudinal correlations between striatal DAT binding and clinical measures. A total of 352 untreated PD individuals and 167 healthy controls with complete baseline clinical measures and neuroimaging data were identified from the Parkinson's Progression and Markers Initiative (PPMI) database. Patients with PD underwent DAT imaging at the screening visit and following months 12, 24, and 48. Multiple linear regression models and linear mixed-effect models were respectively conducted to investigate the cross-sectional and longitudinal correlation between clinical characteristics and DAT binding. Associations between changes in clinical characteristics and changes in DAT binding were further evaluated and the Spearman rank correlation coefficients were reported. In the cross-sectional analysis, baseline striatal DAT binding was significantly associated with the Hoehn and Yahr scale, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores, the rigidity scores, and the axial scores in PD individuals (false discovery rate [FDR]-adjusted p=0.0017 for all above). Patients who developed freezing of gait had lower striatal DAT binding (FDR-adjusted p=0.0161). Healthy controls who had higher tremor scores and suffered more severe olfactory dysfunction had lower striatal DAT binding (FDR-adjusted p=0.0257 for all above). Longitudinal analysis indicated that baseline severity of rapid-eye-movement sleep behavior disorder was significantly associated with longitudinal striatal DAT binding in patients with PD (FDR-adjusted p=0.0120). Furthermore, changes in MDS-UPDRS scores and the State-Trait Anxiety Inventory (STAI) scores demonstrated significant correlations with changes in striatal DAT binding over 4 years (p=0.005 and p=0.032, respectively). Our findings clarified quantitative associations between certain motor and non-motor features with current and future striatal dopamine binding, suggesting the feasibility of using DAT images as a progression predictive marker for PD. Further studies are needed to investigate correlations between different regional dopamine binding with specific clinical features.

Long-Duration Response to Levodopa, Motor Learning, and Neuroplasticity in Early Parkinson's Disease.

Long-duration response (LDR) to levodopa and motor learning could be involved in changes in neuroplasticity of cortical excitability in Parkinson's disease (PD). P300, motor evoked potentials (MEPs), and Bereitschaftspotential (BP) are neurophysiological surrogate markers of neuroplasticity. We aimed to define in PD the effects of LDR and motor learning on neurophysiological parameters involved in neuroplasticity. Drug-naive PD patients underwent a 15-day treatment with levodopa/carbidopa 250/25 mg daily. Achievement of LDR was assessed on the 15th day of treatment (T15). Patients were grouped based on the achievement of a sustained LDR (LDR+) or no LDR (LDR-) and to the assignment of a learning motor exercise (LME) or no motor exercise (NME). Patients underwent clinical and neurophysiological (P300, MEPs, and BP) assessments at baseline (T0) and on T15. Forty-one PD patients and 24 age- and sex-matched normal controls (NCs) were enrolled. Neurophysiological parameters differed between untreated PD patients and NCs. Four groups of patients were obtained at the end of treatments: trained patients with a sustained LDR (LDR + LME group), untrained patients with a sustained LDR (LDR + NME group), trained patients without LDR (LDR-LME group), and untrained patients without LDR (LDR-NME group). At baseline, no differences in clinical and neurophysiological parameters were evident among the groups. After the treatments, significant improvements in neurophysiological parameters were observed in the LDR + LME group. No modifications were found in the groups without LDR. The achievement of a sustained LDR may act synergistically with motor learning to induce adaptive changes in neuroplasticity in basal ganglia and cortical networks. Our findings support LDR as a pharmacological outcome possibly facilitating the action of motor learning on neuroplasticity in early PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Turning and Sitting in Early Parkinsonism: Differences Between Idiopathic Normal Pressure Hydrocephalus Associated with Parkinsonism and Parkinson's Disease.

Differential diagnosis between idiopathic normal pressure hydrocephalus (iNPH) associated with parkinsonism (iNPH-P) and Parkinson's disease (PD) may prove difficult when evaluating patients with early parkinsonism. The objective of this study was to evaluate differences in mobility during standardized tasks between iNPH-P and PD. We selected 21 iNPH-P and 21 pharmacologically untreated PD patients. They all performed the instrumented Timed Up and Go test at the time of diagnosis. Turning tasks showed longer duration and lower speed in iNPH-P than in PD. Vertical variation in acceleration during the sit-to-stand phase was lower in iNPH-P patients, whereas the duration of the stand-to-sit phase was longer. On walking, iNPH-P showed smaller stride length and a longer gait cycle duration. In multivariate analysis adjusting for age and cognitive status as potential confounders, average angular speed on turning before sitting was the discriminating parameter between the two groups. Patients with iNPH-P showed specific abnormal mobility performances with respect to untreated PD, specifically during the turning-to-sitting transition.

A Novel Trial of Mirabegron and Behavioral Modification Including Pelvic Floor Exercise for Overactive Bladder in Parkinson's Disease (MAESTRO).

Overactive bladder (OAB) is experienced by more than half of patients with untreated Parkinson's disease. Treatment of overactive bladder in these patients has included antimuscarinic anticholinergics, raising concerns about the possibility of exacerbating cognitive impairment or constipation. Mirabegron (Myrbetriq), a β3-receptor agonist, provides relief of OAB without increasing cognitive impairment. While prior studies have examined the effect of mirabegron on OAB in a variety of patient populations, this study is the first controlled, prospective study investigating the effect of mirabegron on overactive bladder in patients with Parkinson's disease. By studying effective treatments for overactive bladder, this trial emphasizes the importance of antimicrobial stewardship so that lower urinary tract symptoms are not treated as lower urinary tract infections with antimicrobials and instead overactive bladder can be treated appropriately with medication.The MAESTRO study compared the effect of adding mirabegron to behavioral modification (including pelvic floor exercises) to behavior modification alone. Results from this novel study show that both the mean absolute change in the volume of micturition (objective measure) and the mean percent change increased significantly between visits two and three in the experimental group usingmirabegron. Moreover, improvements in micturition in this study indicate that a larger-scale study of mirabegron with pelvic floor exercises and behavior modification is warranted.