Dwight German - Academia.edu (original) (raw)
Papers by Dwight German
Experimental Neurology, Apr 1, 2012
Parkinson's disease (PD) is characterized by a prominent degeneration of nigrostriatal dopamine (... more Parkinson's disease (PD) is characterized by a prominent degeneration of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. Despite clinical and preclinical studies of neuroprotective strategies for PD, there is no effective treatment for preventing or slowing the progression of neurodegeneration. The inverse correlation between caffeine consumption and risk of PD suggests that caffeine may exert neuroprotection. Whether caffeine is neuroprotective in a chronic progressive model of PD has not been evaluated nor is it known if delayed caffeine treatment can stop DA neuronal loss. We show that a chronic unilateral intra-cerebroventricular infusion of 1-methyl-4-phenylpyridinium in the rat brain for 28 days produces a progressive loss of DA and tyrosine hydroxylase in the ipsilateral striatum and a loss of DA cell bodies and microglial activation in the ipsilateral substantia nigra. Chronic caffeine consumption prevented the degeneration of DA cell bodies in the substantia nigra. Importantly, neuroprotection was still apparent when caffeine was introduced after the onset of the neurodegenerative process. These results add to the clinical relevance for adenosine receptors as a disease-modifying drug target for PD.
Alzheimers & Dementia, Jul 1, 2005
the M-CSF receptor (M-CSFR). We previously showed that increasing expression of the M-CSFR on cul... more the M-CSF receptor (M-CSFR). We previously showed that increasing expression of the M-CSFR on cultured microglia dramatically upregulates microglia M-CSF and IL-1 expression. Objectives: To determine if knockdown of microglial interleukin-1 and M-CSF expression affects NMDA-induced neurotoxicity in a co-culture system. Methods: We used a co-culture model consisting of microglia overexpressing the M-CSFR and hippocampal organotypic cultures treated with the neurotoxin NMDA. To test the importance of microglial IL-1 and M-CSF on neuronal survival, we used an shRNA gene-targeted approach in which we selectively and without toxicity deleted microglial IL-1 or M-CSF expression prior to co-culture assembly. Transfections were performed with the hairpin RNA expression plasmid pGSU6-GFP-shRNA. To quantify neuronal injury, we used propidium iodide as well as FluoroJade staining. Results: We found that when microglia overexpressing the M-CSFR were cocultured with organotypic slices, there was complete protection of neurons from NMDA-induced injury. However, after knockdown of either microglial IL-1 or M-CSF, neuroprotection was abolished. Using TaqMan real-time RT-PCR, we confirmed that the shRNA constructs resulted in a 75% knockdown of cytokine expression. Both M-CSF and IL-1 were necessary for microglial proliferation, but only IL-1 removal also suppressed chemotactic migration of microglia toward the NMDA-injured organotypic culture. Conclusions: These results demonstrate that IL-1 and M-CSF are essential for M-CSFR-induced microglial neuroprotection in a microglial-organotypic hippocampal co-culture system. In AD, increased IL-1 and M-CSF expression by M-CSFR-activated microglia could actually serve to protect, rather than harm neurons. It may be that some inflammatory factors expressed early in AD could be beneficial, so that suppressing inflammation might accelerate rather than prevent disease progression. (Supported by an Alzheimer’s Association New Investigator Award to O.M. and NIH award MH57833).
Journal of Neuroimmunology, Sep 1, 2014
Accumulation and cytotoxicity of amyloid beta (Aβ) are understood as the major cause of Alzheimer... more Accumulation and cytotoxicity of amyloid beta (Aβ) are understood as the major cause of Alzheimer's disease (AD). There is evidence that naturally occurring antibodies against amyloid beta (Aβ) protein play a role in Aβ-clearance, and such a mechanism appears to be impaired in AD. In the present study, the anti-Aβ antibodies in the serum from individuals with and without late onset AD were measured using ELISA and dot-blot methods. Aβ auto-antibodies in serum were mainly targeted to Aβ1-15 epitope and its titer was significantly lower in AD patients than elderly non-AD controls (NC). The dot-blot analysis further demonstrated that auto-antibodies against fibrillar Aβ42, Aβ1-15 and Aβ16-30 epitopes were all in a lower level in AD than in NC. The isotypes of the auto-antibodies were mainly non-inflammatory IgG2 type. We also analyzed the relationship of auto-Aβ antibodies levels with the genotypes of Apolipoprotein E (ApoE) and ANKK1/DRD2 gene.
