A potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson’s disease patients. Both Parkinson’s disease patients and controls were monitored for 2 months for baseline profiling. Parkinson’s disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson’s disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson’s disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson’s disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.
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 MEASURESThe 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. RESULTSBased 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 11.1 [95% CI,] 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.
This claims-based analysis suggests that rehabilitation therapy utilization among older patients with PD in the United States is lower than reported for countries with comparable health care infrastructure. Neurologist care is associated with rehabilitation therapy use; provider supply is not.
In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa’s site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease “off” time, increase “on” time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors’ experiences.FundingAbbVie, Inc.Plain Language SummaryPlain language summary available for this article.
Background: Orthostatic tremor (OT), a rare and complex movement disorder, is characterized by rapid tremor of both legs and the trunk while standing. These disappear while the patient is either lying down or walking. OT may be idiopathic/primary or it may coexist with several neurological conditions (secondary OT/OT plus). Primary OT remains an enigmatic movement disorder and its pathogenesis and neural correlates are not fully understood. Methods: A PubMed search was conducted in July 2017 to identify articles for this review. Results: Structural and functional neuroimaging studies of OT suggest possible alterations in the cerebello-thalamo-cortical network. As with essential tremor, the presence of a central oscillator has been postulated for OT; however, the location of the oscillator within the tremor network remains elusive. Studies have speculated a possible dopaminergic deficit in the pathogenesis of primary OT; however, the evidence in favor of this concept is not particularly robust. There is also limited evidence favoring the concept that primary OT is a neurodegenerative disorder, as a magnetic resonance spectroscopic imaging study revealed significant reduction in cerebral and cerebellar N-acetyl aspartate (NAA) levels, a marker of neuronal compromise or loss. Discussion: Based on the above, it is clear that the pathogenesis of primary OT still remains unclear. However, the available evidence most strongly favors the existence of a central oscillatory network, and involvement of the cerebellum and its connections.
Background Orthostatic Tremor (OT) is characterized by the presence of a sensation of instability while standing, associated with high frequency (13–18 Hz) lower extremity tremor. Diagnosis is confirmed with surface electromyography (EMG). An accurate screening tool that could be used in the routine clinical setting, without any specialized equipment, would be useful in earlier detection of OT and judicial use of additional testing. Objective The objective of this study was to evaluate OT diagnostic test characteristics at bedside using iPhone's built‐in accelerometer and available applications for tremor recordings. Methods We obtained recordings using iPhones (Model 5, 5s, and 6) and free Applications (“LiftPulse” by LiftLabs [App1] and “iSeismometer” by ObjectGraph LLC [App2]) at default settings. Results 24 EMG‐confirmed OT subjects (mostly females, 22/24) and 15 age‐matched controls (mostly males, 11/15) were evaluated. App1 detected OT range tremor in 22/24 patients and none of the controls. (Sensitivity = 92%, Specificity = 100%, NPV = 88%). App2 detected OT range tremor in 21/24 patients and in 1/13 controls (Sensitivity = 88%, Specificity = 92%, NPV = 80%). When combined, 24/24 patients and 1/13 controls had OT range tremor (Sensitivity = 100%, Specificity = 92%, NPV = 100%). Conclusions Smartphone apps that use the built‐in accelerometer provide a simple, accurate and inexpensive bedside screening diagnostic tool for patients with OT.
In-person resident didactics are traditionally limited to the faculty within a single institution. Tele-education efforts have been implemented in neurology to various degrees historically, but the COVID-19 pandemic has necessitated a broad and immediate overhaul in neurology didactic training. To respond to the immediate need for resident didactics, we created a rapid onset, volunteer tele-education didactic series publicized on online forums to the American Academy of Neurology A.B. Baker Section via Synapse and the Women Neurologists Group via Facebook. We describe how, with just one week of lead time, we created an ongoing neurology lecture series featuring faculty from across the country lecturing on a diverse range of neurology topics. The series is ongoing and draws upwards of 120 residents per lecture. Tele-education offers unique benefits to enhance the education of all neurology trainees everywhere.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders that affect millions of individuals worldwide. As incidence of these conditions increases with age, there will undoubtedly be an increased prevalence of cases in the near future. Neuroinflammation is a hallmark in the development and progression of neurodegenerative diseases and prevention or resolution of chronic neuroinflammation may represent a novel approach to treatment. The present review highlights the potential of the anti-inflammatory and pro-resolving effects of polyunsaturated fatty acid (PUFA)-derived mediators (Specialized Pro-resolving Mediators—SPM) in neurodegenerative disorders. PUFA-derived SPM are biosynthesized in response to chemicals produced from acute inflammatory responses. Preclinical studies from both AD and PD models suggest a dysregulation of SPM and their receptors in neurological disorders. Decreased SPM may be due to inadequate substrate, an imbalance between SPM and pro-inflammatory mediators or a disruption in SPM synthesis. SPMs hold great promise for neuroprotection in AD by altering expression of pro-inflammatory genes, modulating macrophage function, serving as a biomarker for AD status, and promoting resolution of neuroinflammation. In PD, data suggest SPM are able to cross the blood-brain barrier, inhibit microglial activation and decrease induced markers of inflammation, possibly as a result of their ability to downregulate NFκB signaling pathways. Several in vivo and in vitro studies suggest a benefit from administration of SPMs in both neurodegenerative disorders. However, extrapolation of these outcomes to humans is difficult as no models are able to replicate all features of AD or PD. Minimal data evaluating these PUFA-derived metabolites in humans with neurodegenerative disorders are available and a gap in knowledge exists regarding behavior of SPM and their receptors in patients with these conditions. There is also large gap in our knowledge regarding which lipid mediator would be most effective in which model of AD or PD and how dietary intake or supplementation can impact SPM levels. Future direction should include focused, translational efforts to investigate SPM as an add-on (in addition to standard treatment) or as standalone agents in patients with neurodegenerative disorders.
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