Day 1 :
Keynote Forum
Harish C Pant
NINDS – NIH, USA
Keynote: A small peptide derived from a neuronal cell cycle like kinase activator, P35, is a possible therapeutic candidate to reduce the phenotypes of neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases
Time : 10:00-10:40
Biography:
Harish C Pant received his MA and PhD degrees in Physics from Agra University, Agra, India. His Postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki, where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979, he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. He moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently the chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
Abstract:
Our previous studies have shown that, neurofilaments, & Tau the major neuronal cytoskeletal proteins are selectively phosphorylated in axons. The phosphorylation activity is tightly regulated under physiological conditions. Under neuropathological conditions, however, phosphorylation is deregulated, occurs abnormally in perikarya and induces pathology resembling that seen in many neurodegenerative diseases (e.g. AD, ALS, PD). We identified cyclin dependent kinase 5 (Cdk5) together with its activator p35, as a major kinase regulating the topographic neuronal cytoskeleton phosphorylation. It is found that Cdk5, when deregulated by neuronal insults (A-beta, glutamate, oxidative stress, mutations and other), is hyperactivated as a stable complex with p25 (a truncated fragment of p35) and induces perikaryal hyperphosphorylated tau, synuclein and NFPs as seen in AD, PD and ALS. At autopsy, AD, PD and ALS brains display hyperactive Cdk5 (Cdk5/p25) and have confirmed that Cdk5/p25 induces neuroinflammation, tau and NF hyperphorylation along with cell death. A p25-overexpressing (P25Tg) AD model mouse displays the typical AD phenotypes. Accordingly, hyperactive Cdk5/p25 has been identified as a possible therapeutic target for neurodegeneration.
All the therapeutic approaches inhibiting activities of kinases have been by interfering with ATP binding domains of the kinases that turned out to be non-specific and highly toxic. To modulate the Cdk5 activity instead of using the analogs of ATP we decided to study the effect of different truncated fragments of p35 on the regulation of Cdk5 activity. We identified a 126 amino acid (aa) truncated peptide of p35, (CIP) and smaller peptide p5 (24 aa) bind with Cdk5 with higher affinity than p25 and selectively inhibited Cdk5/p25 hyperactivity in culture, reduced tau, NFP hyperphosphorylation and cell death without toxicity and affecting endogenous Cdk5/p35 activity. The question arise, will CIP and p5 be non-toxic in vivo, in animals as in cell cultures and may prevent the phenotypes of an AD, PD and ALS transgenic mice models? Consistent with the model, we succeeded in showing that pathological and behavioral phenotypes in AD, PD and ALS model mice (over-expressing p25 transgenic) and the 5XFAD double transgenic can be alleviated after co-expression with CIP in p25 Tg and treatment with modified p5 (TFP5). We propose that CIP and TFP5 is novel therapeutic candidate to prevent Alzheimer’s disease phenotypes and pathologies.
Keynote Forum
Yoland Smith
Emory University, USA
Keynote: Neuroprotective therapies in Parkinson’s disease: From animal models to the human disease
Biography:
Yoland Smith got his PhD in Neuroscience from Laval University, Quebec, Canada in 1988. After Post-doctoral trainings in Oxford and Johns Hopkins University, he became Assistant Professor in the Department of Anatomy at Laval University. Since 1996, he holds a Faculty Position at the Yerkes Primate Center of Emory University, Atlanta, GA. He has published over 250 manuscripts on the anatomy of the basal ganglia and the pathophysiology of Parkinson’s disease. He is Editor of prestigious journals in the field of neuroscience, serves on NIH study sections and sits on the Advisory Board of the Dystonia Medical Research Foundation. He is deeply involved in graduate education as Principal Investigator of various NIH training grants and Previous Director of the Graduate Neuroscience Program at Emory University
Abstract:
Parkinson’s disease (PD) is commonly seen as a progressive neurodegenerative disorder associated with motor deficits that result from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although dopaminergic neuronal loss is, indeed, the main source of Parkinsonian motor signs (rest tremor, bradykinesia, rigidity), it has become clear in recent decades that PD is far more than a mere movement disorder. PD patients often suffer of a large variety of cognitive, autonomic and psychiatric problems which, for many, are far more debilitating than their motor deficits. Furthermore, many of these non-motor signs do not respond well to the conventional dopamine replacement therapy commonly used in most PD patients, thereby suggesting that they rely on dysfunction or degeneration of non-dopaminergic neuronal networks. In this presentation, author will discuss evidence from our laboratory and others showing that key glutamatergic and GABAergic systems undergo significant reorganization and degeneration in PD, which leads to maladaptive synaptic plasticity and complex neuronal network dysfunction. Author will propose that dysregulation of these non-dopaminergic systems contribute to the pathophysiology of various motor and non-motor deficits commonly seen in PD. To conclude, author will highlight the importance that we recognize the complex and diverse nature of PD symptoms and that research efforts in gaining a strong knowledge of the pathophysiology of non-dopaminergic systems in PD are critical to our understanding of the disease and the development of efficient anti-Parkinsonian therapy that extend beyond motor deficits.