Journal of Neurosurgery, Feb 1, 2009
Object The authors previously developed an optical stereotactic probe employing near-infrared (NI... more Object The authors previously developed an optical stereotactic probe employing near-infrared (NIR) spectroscopy to provide intraoperative localization by distinguishing gray matter from white matter. In the current study they extend and further validate this technology. Methods Near-infrared probes were inserted 203 times during 138 procedures for movement disorders. Detailed validation with postoperative imaging was obtained for 121 of these procedures and with microelectrode recording (MER) for 30 procedures. Probes were constructed to interrogate tissue perpendicular to the probe path and to incorporate hollow channels for microelectrodes, deep brain stimulation (DBS) electrodes, and other payloads. Results The NIR data were highly correlated to imaging and MER recordings for thalamic targets. The NIR data were highly sensitive but less specific relative to imaging for subthalamic targets, confirming the ability to detect the subthalamic nucleus and to provide warnings of inaccurate localization. The difference between the NIR- and MER-detected midpoints of the subthalamic nucleus along the chosen tracks was 1.1 ± 1.2 mm (SD). Data obtained during insertion and withdrawal of the NIR probe suggested that DBS electrodes may push their targets ahead of their paths. There was one symptomatic morbidity. Detailed NIR data could be obtained from a 7-cm track in less than 10 minutes. Conclusions The NIR probe is a straightforward, quick, and robust tool for intraoperative localization during functional neurosurgery. Potential future applications include localization of targets for epilepsy and psychiatric disorders, and incorporation of NIR guidance into probes designed to convey various payloads.
Epidemiology, Sep 1, 2012
JAMA Neurology, Aug 1, 2014
Experimental Neurology, Dec 1, 2013
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a prominent... more Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD.
Neurosurgery, Jun 1, 2008
Alzheimers & Dementia, Jul 1, 2011
Background: Because there is immune system activation in Alzheimer’s disease (AD), there may be s... more Background: Because there is immune system activation in Alzheimer’s disease (AD), there may be serum antibodies that can serve as biomarkers for the disease. A novel unbiased approach to identifying disease-related antibodies, using combinatorial organic chemistry, involves the production of peptoid microarrays. Peptoids are oligo-N-substituted glycines which retain the binding characteristics of peptides, are easy to synthesize, and have been shown to be rich sources of protein ligands. Methods: Using a microarray consisting of 15,000 unique 8-mer peptoids, and serum from 6 AD, 6 Parkinson’s disease (PD) and 6 normal control subjects, we identified 3 peptoids that capture IgG antibodies whose levels are 3-10-fold higher in each AD patient compared to each PD and each normal control. Using a larger set of AD (49), PD (20) and normal controls (25), along with 10 MCI cases, we sought to validate the sensitivity and specificity of the 3 AD peptoids. Results: The 3 AD peptoids provide >90% sensitivity and specificity for the identification of AD. In addition, 9 of the 10 MCI cases showed elevated peptoid levels compared to normal controls. Conclusions: The peptoids should be useful biomarkers for AD, and for detecting the disease at an early time-point (i.e., MCI). Also, the antibodies recognized by the peptoids may represent novel drug targets for the treatment of the disease.
Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal lev-els... more Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal lev-els of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxy-gen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK path-way regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the
Alzheimer's & Dementia, 2019
npj Parkinson's Disease, 2018
Parkinson disease (PD) is a progressive neurodegenerative disease with motor symptoms that result... more Parkinson disease (PD) is a progressive neurodegenerative disease with motor symptoms that result from degeneration of midbrain dopaminergic neurons. Biomarker research seeks to identify the disease during the pre-symptomatic phase, which is a time when therapeutic intervention will be most helpful. Previously, we screened a combinatorial peptoid library to search for antibodies that are present at much higher levels in the serum of PD patients than in control subjects. One such compound, called the PD2 peptoid, was 84% accurate for the identification of de novo PD when employed as the capture agent in an enzyme-linked immunosorbent assay. This peptoid recognized an IgG3 antibody, and IgG3 levels were also found to be significantly higher in PD vs. control serum. In that study we used samples from the NINDS Parkinson’s Disease Biomarker Program. The current study sought to validate that finding using serum samples from de novo and control subjects in the Parkinson’s Progression Mark...
Biomarkers in medicine, 2017
Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort ... more Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) coho...
The Lancet. Neurology, Aug 16, 2017
Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disea... more Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generate...
