MRI was suggested as a promising method for the diagnosis and assessment of Parkinson’s Disease (... more MRI was suggested as a promising method for the diagnosis and assessment of Parkinson’s Disease (PD). We aimed to assess the sensitivity of neuromelanin-MRI and T2* with radiomics analysis for detecting PD, identifying individuals at risk, and evaluating genotype-related differences. Patients with PD and non-manifesting (NM) participants [NM-carriers (NMC) and NM-non-carriers (NMNC)], underwent MRI and DAT-SPECT. Imaging-based metrics included 48 neuromelanin and T2* radiomics features and DAT-SPECT specific-binding-ratios (SBR), were extracted from several brain regions. Imaging values were assessed for their correlations with age, differences between groups, and correlations with the MDS-likelihood-ratio (LR) score. Several machine learning classifiers were evaluated for group classification. A total of 127 participants were included: 46 patients with PD (62.3 ± 10.0 years) [15:LRRK2-PD, 16:GBA-PD, and 15:idiopathic-PD (iPD)], 47 NMC (51.5 ± 8.3 years) [24:LRRK2-NMC and 23:GBA-NMC...
Digital health technologies (DHTs) enable us to measure human physiology and behavior remotely, o... more Digital health technologies (DHTs) enable us to measure human physiology and behavior remotely, objectively and continuously. With the accelerated adoption of DHTs in clinical trials, there is an unmet need to identify statistical approaches to address missing data to ensure that the derived endpoints are valid, accurate, and reliable. It is not obvious how commonly used statistical methods to handle missing data in clinical trials can be directly applied to the complex data collected by DHTs. Meanwhile, current approaches used to address missing data from DHTs are of limited sophistication and focus on the exclusion of data where the quantity of missing data exceeds a given threshold. High-frequency time series data collected by DHTs are often summarized to derive epoch-level data, which are then processed to compute daily summary measures. In this article, we discuss characteristics of missing data collected by DHT, review emerging statistical approaches for addressing missingness in epoch-level data including within-patient imputations across common time periods, functional data analysis, and deep learning methods, as well as imputation approaches and robust modeling appropriate for handling missing data in daily summary measures. We discuss strategies for minimizing missing data by optimizing DHT deployment and by including the patients' perspective in the study design. We believe that these approaches provide more insight into preventing missing data when deriving digital endpoints. We hope this article can serve as a starting point for further discussion among clinical trial stakeholders.
Objective: To characterize the effect of PD medication on disease progression as measured by rate... more Objective: To characterize the effect of PD medication on disease progression as measured by rate of change in MDS_UPDRS in PPMI study. Background: PPMI is an ongoing observational study that enrolled 423 treatment-naive (within 2 years of diagnosis) PD subjects. By 1 and 3 years, up to 55% and 78% of subjects, respectively, started PD medication. We analysed the rate of change in MDS-UPDRS total score (Part I, II, III total) prior to, and (6 to 21 months) on PD medication. Design/Methods: Data was download from the PPMI website in June 2017. 386 PD subjects were included in the analyses. Only practically-defined “off” condition data were used for visits after starting PD meds. Change in MDS-UPDRS was estimated from a mixed effects model for repeated measures. Demographics and baseline disease characteristics data were also examined. Results: As of the download date, 90 subjects remained treatment naive; 68, 106 and 118 had begun treatment with dopamine agonists, Levodopa and MAO-B ...
ABSTRACTBackgroundMutations in theGBAgene, which encodes the lysosomal enzyme glucocerebrosidase ... more ABSTRACTBackgroundMutations in theGBAgene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD).ObjectiveTo explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in theGBAandLRRK2genes.MethodsParticipants were genotyped for the G2019S‐LRRK2and nineGBAmutations common in Ashkenazi Jews. Performance‐based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected.ResultsOne hundred and seventy PD patients (102GBA‐PD, 38LRRK2‐PD, and 30 idiopathic PD) and 221 non‐manifesting carriers (NMC) (129GBA‐NMC, 45LRRK2‐NMC, 15GBA‐LRRK2‐NMC, and 32 healthy controls) participated in this study. GCase activity was lower amongGBA‐PD (3.15 ± 0.85 μmol/L/h),GBA‐NMC (3.23 ± 0.91 μmol/L/h), andGBA‐LRRK2‐NMC (3.20 ± 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype.Con...