Keynote Forum
Jie Wu
Barrow Neurological Institute-St. Joseph’s Medical Center, USA
Keynote: Impact of sirtuin-3 in cognitive deficits of Parkinson’s disease
Biography:
Jie Wu has completed his PhD from Sun-Yat Sen University of Medical Sciences, China in 1990 and Post-doctoral studies from Tohoku University, Japan and New Mexico University School of Medicine, USA between 2013 and 2017. Now, he is a Professor and the Director of Neurophysiological Laboratory at Barrow Neurological Institute, St. Joseph’s Hospital. He has published more than 140 papers in reputed journals with total citation of 2,883, h-index 31 and i10 index 82. He has been serving as an Editor in Chief and Editorial Board Member of repute.
Abstract:
Parkinson’s disease (PD) exhibits non-motor symptoms (NMS), including cognitive and neuropsychiatric deficits, and often appear a decade or more before the first signs of motor symptoms. Sirtuin-3 (SIRT3) is a member of the sirtuin family of mitochondria NAD(+)-dependent deacetylase that acts as a regulator of mitochondrial protein function. Emerging evidence demonstrates that activation of SIRT3 exhibits neuroprotection, while reduced SIRT3 exacerbates neuropathogenesis, suggesting SIRT3 is a critical target for neurodegenerative pathogenesis and therapeutics. Here, we evaluated the impact of SIRT3 in PD cognitive deficits including hippocampal synaptic and neural network impairments in PD mouse models. First, we compared hippocampal synaptic function between SIRT3 KO and WT mice, and found that 4-month-old SIRT3 KO mice showed deficits of hippocampal functions including impaired both hippocampal CA1 LTP maintenance and fEPSP amplitude after 40 Hz stimulation for 4 seconds. Second, we found that hippocampal theta oscillations (induced by 50 µM CCh) and gamma oscillations (induced by 100 Hz stimulation for 200 ms) were significantly impaired in SIRT3 KO mice compared to WET mice. Third, when mice were treated with low dose rotenone (RTN, 0.8 mg/k.g., i.p. for 7 days), WT mice did not show detectable change of synaptic function and network synchronizations, while SIRT3 KO mice showed impaired hippocampal CA1 region PPF, LTP and gamma oscillations. Finally, mitochondrial dysfunction in hippocampal slices can be restored by SIRT3 activator, ketone. Collectively, our data suggest an important role played by SIRT3 in hippocampal synaptic and neural network function, which may underlie the cognitive deficits in PD.
- Parkinsons : Pathophysiology and neuropharmacology | Neuromuscular and Neurocognitive disorders
Chair
Yoland Smith
Emory University, USA
Session Introduction
Bennett Weinstock
Weinstock Physical Therapy, USA
Title: Preventing Parkinson’s
Biography:
Ben Weinstock specializes in the rehabilitation of people with neurodegenerative diseases. He is the author of the only book about the prevention of Parkinson Diseases, “Preventing Parkinson’s: How to Cut Your Risk by Strengthening Your Multiple Shields (2015)”. Another innovative approach that he has developed is EPIC-PD (Exercise Prescription, Individualized Care for Parkinson Diseases) which gives physical therapists a unique methodology for developing personalized lifestyle plans for each patient with PD. He also teaches continuing education seminars to undergraduate and post-doctoral physical therapists. He has completed his DPT from University of Montana City and continued his education at University of New York.
Abstract:
Despite the fact that there is a growing movement towards the prevention of diseases (including Alzheimer’s), the concept of preventing Parkinson’s has gained very little attention. However, this is poised to change with the development of blood tests that predict one’s risk of developing the condition (based upon microRNA or other biomarkers). The recent, groundbreaking book Preventing Parkinson’s: How to Cut Your Risk by Strengthening Your Multiple Shields is a comprehensive compilation with over 1,000 peer-reviewed references. It is the only book available that provides proactive lifestyle recommendations for lowering one’s risk of developing PD. Concepts include: Protection of the blood brain barrier; a diet that prevents the development of misfolded proteins, lowers the activity of the mTOR pathway, as well as being anti-inflammatory and rich in antioxidants; an exercise regime that promotes methylation, as well as increasing cellular recycling of misfolded proteins; enhancement of sleep and the glymphatic system; properly timed light exposure to enhance melatonin production; stress reduction to decrease the negative effects of stress hormones; minimization of one’s exposure to toxins and radiation; and avoidance of head injuries. In summary, the synergy of healthy habits may be the best hope for preventing the predicted doubling of PD by the year 2030.
