Zoltan Mari - Academia.edu (original) (raw)
Papers by Zoltan Mari
Movement Disorders Clinical Practice, Apr 1, 2014
Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and ... more Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and symptomatic forms. A distinct subgroup of the symptomatic form presents with progressive ataxia and PT. The histopathology of progressive ataxia and PT has not been previously determined. This study consisted of a clinical review, histopathology, and electron microscopy of the brain of a man with progressive ataxia and PT. The inferior olivary hypertrophy was symmetrical and homogenous, and no focal pathologic lesions could be identified in the brainstem. Insoluble tau deposits were found in neurons, exclusively infratentorially. We present the clinical and pathological evaluation of a case of progressive ataxia and PT that provide evidence for a unique form of 4R tauopathy.
Journal of Neuroscience Research, 2021
The present review asks whether magnetic resonance imaging (MRI) studies are able to define neura... more The present review asks whether magnetic resonance imaging (MRI) studies are able to define neural correlates of episodic memory within the hippocampus in Parkinson's disease (PD). Systematic searches were performed in PubMed, Web of Science, Medline, CINAHL, and EMBASE using search terms related to structural and functional MRI (fMRI), the hippocampus, episodic memory, and PD. Risk of bias was assessed for each study using the Newtown–Ottawa Scale. Thirty‐nine studies met inclusion criteria; eight fMRI, seven diffusion MRI (dMRI), and 24 structural MRI (14 exploring whole hippocampus and 10 exploring hippocampal subfields). Critical analysis of the literature revealed mixed evidence from functional and dMRI, but stronger evidence from sMRI of the hippocampus as a biomarker for episodic memory impairment in PD. Hippocampal subfield studies most often implicated CA1, CA3/4, and subiculum volume in episodic memory and cognitive decline in PD. Despite differences in imaging methodology, study design, and sample characteristics, MRI studies have helped elucidate an important neural correlate of episodic memory impairment in PD with both clinical and theoretical implications. Natural progression of this work encourages future research on hippocampal subfield function as a potential biomarker of, or therapeutic target for, episodic memory dysfunction in PD.
Movement Disorders, 2016
Objective: PD patients can be partitioned into two groups, denoted Tremor Dominant (PD-TD) and no... more Objective: PD patients can be partitioned into two groups, denoted Tremor Dominant (PD-TD) and non-tremor-dominant (PD-NTD) based on their MDS-UPDRS III subscores. Is this distinction correlated with the outcomes of cognitive tests, biomarkers, and dopaminergic imaging within 2 years of the PD diagnosis? Background: The classification of Parkinson’s disease (PD) patients into tremor-dominant (PD-TD) and non-tremor-dominant (PD-NTD) is commonly used clinically. The distinction is based on the relative difficulty the patient has with tremor vs akinetic or rigid aspects of PD, as reflected in scores on specific questions in the MDS-UPDRS III. The Parkinson’s Progression Markers Initiative (PPMI) cohort is a large observational clinical study aimed at verifying progression markers of Parkinson’s disease. This cohort provides us with the data for answering this question. Indeed, it contains 400 patients with a diagnosis of PD within 2 years of the baseline visit and an exhaustive collection of assessments. Methods: We have studied a comprehensive collection of PPMI measurements, including neurological and psychological tests, biofluid-based biomarkers, and dopamine transporter Imaging acquired at the baseline visit. In each case, we conducted a Wilcoxon test for the difference of the median within the two groups PD-TD and PD-NTD and corrected for multiple testing. Results: PD-NTD patients were clinically more severe in regards to their motor and non-motor symptoms of PD, as measured with the MDS-UPDRS I and II, as well as more likely to have depression and anxiety symptomatology. In addition, there were very significant dopamine transporter imaging (DaTscan) differences between the PD subtypes: PD-TD patients had less of a reduction in uptake in the striatum, caudate, and putamen compared to PD-NTD. Conclusions: The distinction between PD-TD and PD-NTD is well established using neurological exams. However, we have shown that the depression, anxiety and DaTscan measurements are also significantly different between these 2 groups at the earliest stages of the disease
JAMA, 2021
IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabo... more 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.
