Hubert Fernandez

• Cleveland Clinic

As Parkinson’s disease (PD) progresses, patients experience motor fluctuations, which may manifest as motor and/or non-motor wearing off symptoms, delayed “ON” time, and/or levodopa-related dyskinesia. Deep brain stimulation (DBS) is an effective therapy but may not be suitable for all patients due to factors such as premorbid conditions age, or ac...

Importance Magnetic resonance imaging (MRI) paired with appropriate disease-specific machine learning holds promise for the clinical differentiation of Parkinson disease (PD), multiple system atrophy (MSA) parkinsonian variant, and progressive supranuclear palsy (PSP). A prospective study is needed to test whether the approach meets primary end poi...

Rapid Eye Movement (REM) sleep behavior disorder (RBD) affects nearly half of Parkinson’s disease (PD) patients. However, the structural heterogeneity within the brainstem, which regulates REM sleep, remains largely unexplored in PD. Our objective was to identify distinct PD subtypes based on microstructural characteristics in the brainstem and exa...

Background Dexterous dysfunction is a bothersome patient‐reported symptom of Parkinson's disease (PD). Current clinical assessments do not directly evaluate goal‐directed hand function. This project sought to determine the capability of the electronic Manual Dexterity Test (MDT) to characterize dexterity across a range of PD patients. Objectives T...

The Neuronal alpha-Synuclein Disease (NSD) biological definition and Integrated Staging System (NSD-ISS) provide a research framework to identify individuals with Lewy body pathology and stage them based on underlying biology and increasing degree of functional impairment. Utilizing data from the PPMI, PASADENA, and SPARK studies, we developed and...

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson’s disease; however, individuals with Parkinson’s disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clin...

The landscape of medical care has rapidly evolved with technological advancements, particularly through the widespread adoption of virtual appointments catalyzed by the COVID-19 pandemic. This shift has transcended geographical barriers, enhancing access for underserved populations and those with disabilities to specialized healthcare providers. A...

Background Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. Methods Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RI...

Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. For TD, safety data were integrated from two 1...

While Parkinson's disease (PD)-related neurodegeneration is associated with structural changes in the brain, conventional magnetic resonance imaging (MRI) has proven less effective for clinical diagnosis due to its inability to reliably identify subtle changes early in the disease course. In this study, we aimed to develop a structural MRI-based bi...

Utilizing technology to precisely quantify Parkinson’s disease motor symptoms has evolved over the past 50 years from single point in time assessments using traditional biomechanical approaches to continuous monitoring of performance with wearables. Despite advances in the precision, usability, availability and affordability of technology, the “gol...

Importance: Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. Objective: To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients wit...

Background: The complexity of antiparkinsonian medications makes patients vulnerable to medication deviations. This study examines the frequency and outcomes of deviations between outpatient and inpatient medication administrations in patients with Parkinson's disease (PD). Methods: We included hospital admissions of patients with PD during a 12...

Background: SYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms. Objectives: We evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD). Methods: In a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-con...

Background: There is no uniform decision-making paradigm to determine which patients with idiopathic normal pressure hydrocephalus (iNPH) benefit from ventriculoperitoneal shunt (VPS). We sought to evaluate factors or a combination of factors that influence long-term outcomes in shunted iNPH patients. Methods: Patients with NPH who underwent VPS pl...

Background: To date, a reliable biomarker of motor severity and progression in Parkinson disease (PD) remains elusive. nQ’s machine learning platform leverages touchscreen keyboard inputs from a personal computer or smartphone to produce quantitative measurements (nQiTouchPD score) passively characterizing motor state. Indeed, typing performance in...

Background: In determining candidacy for ventriculoperitoneal shunt (VPS) implantation for treatment of NPH, external lumbar drain (ELD) trials are routinely performed to assess clinical response to cerebrospinal fluid (CSF) drainage. Optimal changes to monitor pre- and post-ELD trial are unclear. A common strategy is conducting walk tests before a...

Background: Little is known about the impact of the dopamine system on development of cognitive impairment (CI) in Parkinson disease (PD). Objectives: We used data from a multi-site, international, prospective cohort study to explore the impact of dopamine system-related biomarkers on CI in PD. Methods: PD participants were assessed annually f...

Anti-TNF therapy is a treatment option for rheumatoid arthritis (RA) that involves the use of medications that block the action of tumor necrosis factor (TNF), a protein involved in the inflammation process. While anti-TNF therapy has been shown to be effective in reducing inflammation and improving symptoms in RA, its effects on vascular biomarker...

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive m...

Background: Current conflict exists regarding the potential beneficial effects of dopamine medications on facial expressivity in Parkinson's disease. Via digital video analysis software, we previously found reduced facial movement (entropy) and slower time to reach peak entropy in individuals with Parkinson's disease compared to controls. Objecti...