Srinivas Avathvadi Venkatesan
Hershe Medical College, USA
Title: Articulatory kinematics and speech dysfunction in patients with Parkinson’s disease
Biography:
Srinivas Avathvadi Venkatesan serves as an Emeritus Professor at The Tamil Nadu Dr. M.G.R. Medical University; Former Adjunct Prof. IIT Madras and Visiting Professor at Cleveland – Ohio – USA; Hershey Medical College, USA. He has been rewarded with many national & international awards like AINA AWARD-Association of Indian Neurologists in America-2001. He has presented more than 60 papers in national conferences and 25 in international conferences. He has published works include 30 papers & 15 chapters.
Abstract:
Objective: Speech Impairment occurs in 60-89% in Parkinson’s patients and little is known about as how it affects the different speech subsystems. In this communication, we report the articulatory kinematics and speech kinematics and speech dysfunctions in 12 consecutive Parkinson’s patients in scale II and III of Hoehn and Yahr.
Methods: The cross-sectional study on 12 patients aged between 30 and 76 (10 males and 2 females: Hoehn and Yahr scale II and III) were analysed with Buffalo voice profile to identify laryngeal tone and tension, loudness, pitch and it breaks, diplophonia, resonance, nasa emissions, rate articulations tests were also done to study plosives, fricatives, affricatives, aspirates, glides, nasals and blens. Hoehn and Yahr scale IV and V Parkinson’s patients were excluded, patients were video filmed in out Movement Disorder Clinic.
Results: 25% laryngeal tone abnormality, no vocal abuse, 50% loudness being too soft. Pitch was normal in 33% patients and phonation duration varied between 5-15 sec (normal being 20); overall speech disturbance was 50%. Eight percent had plosives error, 33% fricatives error, 8% had affricative error, 8% aspirates error, 8% glide, 8% nasal error and 50% had blends error.
Conclusion: This study highlighted the monotonous quality, laryngeal tone abnormality and loudness, abnormality associated with predominant articulation errors in blends and fricatives. This will help us in the quantitative analysis of the effectiveness of speech therapy in patients with Parkinson’s disease
Srinivas Avathvadi Venkatesan
Hershe Medical College, USA
Title: Articulatory kinematics and speech dysfunction in patients with Parkinson’s disease
Biography:
Srinivas Avathvadi Venkatesan serves as an Emeritus Professor at The Tamil Nadu Dr. M.G.R. Medical University; Former Adjunct Prof. IIT Madras and Visiting Professor at Cleveland – Ohio – USA; Hershey Medical College, USA. He has been rewarded with many national & international awards like AINA AWARD-Association of Indian Neurologists in America-2001. He has presented more than 60 papers in national conferences and 25 in international conferences. He has published works include 30 papers & 15 chapters.
Abstract:
Objective: Speech Impairment occurs in 60-89% in Parkinson’s patients and little is known about as how it affects the different speech subsystems. In this communication, we report the articulatory kinematics and speech kinematics and speech dysfunctions in 12 consecutive Parkinson’s patients in scale II and III of Hoehn and Yahr.
Methods: The cross-sectional study on 12 patients aged between 30 and 76 (10 males and 2 females: Hoehn and Yahr scale II and III) were analysed with Buffalo voice profile to identify laryngeal tone and tension, loudness, pitch and it breaks, diplophonia, resonance, nasa emissions, rate articulations tests were also done to study plosives, fricatives, affricatives, aspirates, glides, nasals and blens. Hoehn and Yahr scale IV and V Parkinson’s patients were excluded, patients were video filmed in out Movement Disorder Clinic.
Results: 25% laryngeal tone abnormality, no vocal abuse, 50% loudness being too soft. Pitch was normal in 33% patients and phonation duration varied between 5-15 sec (normal being 20); overall speech disturbance was 50%. Eight percent had plosives error, 33% fricatives error, 8% had affricative error, 8% aspirates error, 8% glide, 8% nasal error and 50% had blends error.
Conclusion: This study highlighted the monotonous quality, laryngeal tone abnormality and loudness, abnormality associated with predominant articulation errors in blends and fricatives. This will help us in the quantitative analysis of the effectiveness of speech therapy in patients with Parkinson’s disease
Charlene Aldrich
University of Maryland School of Medicine, USA
Title: Clinical Trials using MRI Guided Focused Ultrasound ( ExAblate Transcranial System) for the management of Medically-Refractory Dyskinesia Symptoms of advanced Idiopathic Parkinson’s Disease and in patients with Benign Essential Tremorsrs
Biography:
Charlene Aldrich has a Master’s degree in Nursing and has been involved in clinical trials in neuroscience for 25 years. She is the Clinical Research Manager in the Department of Neurosurgery and manages on an average 10 trials ranging from device trials to drug trials. Typical trials are multi-center national/international, prospective and are Federal or industry funded. She initiates and maintains all trials regulatory and clinical conduct for the respective principal investigators in the Department of Neurosurgery.
Abstract:
The UMD is participating in collaborative studies for treatment of ET and PD. MRI guided focused ultrasound (MRgFUS) is an attractive modality for non-invasive, thermal ablation of soft tissue and brain. This novel technology utilizes the combination of diagnostic imaging with high-intensity focused ultrasound. It concentrates energy from a source outside of the body on a small target-for PD and ET deep inside the brain. “Think sun–magnifying glass–leaf” PD and ET are caused by dysfunction of a circuit and system imbalance caused by functioning parallel circuits. Interruption of a specific parallel circuit using FUS rebalances the system, reducing symptoms (tremor/rigidity). Historical FUS lacked necessary precision; today precision have been overcome by coupling FUS to MRI simultaneous imaging of the target and the applied energy. The studies are designed as prospective, multi-center, single-arm feasibility studies to evaluate the safety and initial clinical effectiveness of ExAblate Transcranial unilateral thermal ablation of the globus pallidus of subjects suffering from medication-refractory advanced idiopathic PD.To Evaluate the Effectiveness and Safety of ExAblate Transcranial MRgFUS Thalamotomy Treatment of Medication Refractory Essential Tremor Subjects
Subjects age 30 and older with confirmed medication-refractory, advanced idiopathic Parkinson’s disease or benign essential tremors are eligible for these studies.
Biography:
Rudy Capildeo is a Consultant Neurologist who set up one of the first PD clinics in London, UK in 1973 at The Charing Cross Hospital, where he also organized the first major International PD Symposium in 1979 when Sinemet Plus was first introduced by MSD. He was a Senior Investigator in the 5-year Sinemet CR First Trial. A frequent presenter in national and international meetings, he continues his interest in PD in his work and in his role as a Teacher.
Abstract:
Since the time of James Parkinson, we have come to recognize a medical condition characterized by the gradual appearance of stiffness, slowness, reduced mobility, feeling old for one’s years, altered gait with stumbles, and even falls. Tremor is not always present. Families are often aware of these changes before the patient. At no stage in this condition is there an obvious illness. Parkinson, in his essay described just six cases. He recognized the slow progress of the condition over many years and that the clinical signs were asymmetric. Charcot and Gower found no neuropathological changes. Gower famously said “you do not die from Parkinson’s Disease (PD) but with it”. We recognize “Non-Motor” features of PD, the slow onset of PD over many years and the positive response of PD to L-Dopa Therapy. PD is now considered to be a disorder of the basal ganglia and with DAT scanning we can measure dopamine transporter uptake. Qualitative assessment of DAT scans reveals loss of the “Comma Shape” in PD cases but quantitative measurements reveal an obvious asymmetry in early PD cases. This data will be presented to show that PD (as opposed to Parkinsonism or PD plus syndromes) is a dopamine deficiency disorder and not a disease.
Biography:
Bhanu kesavamurthy is Senior Neurologist with 30 years of experience and wants to teach basic bedside neurology and how the findings improve patient care. She has awarded the commonwealth fellowship in Neurology at University of Newcastle, Newcastle upon Tyne, UK, from October 1997 to Sep 1998 & also trained at Walton Centre for Neurology & Neurosurgery at Liverpool, UK under Dr David Chadwick, and is also a holder of many prestigious awards. She is currently serving as the Director of Neurology and neurosurgery at Mehtas Hospitals, India
Abstract:
Introduction: Falls are a recurrent phenomenon in Parkinson disease. 40%–70% of patients fall, which occurs during daily activities and when patients are optimally medicated, lead to fractures and restriction of mobility and activities, loss of independence, increased risk of nursing home admission and reduced survival. The fall is many times a life changing event for the patient and affecting quality of life. This is to be considered in treatment planning and ideally, intervention should occur before the first fall has occurred. We carried out a cross sectional study of an unselected group of idiopathic Parkinson disease patients of various ages and disease duration, taking into account most of the clinical variables potentially associated with falls. Detailed analysis of history, clinical features and disease severity of patients with idiopathic Parkinson disease were done.
Aim: To study various risk factors associated with fall and analyze them to see which are predictors of falls.
Materials & Methods: Study was conducted in Institute of Neurology, Madras Medical College, Chennai. 112 consecutive patients with idiopathic Parkinson disease who attended both outpatient department and inpatient ward were studied between: August 2013 to December 2015 and detailed analysis of falls was documented. The diagnosis of Parkinson disease was confirmed according to the United Kingdom Parkinson Disease Brain Bank criteria. Clinical data were obtained from the patients and checked with patient’s relatives, caregivers and case records for accuracy. All patients’ baseline laboratory investigations and brain imaging studies were recorded to identify associated illnesses. All patients underwent a multidisciplinary baseline assessment comprising demographic and historical data, disease specific rating scales, including Tinetti gait and balance test and freezing of gait questionnaire.
Results: In this study, fall occurred in 49.1% of the subjects. Tinetti Balance score and Hoehn and Yahr staging were the best independent variables associated with falls. Previous falls, disease duration and severity, freezing of gait, high dose levodopa, dyskinesia and loss of arm swing were independent predictors of falling in our study.
Conclusion: Falls are a common problem in Parkinson disease and some of the risk factors are modifiable. In this study previous falls, disease duration, disease severity, worse Tinetti score and loss of arm swing are independent predictors of the risk of falling. Freezing of gait, dyskinesia and higher dose of levodopa also associated with increased risk fall in our study. There is a need for future studies to look at interventions to prevent falls in Parkinson disease.
Biography:
Bhanu kesavamurthy is Senior Neurologist with 30 years of experience and wants to teach basic bedside neurology and how the findings improve patient care. She has awarded the commonwealth fellowship in Neurology at University of Newcastle, Newcastle upon Tyne, UK, from October 1997 to Sep 1998 & also trained at Walton Centre for Neurology & Neurosurgery at Liverpool, UK under Dr David Chadwick, and is also a holder of many prestigious awards. She is currently serving as the Director of Neurology and neurosurgery at Mehtas Hospitals, India
Abstract:
Introduction: Falls are a recurrent phenomenon in Parkinson disease. 40%–70% of patients fall, which occurs during daily activities and when patients are optimally medicated, lead to fractures and restriction of mobility and activities, loss of independence, increased risk of nursing home admission and reduced survival. The fall is many times a life changing event for the patient and affecting quality of life. This is to be considered in treatment planning and ideally, intervention should occur before the first fall has occurred. We carried out a cross sectional study of an unselected group of idiopathic Parkinson disease patients of various ages and disease duration, taking into account most of the clinical variables potentially associated with falls. Detailed analysis of history, clinical features and disease severity of patients with idiopathic Parkinson disease were done.
Aim: To study various risk factors associated with fall and analyze them to see which are predictors of falls.
Materials & Methods: Study was conducted in Institute of Neurology, Madras Medical College, Chennai. 112 consecutive patients with idiopathic Parkinson disease who attended both outpatient department and inpatient ward were studied between: August 2013 to December 2015 and detailed analysis of falls was documented. The diagnosis of Parkinson disease was confirmed according to the United Kingdom Parkinson Disease Brain Bank criteria. Clinical data were obtained from the patients and checked with patient’s relatives, caregivers and case records for accuracy. All patients’ baseline laboratory investigations and brain imaging studies were recorded to identify associated illnesses. All patients underwent a multidisciplinary baseline assessment comprising demographic and historical data, disease specific rating scales, including Tinetti gait and balance test and freezing of gait questionnaire.
Results: In this study, fall occurred in 49.1% of the subjects. Tinetti Balance score and Hoehn and Yahr staging were the best independent variables associated with falls. Previous falls, disease duration and severity, freezing of gait, high dose levodopa, dyskinesia and loss of arm swing were independent predictors of falling in our study.
Conclusion: Falls are a common problem in Parkinson disease and some of the risk factors are modifiable. In this study previous falls, disease duration, disease severity, worse Tinetti score and loss of arm swing are independent predictors of the risk of falling. Freezing of gait, dyskinesia and higher dose of levodopa also associated with increased risk fall in our study. There is a need for future studies to look at interventions to prevent falls in Parkinson disease.