The Lancet Neurology, 2021
Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau pro... more Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics
Tremor and Other Hyperkinetic Movements, 2012
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2018
On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuati... more On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuations and severe dysphoria. The impact of these affective symptoms may be overlooked in the treatment of motor fluctuations. Our goal was to examine the relationship between motor fluctuations, their treatment status, and suicidality in PD participants. We analyzed data from the Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study of 223 individuals with PD. Suicidality was measured using items from four depression scales: Hamilton Depression Rating Scale (HAM-D-17); Montgomery-Åsberg Depression Rating Scale (MADRS); Inventory for Depressive Symptomatology (IDS-C); and the self-rated Beck Depression Inventory (BDI). Multivariable Poisson regression analyses tested whether self-reported motor fluctuations and their treatment status were associated with suicidality while controlling for recognized risk factors. Thirty-seven participants (16.6%) self-reported sui...
International journal of geriatric psychiatry, Jan 16, 2017
In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be mo... more In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non-demented PD participants is associated with domain-specific cognitive impairment on the Mini-Mental State Exam (MMSE). The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two-year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM-IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time-varying relationship between MMSE subscale scores and psycho...
The American Journal of Geriatric Psychiatry, 2016
While Parkinson's disease (PD) is defined clinically by its motor symptoms, it is increasingly re... more While Parkinson's disease (PD) is defined clinically by its motor symptoms, it is increasingly recognized that much of the disability and worsened quality of life experienced by patients with PD is attributable to psychiatric symptoms. The authors describe a model of multidisciplinary care that enables these symptoms to be effectively managed. They describe neuropsychiatric complications of PD itself as well as pharmacological and neurostimulation treatments for Parkinsonian motor symptoms, and discuss the management of these complications. Specifically they describe the clinical associations between motor fluctuations and anxiety and depressive symptoms, the compulsive overuse of dopaminergic medications prescribed for motor symptoms (the dopamine dysergulation syndrome) as well as neuropsychiatric complications of these medications including impulse control disorders, psychosis, and manic syndromes. Optimal management of these problems requires close collaboration across disciplines because of the potential for interactions among the pathophysiologic process of PD, motor symptoms, dopaminergic drugs, and psychiatric symptoms. The authors emphasize how their model of multidisciplinary care facilitates close collaboration among psychiatrists, other mental health professionals, neurologists, and functional neurosurgeons and how this facilitates effective care for patients who develop the specific neuropsychiatric complications discussed.
The Journal of Neuroscience, 2015
In Parkinson's disease (PD), the human brain is capable of producing motor commands, but appe... more In Parkinson's disease (PD), the human brain is capable of producing motor commands, but appears to require greater than normal subjective effort, particularly for the more-affected side. What is the nature of this subjective effort and can it be altered? We used an isometric task in which patients produced a goal force by engaging both arms, but were free to assign any fraction of that force to each arm. The patients preferred their less-affected arm, but only in some directions. This preference was correlated with lateralization of signal-dependent noise: the direction of force for which the brain was less willing to assign effort to an arm was generally the direction for which that arm exhibited greater noise. Therefore, the direction-dependent noise in each arm acted as an implicit cost that discouraged use of that arm. To check for a causal relationship between noise and motor cost, we used bilateral transcranial direct current stimulation of the motor cortex, placing the c...
100 Instructive Cases, 2008
A 67-year-old woman suffered a respiratory arrest due to anaphylactic shock during allergy desens... more A 67-year-old woman suffered a respiratory arrest due to anaphylactic shock during allergy desensitization. After resuscitation she remained comatose for several days. Upon regaining consciousness, she was found to have poor vision, rigidity, gait imbalance, and tremor. Most of her symptoms improved gradually, but she was left disabled due to hand tremor. She was evaluated by multiple physicians and thought to have parkinsonism. Several antiparkinsonian medications had no effect on the hand tremor. She then underwent left subthalamic deep brain stimulation (DBS) which provided no benefit and was turned off. The patient was first seen in our clinic 4 years after the arrest. Her general examination and vital signs were unremarkable. Her mentation and language were normal and her speech was fluent, but mildly dysarthric with occasional stuttering. The cranial nerves were significant for low visual acuity, bilateral paracentral scotomas, diplopia on upgaze, and hypometric saccades. She was mildly bradykinetic. Her muscle tone was increased. Muscle strength was normal. Her tremor was seen in the right hand and composed mainly of wrist flexion-extension, but occasionally involved the metacarpophalangeal joints, the left hand, and the right foot. The tremor could be seen at rest (see video, Case 35), while at other times the tremor could be triggered by tactile stimuli and passive or active hand movements, but this was not consistently reproducible. The rate of tremor was about 5 Hz. The tremor was slightly irregular and had a jerky quality. There were occasional larger amplitude jerks in phase with the tremor. She had mild finger incoordination and minimal limb ataxia. Other than the wrist tremor, there were no other abnormal movements. The sensory examination was significant for distal impairment of proprioception and vibration. Her gait was slow and minimally ataxic. Magnetic resonance imaging (MRI) of the brain showed hyperintense Signal on T2 images in the basal ganglia and deep white matter in all lobes, consistent with hypoxic injury. Electrophysiological assessment included somatosensory-evoked potentials and magnetic fields (SEPs/SEFs), jerk-locked back-averaging (JLA), and task-related corticomuscular coherence analysis using multichannel electroencephalographic (EEG), magnetoencephalographic (MEG), and simultaneous Legend to video Case 35 The first segment shows bilateral hand jerking. Note that some jerks appear synchronous between hands, while others are apparently independent. Although we have no video (only electrophysiological) record of exclusively left hand jerking, the second segment shows primarily left hand jerking. The following segments show, respectively, exclusively right hand jerking, jerk-free period, and finger-to-nose testing, followed by transition from jerk-free to exclusively right hand jerking.
100 Instructive Cases, 2008
Recent advances in medications and surgical therapy for neurological disorders may offer new ther... more Recent advances in medications and surgical therapy for neurological disorders may offer new therapeutic options for the treatment of myoclonus. Appropriate therapy for myoclonus depends on the etiology, and in some cases, myoclonus can improve when the provoking cause is eliminated. When the underlying cause for the movements is not immediately reversible, localization, disease pathophysiology, and etiology may each play a role in determining the most appropriate symptomatic treatment of disabling myoclonic jerks. While the use of many agents is still based on small, open-label case series and anecdotes, there is a growing body of evidence from head-to-head comparative trials in several types of myoclonus that may help guide therapy. New therapies for refractory myoclonus, including sodium oxybate and even deep brain stimulation, are also being explored with increasing enthusiasm.
Movement Disorders Clinical Practice, 2014
Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and ... more Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and symptomatic forms. A distinct subgroup of the symptomatic form presents with progressive ataxia and PT. The histopathology of progressive ataxia and PT has not been previously determined. This study consisted of a clinical review, histopathology, and electron microscopy of the brain of a man with progressive ataxia and PT. The inferior olivary hypertrophy was symmetrical and homogenous, and no focal pathologic lesions could be identified in the brainstem. Insoluble tau deposits were found in neurons, exclusively infratentorially. We present the clinical and pathological evaluation of a case of progressive ataxia and PT that provide evidence for a unique form of 4R tauopathy.
Tremor and other hyperkinetic movements (New York, N.Y.), 2013
Differentiating psychogenic parkinsonism from neurodegenerative Parkinson's disease (PD) with... more Differentiating psychogenic parkinsonism from neurodegenerative Parkinson's disease (PD) with psychogenic features is a diagnostic challenge. We report a detailed longitudinal clinical description of three cases presenting with suspected psychogenic parkinsonism. Dopamine transporter single-photon emission computed tomography (DAT-SPECT) was used as a supplemental diagnostic study and influenced clinical management. DAT-SPECT quantified the integrity of the striatal dopaminergic system in these cases of clinically uncertain parkinsonism and supported clinical decision-making.
Current Neurology and Neuroscience Reports, 2014
JAMA, Jan 10, 2015
There are no treatments available to slow or prevent the progression of Parkinson disease, despit... more There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Participants were randomized to placebo or creatine (10 g/d) monohydrate for a min...
Journal of Parkinson's disease, Jan 13, 2014
Background: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson'... more Background: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) has been used as an "Ambulatory Capacity Measure" (ACM in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD. Objective: To examine the construct validity of the ACM and PIGD in PD. Methods: We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1-5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assesse...
Movement Disorders, 2014
ABSTRACTTravel distance, growing disability, and uneven distribution of doctors limit access to c... more ABSTRACTTravel distance, growing disability, and uneven distribution of doctors limit access to care for most Parkinson's disease (PD) patients worldwide. Telemedicine, the use of telecommunications technology to deliver care at a distance, can help overcome these barriers. In this report, we describe the past, present, and likely future applications of telemedicine to PD. Historically, telemedicine has relied on expensive equipment to connect single patients to a specialist in pilot programs in wealthy nations. As the cost of video conferencing has plummeted, these efforts have expanded in scale and scope, now reaching larger parts of the world and extending the focus from care to training of remote providers. Policy, especially limited reimbursement, currently hinders the growth and adoption of these new care models. As these policies change and technology advances and spreads, the following will likely develop: integrated care networks that connect patients to a wide range of...
Movement Disorders Clinical Practice, Apr 1, 2014
Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and ... more Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and symptomatic forms. A distinct subgroup of the symptomatic form presents with progressive ataxia and PT. The histopathology of progressive ataxia and PT has not been previously determined. This study consisted of a clinical review, histopathology, and electron microscopy of the brain of a man with progressive ataxia and PT. The inferior olivary hypertrophy was symmetrical and homogenous, and no focal pathologic lesions could be identified in the brainstem. Insoluble tau deposits were found in neurons, exclusively infratentorially. We present the clinical and pathological evaluation of a case of progressive ataxia and PT that provide evidence for a unique form of 4R tauopathy.
Journal of Neuroscience Research, 2021
The present review asks whether magnetic resonance imaging (MRI) studies are able to define neura... more The present review asks whether magnetic resonance imaging (MRI) studies are able to define neural correlates of episodic memory within the hippocampus in Parkinson's disease (PD). Systematic searches were performed in PubMed, Web of Science, Medline, CINAHL, and EMBASE using search terms related to structural and functional MRI (fMRI), the hippocampus, episodic memory, and PD. Risk of bias was assessed for each study using the Newtown–Ottawa Scale. Thirty‐nine studies met inclusion criteria; eight fMRI, seven diffusion MRI (dMRI), and 24 structural MRI (14 exploring whole hippocampus and 10 exploring hippocampal subfields). Critical analysis of the literature revealed mixed evidence from functional and dMRI, but stronger evidence from sMRI of the hippocampus as a biomarker for episodic memory impairment in PD. Hippocampal subfield studies most often implicated CA1, CA3/4, and subiculum volume in episodic memory and cognitive decline in PD. Despite differences in imaging methodology, study design, and sample characteristics, MRI studies have helped elucidate an important neural correlate of episodic memory impairment in PD with both clinical and theoretical implications. Natural progression of this work encourages future research on hippocampal subfield function as a potential biomarker of, or therapeutic target for, episodic memory dysfunction in PD.
Movement Disorders, 2016
Objective: PD patients can be partitioned into two groups, denoted Tremor Dominant (PD-TD) and no... more Objective: PD patients can be partitioned into two groups, denoted Tremor Dominant (PD-TD) and non-tremor-dominant (PD-NTD) based on their MDS-UPDRS III subscores. Is this distinction correlated with the outcomes of cognitive tests, biomarkers, and dopaminergic imaging within 2 years of the PD diagnosis? Background: The classification of Parkinson’s disease (PD) patients into tremor-dominant (PD-TD) and non-tremor-dominant (PD-NTD) is commonly used clinically. The distinction is based on the relative difficulty the patient has with tremor vs akinetic or rigid aspects of PD, as reflected in scores on specific questions in the MDS-UPDRS III. The Parkinson’s Progression Markers Initiative (PPMI) cohort is a large observational clinical study aimed at verifying progression markers of Parkinson’s disease. This cohort provides us with the data for answering this question. Indeed, it contains 400 patients with a diagnosis of PD within 2 years of the baseline visit and an exhaustive collection of assessments. Methods: We have studied a comprehensive collection of PPMI measurements, including neurological and psychological tests, biofluid-based biomarkers, and dopamine transporter Imaging acquired at the baseline visit. In each case, we conducted a Wilcoxon test for the difference of the median within the two groups PD-TD and PD-NTD and corrected for multiple testing. Results: PD-NTD patients were clinically more severe in regards to their motor and non-motor symptoms of PD, as measured with the MDS-UPDRS I and II, as well as more likely to have depression and anxiety symptomatology. In addition, there were very significant dopamine transporter imaging (DaTscan) differences between the PD subtypes: PD-TD patients had less of a reduction in uptake in the striatum, caudate, and putamen compared to PD-NTD. Conclusions: The distinction between PD-TD and PD-NTD is well established using neurological exams. However, we have shown that the depression, anxiety and DaTscan measurements are also significantly different between these 2 groups at the earliest stages of the disease
JAMA, 2021
IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabo... more 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.
The Lancet Neurology, 2021
Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau pro... more Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics
Tremor and Other Hyperkinetic Movements, 2012
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2018
On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuati... more On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuations and severe dysphoria. The impact of these affective symptoms may be overlooked in the treatment of motor fluctuations. Our goal was to examine the relationship between motor fluctuations, their treatment status, and suicidality in PD participants. We analyzed data from the Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study of 223 individuals with PD. Suicidality was measured using items from four depression scales: Hamilton Depression Rating Scale (HAM-D-17); Montgomery-Åsberg Depression Rating Scale (MADRS); Inventory for Depressive Symptomatology (IDS-C); and the self-rated Beck Depression Inventory (BDI). Multivariable Poisson regression analyses tested whether self-reported motor fluctuations and their treatment status were associated with suicidality while controlling for recognized risk factors. Thirty-seven participants (16.6%) self-reported sui...
International journal of geriatric psychiatry, Jan 16, 2017
In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be mo... more In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non-demented PD participants is associated with domain-specific cognitive impairment on the Mini-Mental State Exam (MMSE). The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two-year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM-IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time-varying relationship between MMSE subscale scores and psycho...
The American Journal of Geriatric Psychiatry, 2016
While Parkinson's disease (PD) is defined clinically by its motor symptoms, it is increasingly re... more While Parkinson's disease (PD) is defined clinically by its motor symptoms, it is increasingly recognized that much of the disability and worsened quality of life experienced by patients with PD is attributable to psychiatric symptoms. The authors describe a model of multidisciplinary care that enables these symptoms to be effectively managed. They describe neuropsychiatric complications of PD itself as well as pharmacological and neurostimulation treatments for Parkinsonian motor symptoms, and discuss the management of these complications. Specifically they describe the clinical associations between motor fluctuations and anxiety and depressive symptoms, the compulsive overuse of dopaminergic medications prescribed for motor symptoms (the dopamine dysergulation syndrome) as well as neuropsychiatric complications of these medications including impulse control disorders, psychosis, and manic syndromes. Optimal management of these problems requires close collaboration across disciplines because of the potential for interactions among the pathophysiologic process of PD, motor symptoms, dopaminergic drugs, and psychiatric symptoms. The authors emphasize how their model of multidisciplinary care facilitates close collaboration among psychiatrists, other mental health professionals, neurologists, and functional neurosurgeons and how this facilitates effective care for patients who develop the specific neuropsychiatric complications discussed.
The Journal of Neuroscience, 2015
In Parkinson's disease (PD), the human brain is capable of producing motor commands, but appe... more In Parkinson's disease (PD), the human brain is capable of producing motor commands, but appears to require greater than normal subjective effort, particularly for the more-affected side. What is the nature of this subjective effort and can it be altered? We used an isometric task in which patients produced a goal force by engaging both arms, but were free to assign any fraction of that force to each arm. The patients preferred their less-affected arm, but only in some directions. This preference was correlated with lateralization of signal-dependent noise: the direction of force for which the brain was less willing to assign effort to an arm was generally the direction for which that arm exhibited greater noise. Therefore, the direction-dependent noise in each arm acted as an implicit cost that discouraged use of that arm. To check for a causal relationship between noise and motor cost, we used bilateral transcranial direct current stimulation of the motor cortex, placing the c...
100 Instructive Cases, 2008
A 67-year-old woman suffered a respiratory arrest due to anaphylactic shock during allergy desens... more A 67-year-old woman suffered a respiratory arrest due to anaphylactic shock during allergy desensitization. After resuscitation she remained comatose for several days. Upon regaining consciousness, she was found to have poor vision, rigidity, gait imbalance, and tremor. Most of her symptoms improved gradually, but she was left disabled due to hand tremor. She was evaluated by multiple physicians and thought to have parkinsonism. Several antiparkinsonian medications had no effect on the hand tremor. She then underwent left subthalamic deep brain stimulation (DBS) which provided no benefit and was turned off. The patient was first seen in our clinic 4 years after the arrest. Her general examination and vital signs were unremarkable. Her mentation and language were normal and her speech was fluent, but mildly dysarthric with occasional stuttering. The cranial nerves were significant for low visual acuity, bilateral paracentral scotomas, diplopia on upgaze, and hypometric saccades. She was mildly bradykinetic. Her muscle tone was increased. Muscle strength was normal. Her tremor was seen in the right hand and composed mainly of wrist flexion-extension, but occasionally involved the metacarpophalangeal joints, the left hand, and the right foot. The tremor could be seen at rest (see video, Case 35), while at other times the tremor could be triggered by tactile stimuli and passive or active hand movements, but this was not consistently reproducible. The rate of tremor was about 5 Hz. The tremor was slightly irregular and had a jerky quality. There were occasional larger amplitude jerks in phase with the tremor. She had mild finger incoordination and minimal limb ataxia. Other than the wrist tremor, there were no other abnormal movements. The sensory examination was significant for distal impairment of proprioception and vibration. Her gait was slow and minimally ataxic. Magnetic resonance imaging (MRI) of the brain showed hyperintense Signal on T2 images in the basal ganglia and deep white matter in all lobes, consistent with hypoxic injury. Electrophysiological assessment included somatosensory-evoked potentials and magnetic fields (SEPs/SEFs), jerk-locked back-averaging (JLA), and task-related corticomuscular coherence analysis using multichannel electroencephalographic (EEG), magnetoencephalographic (MEG), and simultaneous Legend to video Case 35 The first segment shows bilateral hand jerking. Note that some jerks appear synchronous between hands, while others are apparently independent. Although we have no video (only electrophysiological) record of exclusively left hand jerking, the second segment shows primarily left hand jerking. The following segments show, respectively, exclusively right hand jerking, jerk-free period, and finger-to-nose testing, followed by transition from jerk-free to exclusively right hand jerking.
100 Instructive Cases, 2008
Recent advances in medications and surgical therapy for neurological disorders may offer new ther... more Recent advances in medications and surgical therapy for neurological disorders may offer new therapeutic options for the treatment of myoclonus. Appropriate therapy for myoclonus depends on the etiology, and in some cases, myoclonus can improve when the provoking cause is eliminated. When the underlying cause for the movements is not immediately reversible, localization, disease pathophysiology, and etiology may each play a role in determining the most appropriate symptomatic treatment of disabling myoclonic jerks. While the use of many agents is still based on small, open-label case series and anecdotes, there is a growing body of evidence from head-to-head comparative trials in several types of myoclonus that may help guide therapy. New therapies for refractory myoclonus, including sodium oxybate and even deep brain stimulation, are also being explored with increasing enthusiasm.
Movement Disorders Clinical Practice, 2014
Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and ... more Palatal tremor (PT) is an uncommon movement disorder that has been subdivided into essential and symptomatic forms. A distinct subgroup of the symptomatic form presents with progressive ataxia and PT. The histopathology of progressive ataxia and PT has not been previously determined. This study consisted of a clinical review, histopathology, and electron microscopy of the brain of a man with progressive ataxia and PT. The inferior olivary hypertrophy was symmetrical and homogenous, and no focal pathologic lesions could be identified in the brainstem. Insoluble tau deposits were found in neurons, exclusively infratentorially. We present the clinical and pathological evaluation of a case of progressive ataxia and PT that provide evidence for a unique form of 4R tauopathy.
Tremor and other hyperkinetic movements (New York, N.Y.), 2013
Differentiating psychogenic parkinsonism from neurodegenerative Parkinson's disease (PD) with... more Differentiating psychogenic parkinsonism from neurodegenerative Parkinson's disease (PD) with psychogenic features is a diagnostic challenge. We report a detailed longitudinal clinical description of three cases presenting with suspected psychogenic parkinsonism. Dopamine transporter single-photon emission computed tomography (DAT-SPECT) was used as a supplemental diagnostic study and influenced clinical management. DAT-SPECT quantified the integrity of the striatal dopaminergic system in these cases of clinically uncertain parkinsonism and supported clinical decision-making.
Current Neurology and Neuroscience Reports, 2014
JAMA, Jan 10, 2015
There are no treatments available to slow or prevent the progression of Parkinson disease, despit... more There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Participants were randomized to placebo or creatine (10 g/d) monohydrate for a min...
Journal of Parkinson's disease, Jan 13, 2014
Background: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson'... more Background: A construct calculated as the sum of items 13-15, 29, 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) has been used as an "Ambulatory Capacity Measure" (ACM in Parkinson disease (PD). Its construct validity has never been examined. A similar construct, consisting of the mean value of the same UPDRS items has been used under the acronym PIGD as a measure of postural instability and gait disorder in PD. Objective: To examine the construct validity of the ACM and PIGD in PD. Methods: We analyzed data in an existing database of 340 PD patients, Hoehn and Yahr stages (HYS) 1-5 who participated in a study of falls. Number of falls (NOF) was recorded over 4 weeks, and UPDRS (mental, ADL, and motor subscales), HYS, Activities Based Confidence Scale (ABC), Freezing of Gait Questionnaire (FOG), Five Times Sit-to-Stand (FTSS), Timed Up-and Go (TUG), Gait Velocity (GV), and Berg Balance Scale (BBS) evaluations were performed. Internal consistency was assesse...
Movement Disorders, 2014
ABSTRACTTravel distance, growing disability, and uneven distribution of doctors limit access to c... more ABSTRACTTravel distance, growing disability, and uneven distribution of doctors limit access to care for most Parkinson's disease (PD) patients worldwide. Telemedicine, the use of telecommunications technology to deliver care at a distance, can help overcome these barriers. In this report, we describe the past, present, and likely future applications of telemedicine to PD. Historically, telemedicine has relied on expensive equipment to connect single patients to a specialist in pilot programs in wealthy nations. As the cost of video conferencing has plummeted, these efforts have expanded in scale and scope, now reaching larger parts of the world and extending the focus from care to training of remote providers. Policy, especially limited reimbursement, currently hinders the growth and adoption of these new care models. As these policies change and technology advances and spreads, the following will likely develop: integrated care networks that connect patients to a wide range of...