BackgroundThe phenotype of Parkinson's disease (PD) is milder among patients with LRRK2‐PD an... more BackgroundThe phenotype of Parkinson's disease (PD) is milder among patients with LRRK2‐PD and more severe among patients with GBA‐PD; however, whether an additive phenotypical effect occurs among dual‐mutation carriers requires validation.ObjectiveThe objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single‐mutation presentation.MethodsPatients with PD were genotyped for the G2019S‐LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA‐PD, severe GBA‐PD, LRRK2‐PD, and LRRK2+GBA‐PD. Clinical symptoms were evaluated using performance‐based measures.ResultsA total of 1090 patients with idiopathic PD, 155 patients with LRRK2‐PD, 155 patients with mild GBA‐PD, 56 patients with severe GBA‐PD, and 27 patients with LRRK2+GBA‐PD participated in this study. The patients with LRRK2‐PD and LRRK2+GBA‐PD exhibited lower scores on total Unified Parkinso...
Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) each promote the ... more Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) each promote the survival and differentiation of developing motor neurons, but do so through distinct cellular signaling pathways. Administration of either factor alone has been shown to slow, but not to arrest, progression of motor neuron dysfunction in wobbler mice, an animal model of motor neuron disease. Because CNTF and BDNF are known to synergize in vitro and in ovo, the efficacy of CNTF and BDNF cotreatment was tested in the same animal mode. Subcutaneous injection of the two factors on alternate days was found to arrest disease progression in wobbler mice for 1 month, as measured by several behavioral, physiological, and histological criteria.
This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatmen... more This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatment of patients with amyotrophic lateral sclerosis was designed to determine the safety of this new mode of administration as well as the pharmacokinetics and drug distribution. CNTF was administered using a drug pump implanted into the lumbar subarachnoid space in each of four patients with amyotrophic lateral sclerosis. Escalating doses (0.4, 0.8, 1.6, 4, and 8 micrograms/h) were infused for 48 hours per week in 2-week cycles until the highest tolerated dose was achieved. Patients were observed for side effects, and standardized muscle and respiratory function tests were performed. Cerebrospinal fluid (CSF) levels of CNTF were determined using simultaneous lumbar and cervical taps. Plasma and CSF levels of antibodies, CSF cells and protein, and routine blood chemistries were monitored, as were weight and vital signs. Pharmacokinetic studies of four patients demonstrated that the distribution and clearance of recombinant human (rH)CNTF are similar to those of many small, water-soluble agents (morphine, baclofen, clonidine) and that the steady-state concentration of rHCNTF at the cervical level was 18 to 36% of that at the lumbar level. Lumbar CSF levels were in the range of 44 to 1230 ng/ml. Intrathecally administered rHCNTF had different adverse effects than the systemically delivered drug. With intrathecal administration, no asthenia, fever, chills, nausea, weight loss, increased cough, or sputum production was found. All patients who received rHCNTF intrathecally experienced dose-related CSF pleocytosis (primarily lymphocytic) and rises in protein levels. No clinical signs of meningeal irritation, such as stiff neck, photophobias, or nausea, were seen. However, one patient who had lumbar spinal stenosis developed severe burning and cramping leg pain. A second patient developed a severe headache and leg and back cramping. No abnormal clinical chemistry or hematological findings were encountered. Plasma levels of rHCNTF were below detection. Antibodies to rHCNTF were found in the systemic circulation of only one patient. The gradual decline in motor strength and performance of standard skills did not improve or worsen. In this first trial of a recombinant neurotrophic factor to be administered intrathecally by drug pump, the CNTF was well distributed along the spinal canal. Pain syndromes (headache, radicular pain) that were dose-related occurred in two patients, but systemic side effects, which had been observed with subcutaneous rHCNTF, did not occur. Intrathecal drug pump delivery of neurotrophic factors may be the most appropriate way in which to test the efficacy of these high-molecular weight proteins, because high CSF levels can be achieved without significant systemic side effects.
We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxygl... more We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxyglucose (FDG) and [18F]fluorodopa (FDOPA) and positron emission tomography (PET). Fourteen PD patients (mean age 49 years) had FDG/PET scans, of which 11 were scanned with both FDOPA and FDG. After the injection of FDOPA, brain uptake and arterial plasma radioactivity were monitored for 2 h. Striatal FDOPA uptake was analyzed with regard to a two‐compartment model, and target‐to‐background ratios (TBRs) and TBR‐versus‐time slopes were also calculated. Regional patterns of metabolic covariation were extracted from FDG/PET data using the Scaled Subprofile Model (SSM). SSM pattern weights, FDOPA uptake constants (Ki), TBRs, and TBR slopes were correlated with clinical measures for bradykinesia, rigidity, tremor, gait disturbance, left‐right asymmetry, dementia, and overall disease severity. In PD patients, rate constants for FDOPA uptake correlated with individual measures of bradykinesia (p ...