Alzheimer's & Dementia, 2016
Movement disorders : official journal of the Movement Disorder Society, Jun 7, 2015
Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of ... more Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. Using a novel consortium design, the…
Parkinsonism & related disorders, 2008
Animal models of Parkinson's disease (PD) that more closely exhibit the chronic neuropatholog... more Animal models of Parkinson's disease (PD) that more closely exhibit the chronic neuropathology seen in the human condition are needed in order to reveal processes involved with progressive neurodegeneration and for testing potential interventions for retarding dopamine (DA) neuronal loss. Here we describe the recently developed chronic rat model of PD in which 1-methyl-4-phenylpyridinium ion (MPP(+)) is infused chronically into the lateral cerebral ventricle. We review features of this model that include loss of nigral DA neurons, swollen and abnormal mitochondria, striatal inclusion-like bodies and microgliosis. Advantages as well as limitations of the model are addressed.
Journal of Neurosurgery, 2009
Object The authors previously developed an optical stereotactic probe employing near-infrared (NI... more Object The authors previously developed an optical stereotactic probe employing near-infrared (NIR) spectroscopy to provide intraoperative localization by distinguishing gray matter from white matter. In the current study they extend and further validate this technology. Methods Near-infrared probes were inserted 203 times during 138 procedures for movement disorders. Detailed validation with postoperative imaging was obtained for 121 of these procedures and with microelectrode recording (MER) for 30 procedures. Probes were constructed to interrogate tissue perpendicular to the probe path and to incorporate hollow channels for microelectrodes, deep brain stimulation (DBS) electrodes, and other payloads. Results The NIR data were highly correlated to imaging and MER recordings for thalamic targets. The NIR data were highly sensitive but less specific relative to imaging for subthalamic targets, confirming the ability to detect the subthalamic nucleus and to provide warnings of inaccu...
Experimental Neurology, Apr 1, 2012
Parkinson's disease (PD) is characterized by a prominent degeneration of nigrostriatal dopamine (... more Parkinson's disease (PD) is characterized by a prominent degeneration of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. Despite clinical and preclinical studies of neuroprotective strategies for PD, there is no effective treatment for preventing or slowing the progression of neurodegeneration. The inverse correlation between caffeine consumption and risk of PD suggests that caffeine may exert neuroprotection. Whether caffeine is neuroprotective in a chronic progressive model of PD has not been evaluated nor is it known if delayed caffeine treatment can stop DA neuronal loss. We show that a chronic unilateral intra-cerebroventricular infusion of 1-methyl-4-phenylpyridinium in the rat brain for 28 days produces a progressive loss of DA and tyrosine hydroxylase in the ipsilateral striatum and a loss of DA cell bodies and microglial activation in the ipsilateral substantia nigra. Chronic caffeine consumption prevented the degeneration of DA cell bodies in the substantia nigra. Importantly, neuroprotection was still apparent when caffeine was introduced after the onset of the neurodegenerative process. These results add to the clinical relevance for adenosine receptors as a disease-modifying drug target for PD.
Alzheimers & Dementia, Jul 1, 2005
the M-CSF receptor (M-CSFR). We previously showed that increasing expression of the M-CSFR on cul... more the M-CSF receptor (M-CSFR). We previously showed that increasing expression of the M-CSFR on cultured microglia dramatically upregulates microglia M-CSF and IL-1 expression. Objectives: To determine if knockdown of microglial interleukin-1 and M-CSF expression affects NMDA-induced neurotoxicity in a co-culture system. Methods: We used a co-culture model consisting of microglia overexpressing the M-CSFR and hippocampal organotypic cultures treated with the neurotoxin NMDA. To test the importance of microglial IL-1 and M-CSF on neuronal survival, we used an shRNA gene-targeted approach in which we selectively and without toxicity deleted microglial IL-1 or M-CSF expression prior to co-culture assembly. Transfections were performed with the hairpin RNA expression plasmid pGSU6-GFP-shRNA. To quantify neuronal injury, we used propidium iodide as well as FluoroJade staining. Results: We found that when microglia overexpressing the M-CSFR were cocultured with organotypic slices, there was complete protection of neurons from NMDA-induced injury. However, after knockdown of either microglial IL-1 or M-CSF, neuroprotection was abolished. Using TaqMan real-time RT-PCR, we confirmed that the shRNA constructs resulted in a 75% knockdown of cytokine expression. Both M-CSF and IL-1 were necessary for microglial proliferation, but only IL-1 removal also suppressed chemotactic migration of microglia toward the NMDA-injured organotypic culture. Conclusions: These results demonstrate that IL-1 and M-CSF are essential for M-CSFR-induced microglial neuroprotection in a microglial-organotypic hippocampal co-culture system. In AD, increased IL-1 and M-CSF expression by M-CSFR-activated microglia could actually serve to protect, rather than harm neurons. It may be that some inflammatory factors expressed early in AD could be beneficial, so that suppressing inflammation might accelerate rather than prevent disease progression. (Supported by an Alzheimer’s Association New Investigator Award to O.M. and NIH award MH57833).