Parkinson’s disease (PD) is in some cases predisposed-or-caused by genetic variants, contributing to the expression of different phenotypes. Regardless of etiology, as the disease progresses, motor fluctuations and/or levodopa-induced dyskinesias limit the benefit of pharmacotherapy. Device-aided therapies are good alternatives in advanced disease,...

Background: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. Methods: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2...

We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n = 15), multiple system atrophy (n = 1), and Dementia with Lewy bodies (n = 1); average age of death = 72 ± 8 yr. Cognitive assessment at last...

Dopamine agonist withdrawal syndrome (DAWS) has been introduced to describe the constellation of symptoms resulting from reduction or suspension of dopamine agonist medications. In patients with Parkinson’s disease (PD) the impact of DAWS can be significant in terms of distress and disability. Unfortunately, no standard treatment exists other than...

Objective: Evaluate intermediate-term outcomes (4–24 months) in patients undergoing unilateral VIM-DBS for tremor control at the Functional Neurosurgical Program of the Center for Neurological Restoration at Cleveland Clinic. Background: Tremors are common and can significantly affect the quality of life. Medications have limited efficacy in some c...

Background: Currently, there is no uniform decision-making paradigm to determine which patients with idiopathic normal pressure hydrocephalus (iNPH) benefit from ventriculoperitoneal shunt (VPS). To deter- mine surgical candidacy, most institutions perform a standardized walk test before and after an external lumbar drain trial (elD). However, many...

Introduction Tardive dyskinesia (TD) is an involuntary movement disorder that can result from exposure to dopamine-receptor antagonists (DRAs). Deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores in the 12-week pivotal trials (ARM-TD/AIM-TD). This post hoc analysis assessed the long-term effic...

Introduction Deutetrabenazine is FDA-approved for the treatment of tardive dyskinesia (TD) in adults. In two 12-week pivotal trials (ARM-TD/AIM-TD), deutetrabenazine significantly improved Abnormal Involuntary Movement Scale (AIMS) scores and was well-tolerated. This post hoc analysis examined the efficacy and safety of long-term deutetrabenazine t...

Non-motor Parkinson's Disease is a burgeoning area of the movement disorders field, as patients increasingly live longer and encounter more late-stage symptoms. The spectrum of non-motor manifestations spans much of the body, with non-motor features occurring in all stages of the disease. Identification of symptoms is key for preserving quality of...

Background Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia (TD) in adults. In two 12-week pivotal studies, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores, with favorable safety/tolerability in TD patients. Th...

A correction to this paper has been published: https://doi.org/10.1007/s00702-021-02361-9

Acute parkinsonism is rare. The most common causes are neuroleptic malignant syndrome, encephalitis (viral, autoimmune, paraneoplastic), functional parkinsonism, and catatonia. Cerebrospinal fluid analyses, toxicology, routine blood evaluations, imaging, and electroencephalography assume a much greater role in acute parkinsonism than in the evaluat...

Wilson disease (WD) is a rare autosomal recessive inborn error of copper metabolism, caused by mutations in ATP7B which encodes a transmembrane copper-transporting ATPase. This leads to copper overload in the liver, brain, cornea, and other tissues, often presenting with a hepatolenticular syndrome. Hepatic dysfunction varies from mild asymptomatic...

Background Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istr...

X-linked adrenoleukodystrophy (ALD) is the most common inborn error of peroxisomal beta-oxidation, caused by pathogenic variants in the ABCD1 gene, affecting the functioning of a protein responsible for the transportation of very long-chain fatty acids (VLCFA) into the peroxisome. This defect results in the accumulation of VLCFA in different tissue...

BACKGROUND Deep brain stimulation (DBS) was first approved by the United States Food and Drug Administration in 1997. Although the fundamentals of DBS remain the same, hardware, software, and imaging have evolved significantly. OBJECTIVE To test our hypothesis that the aggregate complication rate in the medical literature in the past 12 years woul...

The most common cause of parkinsonism is idiopathic Parkinson disease (PD), accounting for about 75% of all cases, however, other neurodegenerative, genetically determined and secondary disorders can result in parkinsonism. Defining the underlying etiology of parkinsonism may not be an easy task, but it is important for prognosis and therapeutic st...

Parkinson disease (PD) is a complex heterogeneous neurodegenerative disorder. Association studies have revealed numerous genetic risk loci and variants, and about 5-10% suffer from a monogenic form. Because the presentation and course of PD is unique to each patient, personalized symptomatic treatment should ideally be offered to treat the most dis...

Introduction: To overcome travel restrictions during the COVID-19 pandemic, consumer-based technology was rapidly deployed to the smartphones of individuals with Parkinson's disease (PD) participating in a 12-month exercise trial. The aim of the project was to determine the feasibility of utilizing a combined synchronous and asynchronous self-admi...