Journal of the American Medical Directors Association, 2002
This study investigates the cost of chronic constipation care. A consecutive sample of 31 chronic... more This study investigates the cost of chronic constipation care. A consecutive sample of 31 chronically constipated elderly patients. A not-for-profit long-term care facility in New Hyde Park, New York. Patient demographics and functional status, including activity of daily living scores, diagnosis, and medications were recorded. All constipation medication costs were obtained using the average wholesale price obtained from the Redbook (November 1999). All subjects were closely monitored for constipation care during two shifts a day (from 7:00 AM to 11:00 PM), over a 6-week period resulting in the collection of 1,860 shift reports. Each component of constipation treatment cost, namely drugs and staff time for drug administration, was identified and analyzed. The average number of nursing interactions for constipation treatment was 23.3 per month. The average cost per day for care specifically for the treatment of constipation was 2.11 US dollars. Fleet Enema trade mark and milk of magnesia accounted for 49% of all treatments. Administration (staffing) costs accounted for 70% of total drug costs. Although laxatives are the most frequently prescribed drugs used in long-term care settings, drug utilization patterns and associated costs in the treatment of chronic constipation have not been systematically reported. Our study identified staffing as the major cost factor in constipation care.
Afferent connections to the rat locus coeruleus (LC), which contains exclusively noradrenergic ne... more Afferent connections to the rat locus coeruleus (LC), which contains exclusively noradrenergic neurons, have been traced using the technique of retrograde transport of horseradish peroxidase (HRP). In order to ensure accurate placement of adequate amounts of HRP in the LC, a microiontophoretic delivery technique coupled with single cell recording was employed. The use of electrophysiological “landmarks” as aids in placing the injections is described. Following HRP injections into the LC, forebrain structures containing labelled neurons included the insular cortex, the central nucleus of the amygdala, the medial, lateral and magnocellular preoptic areas, the bed nucleus of the stria terminalis, and the dorsomedial, paraventricular and lateral hypothalamic areas. In the brainstem reactive neurons were observed in the central grey substance, the reticular formation, the raphe, vestibular, solitary tract and lateral reticular nuclei. In particular, the areas of catecholamine cell groups...
MRI was suggested as a promising method for the diagnosis and assessment of Parkinson’s Disease (... more MRI was suggested as a promising method for the diagnosis and assessment of Parkinson’s Disease (PD). We aimed to assess the sensitivity of neuromelanin-MRI and T2* with radiomics analysis for detecting PD, identifying individuals at risk, and evaluating genotype-related differences. Patients with PD and non-manifesting (NM) participants [NM-carriers (NMC) and NM-non-carriers (NMNC)], underwent MRI and DAT-SPECT. Imaging-based metrics included 48 neuromelanin and T2* radiomics features and DAT-SPECT specific-binding-ratios (SBR), were extracted from several brain regions. Imaging values were assessed for their correlations with age, differences between groups, and correlations with the MDS-likelihood-ratio (LR) score. Several machine learning classifiers were evaluated for group classification. A total of 127 participants were included: 46 patients with PD (62.3 ± 10.0 years) [15:LRRK2-PD, 16:GBA-PD, and 15:idiopathic-PD (iPD)], 47 NMC (51.5 ± 8.3 years) [24:LRRK2-NMC and 23:GBA-NMC...
Digital health technologies (DHTs) enable us to measure human physiology and behavior remotely, o... more Digital health technologies (DHTs) enable us to measure human physiology and behavior remotely, objectively and continuously. With the accelerated adoption of DHTs in clinical trials, there is an unmet need to identify statistical approaches to address missing data to ensure that the derived endpoints are valid, accurate, and reliable. It is not obvious how commonly used statistical methods to handle missing data in clinical trials can be directly applied to the complex data collected by DHTs. Meanwhile, current approaches used to address missing data from DHTs are of limited sophistication and focus on the exclusion of data where the quantity of missing data exceeds a given threshold. High-frequency time series data collected by DHTs are often summarized to derive epoch-level data, which are then processed to compute daily summary measures. In this article, we discuss characteristics of missing data collected by DHT, review emerging statistical approaches for addressing missingness in epoch-level data including within-patient imputations across common time periods, functional data analysis, and deep learning methods, as well as imputation approaches and robust modeling appropriate for handling missing data in daily summary measures. We discuss strategies for minimizing missing data by optimizing DHT deployment and by including the patients' perspective in the study design. We believe that these approaches provide more insight into preventing missing data when deriving digital endpoints. We hope this article can serve as a starting point for further discussion among clinical trial stakeholders.
Objective: To characterize the effect of PD medication on disease progression as measured by rate... more Objective: To characterize the effect of PD medication on disease progression as measured by rate of change in MDS_UPDRS in PPMI study. Background: PPMI is an ongoing observational study that enrolled 423 treatment-naive (within 2 years of diagnosis) PD subjects. By 1 and 3 years, up to 55% and 78% of subjects, respectively, started PD medication. We analysed the rate of change in MDS-UPDRS total score (Part I, II, III total) prior to, and (6 to 21 months) on PD medication. Design/Methods: Data was download from the PPMI website in June 2017. 386 PD subjects were included in the analyses. Only practically-defined “off” condition data were used for visits after starting PD meds. Change in MDS-UPDRS was estimated from a mixed effects model for repeated measures. Demographics and baseline disease characteristics data were also examined. Results: As of the download date, 90 subjects remained treatment naive; 68, 106 and 118 had begun treatment with dopamine agonists, Levodopa and MAO-B ...
ABSTRACTBackgroundMutations in theGBAgene, which encodes the lysosomal enzyme glucocerebrosidase ... more ABSTRACTBackgroundMutations in theGBAgene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD).ObjectiveTo explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in theGBAandLRRK2genes.MethodsParticipants were genotyped for the G2019S‐LRRK2and nineGBAmutations common in Ashkenazi Jews. Performance‐based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected.ResultsOne hundred and seventy PD patients (102GBA‐PD, 38LRRK2‐PD, and 30 idiopathic PD) and 221 non‐manifesting carriers (NMC) (129GBA‐NMC, 45LRRK2‐NMC, 15GBA‐LRRK2‐NMC, and 32 healthy controls) participated in this study. GCase activity was lower amongGBA‐PD (3.15 ± 0.85 μmol/L/h),GBA‐NMC (3.23 ± 0.91 μmol/L/h), andGBA‐LRRK2‐NMC (3.20 ± 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype.Con...
BackgroundThe phenotype of Parkinson's disease (PD) is milder among patients with LRRK2‐PD an... more BackgroundThe phenotype of Parkinson's disease (PD) is milder among patients with LRRK2‐PD and more severe among patients with GBA‐PD; however, whether an additive phenotypical effect occurs among dual‐mutation carriers requires validation.ObjectiveThe objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single‐mutation presentation.MethodsPatients with PD were genotyped for the G2019S‐LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA‐PD, severe GBA‐PD, LRRK2‐PD, and LRRK2+GBA‐PD. Clinical symptoms were evaluated using performance‐based measures.ResultsA total of 1090 patients with idiopathic PD, 155 patients with LRRK2‐PD, 155 patients with mild GBA‐PD, 56 patients with severe GBA‐PD, and 27 patients with LRRK2+GBA‐PD participated in this study. The patients with LRRK2‐PD and LRRK2+GBA‐PD exhibited lower scores on total Unified Parkinso...
Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) each promote the ... more Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) each promote the survival and differentiation of developing motor neurons, but do so through distinct cellular signaling pathways. Administration of either factor alone has been shown to slow, but not to arrest, progression of motor neuron dysfunction in wobbler mice, an animal model of motor neuron disease. Because CNTF and BDNF are known to synergize in vitro and in ovo, the efficacy of CNTF and BDNF cotreatment was tested in the same animal mode. Subcutaneous injection of the two factors on alternate days was found to arrest disease progression in wobbler mice for 1 month, as measured by several behavioral, physiological, and histological criteria.
This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatmen... more This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatment of patients with amyotrophic lateral sclerosis was designed to determine the safety of this new mode of administration as well as the pharmacokinetics and drug distribution. CNTF was administered using a drug pump implanted into the lumbar subarachnoid space in each of four patients with amyotrophic lateral sclerosis. Escalating doses (0.4, 0.8, 1.6, 4, and 8 micrograms/h) were infused for 48 hours per week in 2-week cycles until the highest tolerated dose was achieved. Patients were observed for side effects, and standardized muscle and respiratory function tests were performed. Cerebrospinal fluid (CSF) levels of CNTF were determined using simultaneous lumbar and cervical taps. Plasma and CSF levels of antibodies, CSF cells and protein, and routine blood chemistries were monitored, as were weight and vital signs. Pharmacokinetic studies of four patients demonstrated that the distribution and clearance of recombinant human (rH)CNTF are similar to those of many small, water-soluble agents (morphine, baclofen, clonidine) and that the steady-state concentration of rHCNTF at the cervical level was 18 to 36% of that at the lumbar level. Lumbar CSF levels were in the range of 44 to 1230 ng/ml. Intrathecally administered rHCNTF had different adverse effects than the systemically delivered drug. With intrathecal administration, no asthenia, fever, chills, nausea, weight loss, increased cough, or sputum production was found. All patients who received rHCNTF intrathecally experienced dose-related CSF pleocytosis (primarily lymphocytic) and rises in protein levels. No clinical signs of meningeal irritation, such as stiff neck, photophobias, or nausea, were seen. However, one patient who had lumbar spinal stenosis developed severe burning and cramping leg pain. A second patient developed a severe headache and leg and back cramping. No abnormal clinical chemistry or hematological findings were encountered. Plasma levels of rHCNTF were below detection. Antibodies to rHCNTF were found in the systemic circulation of only one patient. The gradual decline in motor strength and performance of standard skills did not improve or worsen. In this first trial of a recombinant neurotrophic factor to be administered intrathecally by drug pump, the CNTF was well distributed along the spinal canal. Pain syndromes (headache, radicular pain) that were dose-related occurred in two patients, but systemic side effects, which had been observed with subcutaneous rHCNTF, did not occur. Intrathecal drug pump delivery of neurotrophic factors may be the most appropriate way in which to test the efficacy of these high-molecular weight proteins, because high CSF levels can be achieved without significant systemic side effects.
We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxygl... more We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxyglucose (FDG) and [18F]fluorodopa (FDOPA) and positron emission tomography (PET). Fourteen PD patients (mean age 49 years) had FDG/PET scans, of which 11 were scanned with both FDOPA and FDG. After the injection of FDOPA, brain uptake and arterial plasma radioactivity were monitored for 2 h. Striatal FDOPA uptake was analyzed with regard to a two‐compartment model, and target‐to‐background ratios (TBRs) and TBR‐versus‐time slopes were also calculated. Regional patterns of metabolic covariation were extracted from FDG/PET data using the Scaled Subprofile Model (SSM). SSM pattern weights, FDOPA uptake constants (Ki), TBRs, and TBR slopes were correlated with clinical measures for bradykinesia, rigidity, tremor, gait disturbance, left‐right asymmetry, dementia, and overall disease severity. In PD patients, rate constants for FDOPA uptake correlated with individual measures of bradykinesia (p ...
Journal of the American Medical Directors Association, 2002
This study investigates the cost of chronic constipation care. A consecutive sample of 31 chronic... more This study investigates the cost of chronic constipation care. A consecutive sample of 31 chronically constipated elderly patients. A not-for-profit long-term care facility in New Hyde Park, New York. Patient demographics and functional status, including activity of daily living scores, diagnosis, and medications were recorded. All constipation medication costs were obtained using the average wholesale price obtained from the Redbook (November 1999). All subjects were closely monitored for constipation care during two shifts a day (from 7:00 AM to 11:00 PM), over a 6-week period resulting in the collection of 1,860 shift reports. Each component of constipation treatment cost, namely drugs and staff time for drug administration, was identified and analyzed. The average number of nursing interactions for constipation treatment was 23.3 per month. The average cost per day for care specifically for the treatment of constipation was 2.11 US dollars. Fleet Enema trade mark and milk of magnesia accounted for 49% of all treatments. Administration (staffing) costs accounted for 70% of total drug costs. Although laxatives are the most frequently prescribed drugs used in long-term care settings, drug utilization patterns and associated costs in the treatment of chronic constipation have not been systematically reported. Our study identified staffing as the major cost factor in constipation care.
Afferent connections to the rat locus coeruleus (LC), which contains exclusively noradrenergic ne... more Afferent connections to the rat locus coeruleus (LC), which contains exclusively noradrenergic neurons, have been traced using the technique of retrograde transport of horseradish peroxidase (HRP). In order to ensure accurate placement of adequate amounts of HRP in the LC, a microiontophoretic delivery technique coupled with single cell recording was employed. The use of electrophysiological “landmarks” as aids in placing the injections is described. Following HRP injections into the LC, forebrain structures containing labelled neurons included the insular cortex, the central nucleus of the amygdala, the medial, lateral and magnocellular preoptic areas, the bed nucleus of the stria terminalis, and the dorsomedial, paraventricular and lateral hypothalamic areas. In the brainstem reactive neurons were observed in the central grey substance, the reticular formation, the raphe, vestibular, solitary tract and lateral reticular nuclei. In particular, the areas of catecholamine cell groups...
Uploads