Journal of Neuroimmunology, Sep 1, 2014
Accumulation and cytotoxicity of amyloid beta (Aβ) are understood as the major cause of Alzheimer... more Accumulation and cytotoxicity of amyloid beta (Aβ) are understood as the major cause of Alzheimer's disease (AD). There is evidence that naturally occurring antibodies against amyloid beta (Aβ) protein play a role in Aβ-clearance, and such a mechanism appears to be impaired in AD. In the present study, the anti-Aβ antibodies in the serum from individuals with and without late onset AD were measured using ELISA and dot-blot methods. Aβ auto-antibodies in serum were mainly targeted to Aβ1-15 epitope and its titer was significantly lower in AD patients than elderly non-AD controls (NC). The dot-blot analysis further demonstrated that auto-antibodies against fibrillar Aβ42, Aβ1-15 and Aβ16-30 epitopes were all in a lower level in AD than in NC. The isotypes of the auto-antibodies were mainly non-inflammatory IgG2 type. We also analyzed the relationship of auto-Aβ antibodies levels with the genotypes of Apolipoprotein E (ApoE) and ANKK1/DRD2 gene.
Journal of Neurosurgery, Feb 1, 2009
Object The authors previously developed an optical stereotactic probe employing near-infrared (NI... more Object The authors previously developed an optical stereotactic probe employing near-infrared (NIR) spectroscopy to provide intraoperative localization by distinguishing gray matter from white matter. In the current study they extend and further validate this technology. Methods Near-infrared probes were inserted 203 times during 138 procedures for movement disorders. Detailed validation with postoperative imaging was obtained for 121 of these procedures and with microelectrode recording (MER) for 30 procedures. Probes were constructed to interrogate tissue perpendicular to the probe path and to incorporate hollow channels for microelectrodes, deep brain stimulation (DBS) electrodes, and other payloads. Results The NIR data were highly correlated to imaging and MER recordings for thalamic targets. The NIR data were highly sensitive but less specific relative to imaging for subthalamic targets, confirming the ability to detect the subthalamic nucleus and to provide warnings of inaccurate localization. The difference between the NIR- and MER-detected midpoints of the subthalamic nucleus along the chosen tracks was 1.1 ± 1.2 mm (SD). Data obtained during insertion and withdrawal of the NIR probe suggested that DBS electrodes may push their targets ahead of their paths. There was one symptomatic morbidity. Detailed NIR data could be obtained from a 7-cm track in less than 10 minutes. Conclusions The NIR probe is a straightforward, quick, and robust tool for intraoperative localization during functional neurosurgery. Potential future applications include localization of targets for epilepsy and psychiatric disorders, and incorporation of NIR guidance into probes designed to convey various payloads.
Epidemiology, Sep 1, 2012
JAMA Neurology, Aug 1, 2014
Experimental Neurology, Dec 1, 2013
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a prominent... more Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a prominent loss of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. The peptide angiotensin II (AngII) plays a role in oxidative-stress induced disorders and is thought to mediate its detrimental actions via activation of AngII AT1 receptors. The brain renin-angiotensin system is implicated in neurodegenerative disorders including PD. Blockade of the angiotensin converting enzyme or AT1 receptors provides protection in acute animal models of parkinsonism. We demonstrate here that treatment of mice with the angiotensin converting enzyme inhibitor captopril protects the striatum from acutely administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), and that chronic captopril protects the nigral DA cell bodies from degeneration in a progressive rat model of parkinsonism created by the chronic intracerebral infusion of 1-methyl-4phenylpyridinium (MPP+). The accompanying activation of microglia in the substantia nigra of MPP+-treated rats was reduced by the chronic captopril treatment. These findings indicate that captopril is neuroprotective for nigrostriatal DA neurons in both acute and chronic rodent PD models. Targeting the brain AngII pathway may be a feasible approach to slowing neurodegeneration in PD.
Neurosurgery, Jun 1, 2008
Alzheimers & Dementia, Jul 1, 2011
Background: Because there is immune system activation in Alzheimer’s disease (AD), there may be s... more Background: Because there is immune system activation in Alzheimer’s disease (AD), there may be serum antibodies that can serve as biomarkers for the disease. A novel unbiased approach to identifying disease-related antibodies, using combinatorial organic chemistry, involves the production of peptoid microarrays. Peptoids are oligo-N-substituted glycines which retain the binding characteristics of peptides, are easy to synthesize, and have been shown to be rich sources of protein ligands. Methods: Using a microarray consisting of 15,000 unique 8-mer peptoids, and serum from 6 AD, 6 Parkinson’s disease (PD) and 6 normal control subjects, we identified 3 peptoids that capture IgG antibodies whose levels are 3-10-fold higher in each AD patient compared to each PD and each normal control. Using a larger set of AD (49), PD (20) and normal controls (25), along with 10 MCI cases, we sought to validate the sensitivity and specificity of the 3 AD peptoids. Results: The 3 AD peptoids provide >90% sensitivity and specificity for the identification of AD. In addition, 9 of the 10 MCI cases showed elevated peptoid levels compared to normal controls. Conclusions: The peptoids should be useful biomarkers for AD, and for detecting the disease at an early time-point (i.e., MCI). Also, the antibodies recognized by the peptoids may represent novel drug targets for the treatment of the disease.
Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal lev-els... more Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal lev-els of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxy-gen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK path-way regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the
Alzheimer's & Dementia, 2019
npj Parkinson's Disease, 2018
Parkinson disease (PD) is a progressive neurodegenerative disease with motor symptoms that result... more Parkinson disease (PD) is a progressive neurodegenerative disease with motor symptoms that result from degeneration of midbrain dopaminergic neurons. Biomarker research seeks to identify the disease during the pre-symptomatic phase, which is a time when therapeutic intervention will be most helpful. Previously, we screened a combinatorial peptoid library to search for antibodies that are present at much higher levels in the serum of PD patients than in control subjects. One such compound, called the PD2 peptoid, was 84% accurate for the identification of de novo PD when employed as the capture agent in an enzyme-linked immunosorbent assay. This peptoid recognized an IgG3 antibody, and IgG3 levels were also found to be significantly higher in PD vs. control serum. In that study we used samples from the NINDS Parkinson’s Disease Biomarker Program. The current study sought to validate that finding using serum samples from de novo and control subjects in the Parkinson’s Progression Mark...
Biomarkers in medicine, 2017
Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort ... more Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) coho...
The Lancet. Neurology, Aug 16, 2017
Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disea... more Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generate...
Alzheimer's & Dementia, 2016
Movement disorders : official journal of the Movement Disorder Society, Jun 7, 2015
Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of ... more Neuroprotection for Parkinson's disease (PD) remains elusive. Biomarkers hold the promise of removing roadblocks to therapy development. The National Institute of Neurological Disorders and Stroke has therefore established the Parkinson's Disease Biomarkers Program to promote discovery of PD biomarkers for use in phase II and III clinical trials. Using a novel consortium design, the…
Parkinsonism & related disorders, 2008
Animal models of Parkinson's disease (PD) that more closely exhibit the chronic neuropatholog... more Animal models of Parkinson's disease (PD) that more closely exhibit the chronic neuropathology seen in the human condition are needed in order to reveal processes involved with progressive neurodegeneration and for testing potential interventions for retarding dopamine (DA) neuronal loss. Here we describe the recently developed chronic rat model of PD in which 1-methyl-4-phenylpyridinium ion (MPP(+)) is infused chronically into the lateral cerebral ventricle. We review features of this model that include loss of nigral DA neurons, swollen and abnormal mitochondria, striatal inclusion-like bodies and microgliosis. Advantages as well as limitations of the model are addressed.
Journal of Neurosurgery, 2009
Object The authors previously developed an optical stereotactic probe employing near-infrared (NI... more Object The authors previously developed an optical stereotactic probe employing near-infrared (NIR) spectroscopy to provide intraoperative localization by distinguishing gray matter from white matter. In the current study they extend and further validate this technology. Methods Near-infrared probes were inserted 203 times during 138 procedures for movement disorders. Detailed validation with postoperative imaging was obtained for 121 of these procedures and with microelectrode recording (MER) for 30 procedures. Probes were constructed to interrogate tissue perpendicular to the probe path and to incorporate hollow channels for microelectrodes, deep brain stimulation (DBS) electrodes, and other payloads. Results The NIR data were highly correlated to imaging and MER recordings for thalamic targets. The NIR data were highly sensitive but less specific relative to imaging for subthalamic targets, confirming the ability to detect the subthalamic nucleus and to provide warnings of inaccu...