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicat...

Introduction Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. Methods This was an open-label extension (OLE) study in patient...

Background Deutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance. Methods Safety was assessed during titration versus maintenance using i...

The paroxysmal dyskinesias are a diverse group of genetic disorders that manifest as episodic movements, with specific triggers, attack frequency, and duration. With recent advances in genetic sequencing, the number of genetic variants associated with paroxysmal dyskinesia has dramatically increased, and it is now evident that there is significant...

Background Deutetrabenazine, a novel vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. Dopamine-receptor antagonists (DRAs) are associated with worsening of metabolic parameters, including weight gain, hyperlipidemia, and elevated blood glucose. This post hoc analysis ass...

Background The 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C−20) evaluated long-term efficacy and safety of deutetrabenazine in TD. Methods Patients who completed ARM-TD or AIM-TD enro...

Dopamine agonists are one of the main stay of treatment option for Parkinson disease (PD). Side effects that develop from their use are generally categorized into behavioral and non-behavioral. Behavioral side effects include: impulse control behavior disorder (ICD), psychosis and cognitive impairment. Non-behavioral side effects include: nausea/vo...

Background There is concern that the Patient Health Questionnaire‐9 (PHQ‐9) depression scale may be impacted by the presence of somatic symptoms (differential item functioning (DIF)) in patients with neurological conditions. We evaluated the PHQ‐9 for the presence and impact of DIF in large clinical samples of neurological patients. Methods We con...

Background: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. Objectives: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoM...

Background: Teleneurology has been well described for acute stroke, but outpatient use has been limited. At home, virtual visits have the potential to improve access to neurological care. Introduction: This study reports on the use of a personal device videoconferencing platform for outpatient neurologic follow-up visits. Materials and Methods:...

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based...

Introduction Pimavanserin is a selective 5-HT2A inverse agonist/antagonist approved for treating hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Results from short-term, placebo-controlled studies demonstrated a positive benefit/risk profile. This multi-year, open-label study assessed long-term safety and tolerabil...

Background Deutetrabenazine (Austedo) is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared with placebo, and there were low rates of overall adverse events (AEs) an...

Background In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associat...

An international panel of movement disorders specialists explored the views and perceptions of people with Parkinson's disease (PD) about their condition and its treatment, including the potential mismatch between the clinician's view of the patient's condition and their own view of what aspects of the disease most affect their daily lives. The ini...

Neurodegenerative motor conditions include many sporadic and hereditary disorders that target the neural circuits involved in modulation of movements. Amyotrophic lateral sclerosis, is the most common affecting motor neurons. Alteration of basal ganglia circuitry is common to different diseases, and may be expressed with parkinsonism (i.e., Parkins...

Objective: To investigate the topographic arrangement and strength of whole-brain white matter (WM) structural connectivity in patients with early-stage, drug-naive Parkinson disease (PD). Methods: We employed a model-free data-driven approach for computing whole-brain WM topologic arrangement and connectivity strength between brain regions by u...

Background: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All par...

Background: Several patient and disease characteristics are thought to influence DBS outcomes; however, most previous studies have focused on long-term outcomes with only a few addressing immediate postoperative course. Objective: To evaluate predictors of immediate outcomes (postoperative confusion and length of postoperative hospitalization) f...

Objective To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). Method Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term mainte...

Increased body mass index (BMI) after deep brain stimulation (DBS) in Parkinson's disease (PD) has been repeatedly reported in literature. However, little is known about the effect of PD clinical subtypes on weight and height changes after DBS. We aimed to study the differential effect of tremor-predominant versus hypokinetic-rigid disease on weigh...

Parkinson disease psychosis (PDP) is a common and significant behavioral problem associated with increased mortality and morbidity in patients. It is no longer thought to arise solely as a side effect to dopaminergic medications, but from a complex interplay of extrinsic and intrinsic factors. Management of PDP involves a search for medical causes...

Objective: To determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC). Background: Cerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery...

Background: Spasticity can be associated with several hyperkinetic involuntary movements generally referred to as "spasms" despite different phenomenology and clinical characteristics. Objective: To better characterize the phenomenology and clinical characteristics of spasticity-associated involuntary movements. Methods: We performed a cross-s...

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation a...

Background Little is known about the true prevalence and clinical characteristics of movement disorders in early multiple sclerosis (MS) and related demyelinating diseases. We conducted a prospective study to fill this knowledge gap.MethodsA consecutive patient sample was recruited from the MS clinic within a 1-year-period. Patients diagnosed over...

Study Objective To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis. Background In the 12-week ARM-TD and AIM-TD studies, the odds of res...

Background Tardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant...