Multi-session transcutaneous auricular vagus nerve stimulation for Parkinson's disease: evaluating feasibility, safety, and preliminary efficacy.

Background: In pre-clinical animal models of Parkinson's disease (PD), vagus nerve stimulation (VNS) can rescue motor deficits and protect susceptible neuronal populations. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a non-invasive alternative to traditional invasive cervical VNS. This is the first report summarizing the safety, feasibility, and preliminary efficacy of repeated sessions of taVNS in participants with PD. Objectives: To evaluate the feasibility, safety, and possible efficacy of taVNS for motor and non-motor symptoms in mild to moderate PD. Methods: This is a double-blind, sham controlled RCT (NCT04157621) of taVNS in 30 subjects with mild to moderate PD without cognitive impairment. Participants received 10, 1-h taVNS sessions (25 Hz, 200% of sensory threshold, 500 µs pulse width, 60 s on and 30 s off) over a 2-week period. Primary outcome measures were feasibility and safety of the intervention; secondary outcomes included the MDS-UPDRS, cognitive function and self-reported symptom improvement. Results: taVNS treatment was feasible, however, daily in-office visits were reported as being burdensome for participants. While five participants in the taVNS group and three in the sham group self-reported one or more minor adverse events, no major adverse events occurred. There were no group differences on blood pressure and heart rate throughout the intervention. There were no group differences in MDS-UPDRS scores or self-reported measures. Although global cognitive scores remained stable across groups, there was a reduction in verbal fluency within the taVNS group. Conclusions: taVNS was safe, and well-tolerated in PD participants. Future studies of taVNS for PD should explore at-home stimulation devices and optimize stimulation parameters to reduce variability and maximize engagement of neural targets.

Prevalence of Rhinorrhea in Parkinson Disease: A Systematic Review and Meta-analysis.

Purpose of Review: To perform a systematic review and determine the prevalence of rhinorrhea in Parkinson disease (PD). Recent Findings: Of 451 patients with PD and 233 controls, the pooled prevalence of rhinorrhea in patients with PD was 45.0% (95% confidence interval 33.94-56.40), which was significantly greater than that in controls (p < 0.001). The prevalence of self-reported olfactory dysfunction was greater in patients with PD; however, a pooled analysis of studies using objective scores showed no difference. The mean age of patients with PD was greater than that of controls (p = 0.002). The mean age of patients with PD with rhinorrhea was also greater than that of patients with PD without rhinorrhea (p < 0.001), but disease characteristics did not differ. Summary: There is a high prevalence of rhinorrhea in patients with PD; therefore, providers should query for rhinorrhea during visits and understand the treatment options available. Future studies should explore the pathophysiology of rhinorrhea in PD and the relationship between rhinorrhea and disease severity and duration, as well as determine whether treatment-specific outcomes differ in patients with PD.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson's disease.

BACKGROUND: Vagus nerve stimulation (VNS) modifies brain rhythms in the locus coeruleus (LC) via the solitary nucleus. Degeneration of the LC in Parkinson's disease (PD) is an early catalyst of the spreading neurodegenerative process, suggesting that stimulating LC output with VNS has the potential to modify disease progression. We previously showed in a lesion PD model that VNS delivered twice daily reduced neuroinflammation and motor deficits, and attenuated tyrosine hydroxylase (TH)-positive cell loss. OBJECTIVE: The goal of this study was to characterize the differential effects of three clinically-relevant VNS paradigms in a PD lesion model. METHODS: Eleven days after DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, noradrenergic lesion, administered systemically)/6-OHDA (6-hydroxydopamine, dopaminergic lesion, administered intrastriatally) rats were implanted with VNS devices, and received either low-frequency VNS, standard-frequency VNS, or high-frequency microburst VNS. After 10 days of treatment and behavioral assessment, rats were euthanized, right prefrontal cortex (PFC) was dissected for norepinephrine assessment, and the left striatum, bilateral substantia nigra (SN), and LC were sectioned for immunohistochemical detection of catecholamine neurons, α-synuclein, astrocytes, and microglia. RESULTS: At higher VNS frequencies, specifically microburst VNS, greater improvements occurred in motor function, attenuation of TH-positive cell loss in SN and LC, and norepinephrine concentration in the PFC. Additionally, higher VNS frequencies resulted in lower intrasomal α-synuclein accumulation and glial density in the SN. CONCLUSIONS: These data indicate that higher stimulation frequencies provided the greatest attenuation of behavioral and pathological markers in this PD model, indicating therapeutic potential for these VNS paradigms.

Effects of vagus nerve stimulation are mediated in part by TrkB in a parkinson's disease model.

Vagus nerve stimulation (VNS) is being explored as a potential therapeutic for Parkinson's disease (PD). VNS is less invasive than other surgical treatments and has beneficial effects on behavior and brain pathology. It has been suggested that VNS exerts these effects by increasing brain-derived neurotrophic factor (BDNF) to enhance pro-survival mechanisms of its receptor, tropomyosin receptor kinase-B (TrkB). We have previously shown that striatal BDNF is increased after VNS in a lesion model of PD. By chronically administering ANA-12, a TrkB-specific antagonist, we aimed to determine TrkB's role in beneficial VNS effects for a PD model. In this study, we administered a noradrenergic neurotoxin, DSP-4, intraperitoneally and one week later administered a bilateral intrastriatal dopaminergic neurotoxin, 6-OHDA. At this time, the left vagus nerve was cuffed for stimulation. Eleven days later, rats received VNS twice per day for ten days, with daily locomotor assessment. Daily ANA-12 injections were given one hour prior to the afternoon stimulation and concurrent locomotor session. Following the final VNS session, rats were euthanized, and left striatum, bilateral substantia nigra and locus coeruleus were sectioned for immunohistochemical detection of neurons, α-synuclein, astrocytes, and microglia. While ANA-12 did not avert behavioral improvements of VNS, and only partially prevented VNS-induced attenuation of neuronal loss in the locus coeruleus, it did stop neuronal and anti-inflammatory effects of VNS in the nigrostriatal system, indicating a role for TrkB in mediating VNS efficacy. However, our data also suggest that BDNF-TrkB is not the sole mechanism of action for VNS in PD.

Vagus nerve stimulation improves locomotion and neuronal populations in a model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive, neurodegenerative disorder with no disease-modifying therapies, and symptomatic treatments are often limited by debilitating side effects. In PD, locus coeruleus noradrenergic (LC-NE) neurons degenerate prior to substantia nigra dopaminergic (SN-DA) neurons. Vagus nerve stimulation (VNS) activates LC neurons, and decreases pro-inflammatory markers, allowing improvement of LC targets, making it a potential PD therapeutic. OBJECTIVE: To assess therapeutic potential of VNS in a PD model. METHODS: To mimic the progression of PD degeneration, rats received a systemic injection of noradrenergic neurotoxin DSP-4, followed one week later by bilateral intrastriatal injection of dopaminergic neurotoxin 6-hydroxydopamine. At this time, a subset of rats also had vagus cuffs implanted. After eleven days, rats received a precise VNS regimen twice a day for ten days, and locomotion was measured during each afternoon session. Immediately following final stimulation, rats were euthanized, and left dorsal striatum, bilateral SN and LC were sectioned for immunohistochemical detection of monoaminergic neurons (tyrosine hydroxylase, TH), α-synuclein, astrocytes (GFAP) and microglia (Iba-1). RESULTS: VNS significantly increased locomotion of lesioned rats. VNS also resulted in increased expression of TH in striatum, SN, and LC; decreased SN α-synuclein expression; and decreased expression of glial markers in the SN and LC of lesioned rats. Additionally, saline-treated rats after VNS, had higher LC TH and lower SN Iba-1. CONCLUSIONS: Our findings of increased locomotion, beneficial effects on LC-NE and SN-DA neurons, decreased α-synuclein density in SN TH-positive neurons, and neuroinflammation suggest VNS has potential as a novel PD therapeutic.

Validation of a Behavioral Approach for Measuring Saccades in Parkinson's Disease.

Speed and control of saccades are related to disease progression and cognitive functioning in Parkinson's disease (PD). Traditional eye-tracking complexities encumber application for individual evaluations and clinical trials. The authors examined psychometric properties of standalone tasks for reflexive prosaccade latency, volitional saccade initiation, and saccade inhibition (antisaccade) in a heterogeneous sample of 65 PD patients. Demographics had minimal impact on task performance. Thirty-day test-retest reliability estimates for behavioral tasks were acceptable and similar to traditional eye tracking. Behavioral tasks demonstrated concurrent validity with traditional eye-tracking measures; discriminant validity was less clear. Saccade initiation and inhibition discriminated PD patients with cognitive impairment. The present findings support further development and use of the behavioral tasks for assessing latency and control of saccades in PD.

Assessing Visuospatial Skills in Parkinson's: Comparison of Neuropsychological Assessment Battery Visual Discrimination to the Judgment of Line Orientation.

OBJECTIVE: Judgment of Line Orientation (JOLO) test is widely used in assessing visuospatial deficits in Parkinson's disease (PD). The neuropsychological assessment battery (NAB) offers the Visual Discrimination test, with age and education correction, parallel forms, and co-normed standardization sample for comparisons within and between domains. However, NAB Visual Discrimination has not been validated in PD, and may not measure the same construct as JOLO. METHOD: A heterogeneous sample of 47 PD patients completed the JOLO and NAB Visual Discrimination within a broader neuropsychological evaluation. Pearson correlations assessed relationships between JOLO and NAB Visual Discrimination performances. RESULTS: Raw and demographically corrected scores from JOLO and Visual Discrimination were only weakly correlated. NAB Visual Discrimination subtest was moderately correlated with overall cognitive functioning, whereas the JOLO was not. CONCLUSIONS: Despite apparent virtues, results do not support NAB Visual Discrimination as an alternative to JOLO in assessing visuospatial functioning in PD.

A Randomized Clinical Trial of Atomoxetine for Mild Cognitive Impairment in Parkinson's Disease.

BACKGROUND: Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with diminished norepinephrine from the locus coeruleus to the prefrontal cortex. Atomoxetine is a specific norepinephrine reuptake inhibitor that has been approved by the US Food and Drug Administration to treat attention deficit hyperactivity disorder in adults. The authors hypothesized that atomoxetine would improve attention and executive functioning in patients with PD-MCI. METHODS: Thirty participants who met Movement Disorder Society Task Force Level I criteria for PD-MCI were enrolled in a randomized controlled trial of atomoxetine. Cognitive evaluations were performed at baseline and after 10 weeks of treatment or placebo. A safety visit was performed at Week 12. A global statistical test was used to examine treatment effects on standardized tests of attention, working memory, processing speed, and set shifting (primary outcome measure). Secondary outcomes included cognitive measures hypothesized to be insensitive to atomoxetine, the Conners Adult Attention Deficit Hyperactivity Disorder Rating Scale, and safety measures. RESULTS: Fifteen participants were randomized to each arm. Groups were similar on medical and demographic variables and baseline cognition. Three serious adverse events occurred; 2 on atomoxetine (syncope, isolated episode of atrial fibrillation) and 1 on placebo (atrial fibrillation). The global statistical test of primary outcome measures did not reveal a significant difference between groups. However, significant improvements were observed for atomoxetine but not placebo on subjective measures of attention and impulsivity (Conners Adult Attention Deficit Hyperactivity Disorder Rating Scale). CONCLUSIONS: Atomoxetine treatment produced subjective, but not objective, improvements in PD-MCI. Failure to detect objective differences may be due to insensitivity of cognitive tests or severity of cognitive deficits in the study participants.

Cognitive function in 1736 participants in NINDS Exploratory Trials in PD Long-term Study-1.

INTRODUCTION: Clinical cohort studies suggest that mild cognitive impairment (MCI) is common in early Parkinson's disease (PD). The objectives of this paper were to describe cognitive function in a large clinical trial of early treated PD patients at baseline and over time using two brief cognitive screening tests. METHODS: In total 1741 participants were enrolled in the NINDS Exploratory Trials in Parkinson's disease (NET-PD) Long-term Study-1 (LS-1). The Symbol Digit Modalities Test (SDMT) was collected annually. The SCales for Outcomes in PArkinson's disease-COGnition (SCOPA-COG) was collected at baseline and at year 5. The trial was stopped early based on a planned interim analysis after half the cohort completed 5 years of follow-up. The median length of follow-up was 4 years (range 3-6 years). Predictors of cognitive change were examined using cross sectional (baseline) and longitudinal multivariable linear regression. RESULTS: The mean (SD) change from baseline to 5 years was -1.9 (5.1) for the SCOPA-COG and -2.1 (11.1) for the SDMT. Age and baseline UPDRS motor scores were associated with a more rapid decline in SDMT scores and 5 year SCOPA-COG scores. Male gender was associated with more rapid decline in SDMT. Self-reported income was a novel predictor of baseline cognitive function, even adjusted for educational status, although not significantly associated with change over time. CONCLUSION: This large prospective cohort study demonstrated mild cognitive decline in early treated Parkinson's disease. The study identified income level as a novel predictor of cognitive function.

BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson׳s disease.

The anti-Parkinsonian drug rasagiline is a selective, irreversible inhibitor of monoamine oxidase and is used in the treatment of Parkinson׳s disease (PD). Its postulated neuroprotective effects may be attributed to MAO inhibition, or to its propargylamine moiety. The major metabolite of rasagiline, aminoindan, has shown promising neuroprotective properties in vitro but there is a paucity of studies investigating in vivo effects of this compound. Therefore, we examined neuroprotective effects of rasagiline and its metabolite aminoindan in a double lesion model of PD. Male Fisher 344 rats received i.p. injections of the noradrenergic neurotoxin DSP-4 and intra-striatal stereotaxic microinjections of the dopamine neurotoxin 6-OHDA. Saline, rasagiline or aminoindan (3mg/kg/day s.c.) were delivered via Alzet minipumps for 4 weeks. Rats were then tested for spontaneous locomotion and a novel object recognition task. Following behavioral testing, brain tissue was processed for ELISA measurements of growth factors and immunohistochemistry. Double-lesioned rats treated with rasagiline or aminoindan had reduced behavioral deficits, both in motor and cognitive tasks compared to saline-treated double-lesioned rats. BDNF levels were significantly increased in the hippocampus and striatum of the rasagiline- and aminoindan-lesioned groups compared to the saline-treated lesioned group. Double-lesioned rats treated with rasagiline or aminoindan exhibited a sparing in the mitochondrial marker Hsp60, suggesting mitochondrial involvement in neuroprotection. Tyrosine hydroxylase (TH) immunohistochemistry revealed a sparing of TH-immunoreactive terminals in double-lesioned rats treated with rasagiline or aminoindan in the striatum, hippocampus, and substantia nigra. These data provide evidence of neuroprotection by aminoindan and rasagiline via their ability to enhance BDNF levels.

Pilot study of atomoxetine in patients with Parkinson's disease and dopa-unresponsive Freezing of Gait.

BACKGROUND: Freezing of gait (FoG) is a common and debilitating condition in Parkinson's disease (PD) associated with executive dysfunction. A subtype of FoG does not respond to dopaminergic therapy and may be related to noradrenergic deficiency. This pilot study explores the effects of atomoxetine on gait in PD patients with dopa-unresponsive FoG using a novel paradigm for objective gait assessment. FINDINGS: Ten patients with PD and dopa-unresponsive FoG were enrolled in this eight-week open label pilot study. Assessments included an exploratory gait analysis protocol that quantified spatiotemporal parameters during straight-away walking and turning, while performing a dual task. Clinical, and subjective assessments of gait, quality of life, and safety were also administered. The primary outcome was a validated subjective assessment for FoG (FOG-Q). Atomoxetine was well tolerated, however, no significant change was observed in the primary outcome. The gait analysis protocol correlated well with clinical scales, but not with subjective assessments. DBS patients were more likely to increase gait velocity (p = 0.033), and improved in other clinical assessments. CONCLUSIONS: Objective gait analysis protocols assessing gait while dual tasking are feasible and useful for this patient population, and may be superior correlates of FoG severity than subjective measures. These findings can inform future trials in this population.

Immediate vs. delayed treatment of psychogenic movement disorders with short term psychodynamic psychotherapy: randomized clinical trial.

OBJECTIVE: In subjects with psychogenic movement disorders (PMDs), we conducted a 6 month randomized, cross-over design study to assess the effect of 3 months of psychodynamic psychotherapy followed by observation by the neurologist vs. observation by the neurologist, then 3 months of psychiatric intervention. BACKGROUND: PMDs are often disabling but no uniformly successful treatment strategies have been identified. Short term, open label psychodynamic psychotherapy has been successful in improving PMDs but whether PMDs improve equally well with neurological observation and support has not been tested. DESIGN: Fifteen patients with PMDs were randomized to immediate vs. delayed (after 3 months) weekly psychodynamic psychotherapy for 12 weeks. During the phase without psychiatric intervention, they were monitored by the treating neurologist. Patients were assessed at baseline, 3 and 6 months. Change in their movement disorder was assessed using a clinical global impression scale change (CGI-c), depression and anxiety using the Hamilton Depression Scale (HAM-D) and Beck Anxiety Inventory (Beck-A). RESULTS: Fourteen women and one man, age 42.3 ± 11, disease duration 63.2 ± 73 months, were randomized to immediate (7 patients) or delayed (8 patients) treatment. Over the six month study, PMDs, depression and anxiety were significantly improved but time was the determinant factor without an independent effect of treatment assignment. CONCLUSION: In this group of PMD patients, where patients were kept within the medical system and involved in a research program, PMDs as well as depression and anxiety improved, but without specific benefit time-linked to psychotherapy as opposed to neurological observation and support.

Mattis Dementia Rating Scale cutoffs are inadequate for detecting dementia in Parkinson's disease.

The Mattis Dementia Rating Scale (DRS) is widely used to assess cognition and screen for dementia in Parkinson's disease (PD). In 2008, Llebaria and colleagues reported excellent sensitivity and specificity detecting dementia in PD using a DRS total score cutoff of 123. However, this study used a sample with rather low mean educational achievement (8.9 years). The 123 cutoff score was cross-validated in a sample of 51 PD patients with a rather high mean educational achievement (14.84 years). A total score cutoff of 123 correctly classified 60.7% of the sample, with 20% sensitivity and 100% specificity. Use of age- and education-corrected scaled scores improved classification accuracy, but these cutoffs corresponded to the 25th percentile. Optimal classification of 82.4% accuracy was achieved using a raw total score cutoff of 133, corresponding roughly to the 16th percentile. Neither age nor education evinced a strong correlation to DRS total score in our sample. Results suggest caution in applying the DRS-2 total score cutoff of 123 and highlight the importance of comprehensive neuropsychological evaluations for clinical diagnosis of dementia in PD.

Adjunctive therapy in Parkinson's disease: the role of rasagiline.

Parkinson's disease is the second most common neurodegenerative disorder, currently affecting 1.5 million people in the US. In this review, we describe the diagnostic and pathological features of Parkinson's disease, as well as its clinical course. We then review pharmacologic treatments for the disease, with a particular focus on therapies adjunctive to levodopa and specifically the role of rasagiline. We review the four pivotal rasagiline trials, and discuss rasagiline and its use as adjunctive therapy for Parkinson's disease. Finally, we discuss potential side effects, drug interactions, and other practical aspects concerning the use of rasagiline in Parkinson's disease.

Flexible analytical methods for adding a treatment arm mid-study to an ongoing clinical trial.

It is not uncommon to have experimental drugs under different stages of development for a given disease area. Methods are proposed for use when another treatment arm is to be added mid-study to an ongoing clinical trial. Monte Carlo simulation was used to compare potential analytical approaches for pairwise comparisons through a difference in means in independent normal populations including (1) a linear model adjusting for the design change (stage effect), (2) pooling data across the stages, or (3) the use of an adaptive combination test. In the presence of intra-stage correlation (or a non-ignorable fixed stage effect), simply pooling the data will result in a loss of power and will inflate the type I error rate. The linear model approach is more powerful, but the adaptive methods allow for flexibility (re-estimating sample size). The flexibility to add a treatment arm to an ongoing trial may result in cost savings as treatments that become ready for testing can be added to ongoing studies.

Reduced parietal activation in cervical dystonia after parietal TMS interleaved with fMRI.

OBJECTIVE: Clinically normal hand movement with altered cerebral activation patterns in cervical dystonia (CD) may imply cerebral adaptation. Since impaired sensorimotor integration appears to play a role in dystonia, left superior parietal cortex modulation with repetitive transcranial magnetic stimulation (TMS) was employed to further challenge adaptation mechanisms reflected by changes in cerebral activation. METHODS: Seven CD patients and ten healthy controls were scanned on a 3T magnetic resonance imaging (MRI) scanner with 1 Hz inhibitory interleaved TMS. They executed and imagined right wrist flexion/extension movements. Each task was preceded by a 10-s period with or without TMS. RESULTS: The activations of both tasks after TMS in controls showed a similar pattern as found in CD without TMS, i.e. activation increases in bilateral prefrontal and posterior parietal regions during both tasks and decreases in right anterior parietal cortex during imagery (P<0.001). the activations of both tasks after TMS in CD were weaker but with a similar trend in activation changes. Only in the right angular gyrus, TMS significantly failed to induce an activation increase in CD as was seen in the controls (P<0.001). CONCLUSION: The similarity between TMS effects on the distribution of cerebral activations in controls and the pattern seen in CD may support the concept that CD make use of compensatory circuitry enabling clinically normal hand movement. The fact that a similar but weaker TMS effect occurred in CD could suggest that the capacity of compensation is reduced. Particularly for the right angular gyrus, this reduction was statistically significant.