YLOPD Study: Research on Parkinson’s Disease Progression

Young and Late-onset Parkinson’s Disease (YLOPD) Study

SKAN Research Trust, a public charitable trust set up by the Soota and Karedan families, aims to promote research and development in medical science, with a focus on the treatment of geriatric and neurological diseases. As SKAN’s strategic partner for neurological research, CBR has built a consortium of scientists and clinicians to plan and carry out a project on Parkinson’s disease, which is the first among several clinical areas of research that will be pursued through this exciting collaboration.

The ‘Young and Late-onset Parkinson’s Disease’ (YLOPD) study is a longitudinal study on Parkinson’s disease (PD), the second most common neurodegenerative disorder characterized by slowness in movements and impaired posture and balance. PD has a prolonged course with slow and gradual progression. It is caused by the degeneration of nerve cells in a part of the brain called substantia nigra, and the loss of the ability to produce a key neurotransmitter called dopamine. PD typically manifests around the age of 60 and is more prevalent in men than women, with a 50% higher risk.

Funded by the SKAN Research Trust, the study began in 2021 as a collaborative undertaking between CBR and the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru. This study aims to recruit 1000 patients with young and late-onset PD and follow them up periodically to study the natural history of the disease.

Existing literature shows that people who develop young-onset PD (YOPD) have different initial symptoms, non-motor symptoms, environmental risk factors, rate of progression, choice of deep brain stimulation target, and quality of life impairment as compared to late-onset PD (LOPD). Growing evidence highlights the importance of YOPD and LOPD and their impact on a person’s quality of life. However, the multifactorial causation, neuroanatomical features, and genetic architecture of YOPD and LOPD are not fully understood; the YLOPD study strives to address this crucial gap.

The YLOPD study involves comprehensive multimodal evaluation of clinical, electrophysiological, and cognitive functions, brain and retinal imaging, genome-wide association and whole genome sequencing, blood-based inflammatory and protein biomarkers, and studies on heavy metal and pesticide exposure with emphasis on differential involvement in YOPD and LOPD.

The study is focused on linking the insights from clinical literature to explore translational research in animal models of PD in order to decipher molecular underpinnings of the emergence of non-motor symptoms (NMS) and motor symptoms (MS). In PD it is known that degeneration of substantia nigra (SNpc) dopaminergic neurons and their projections to striatum causing dopamine depletion is associated with MS. However, a broad spectrum of neuropsychiatric symptoms, including NMS (like anxiety and depression) frequently observed in PD, are probably related to other non-dopaminergic neurons and their projections to target regions in the brain. The etiology, in terms of aggregation of the presynaptic protein alpha-synuclein in Lewy bodies or in the neurites that may contribute to NMS, is not clear. We are using the MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride) neurotoxicity mouse model of PD at sub-chronic dosing and alpha-synuclein- dependent progressive disease mice model of PD to understand the molecular basis for the emergence of these NMS.

Our mouse model of PD shows a loss of dopaminergic neurons in the substantia niagra, thereby closely mimicking the clinical condition.

Schematics and images from behavioural experiments on mice models of PD

To investigate non-motor symptoms, mice are subjected to a series of behavioural tests such as the elevated plus maze, open field test, and forced swim test. These tests allow us to assess anxiety- and depression-like behaviours. Tests such as the rotarod test, tail swing test, and beam walk test aid in the assessment of motor coordination and balance in the mice. Data from these experiments, together with those from histopathology analyses and complementary studies, would lead to a comprehensive view of the potential mechanisms of disease progression.

We hope that this ‘bench-to-bedside’ study will shed light on many unanswered questions on PD which can be effectively used to support the implementation of effective interventions and modification of existing treatment protocols.

Flagship Projects

Prof. K. V. S. Hari

Director

Prof. K. V. S. Hari joins CBR with over 30 years of experience in research, teaching, and leadership. With a PhD in Systems Science from the University of California San Diego, he has been a Faculty Member of the Department of ECE, Indian Institute of Science, since 1992 and served as its Chair from 2015 to 2017.

Besides holding Visiting Faculty appointments at premier universities like Stanford and KTH, Stockholm, he built and nurtured enterprising collaborations with leading research groups at Oxford University, TU Delft, and CMC Vellore, among other institutes. He is a Fellow of IEEE, INAE, and INSA and Editor-in-Chief (Electrical Sciences) of Sadhana – Academy Proceedings in Engineering Sciences, published by Springer.

Over the years, he earned unique recognition for his exemplary contribution through several prominent leadership positions in academia and industry.

His current research interests are centred on data science and applications of signal processing to solve problems in neuroscience and medicine.

Please visit https://ece.iisc.ac.in/~hari/ for more information.

Prof. Y. Narahari

Former Director

Dr. Y. Narahari has been on the faculty at the Department of Computer Science and automation, Indian Institute of Science since February 1988. He was Chair of the Department during December 2009 – July 2014. He was the Dean, Division of EECS (Electrical, Electronics, and Computer Sciences) at IISc from August 2014 till July 2021. He was chairing the Office of DIGITS (Digital Campus and Informational Technology Services) during January 2016-December 2020. He is a part of the AI Research Cluster and has been the convener of the Pratiksha Trust Initiative on Brain, Computation, and Data Science at the Institute since 2015.

He is an elected fellow of: IEEE, New York (FIEEE); Indian National Science Academy (FNA), New Delhi; Indian Academy of Sciences (FASc), Bangalore; Indian National Academy of Engineering (FNAE), New Delhi; and the National Academy of Sciences (FNASc), Allahabad. He is a recipient of the J.C. Bose National Fellowship from the Department of Science and Technology, Government of India. In 2009, he received the IISc Alumni Award for Research Excellence in Engineering at the Indian Institute of Science.

He has authored or co-authored three books: Game Theory and Mechanism Design (IISc Press and World Scientific) (2014); Game Theoretic Problems in Network Economics and Mechanism Design Solutions (2009) (Springer Monograph); and Performance Modeling of Automated Manufacturing Systems (Prentice Hall, Englewood Cliffs) (1992).

His work has been driven by talented and brilliant students: 23 of them have completed Ph.D.; 18 have completed Master’s by Research; more than 100 have completed M.Tech. projects. Currently, the group consists of 6 Ph.D. students and 6 M.Tech. project students.

The main thread in his research is to apply game theory, mechanism design, and artificial intelligence techniques to research problems at the interface of computer science and economics. He is also exploring the application of AIML techniques to digital agriculture and public health problems.

Please look up https://gtl.csa.iisc.ac.in/hari for more details.

Prof. Vijayalakshmi Ravindranath

Founding Director

Dr. Vijayalakshmi Ravindranath obtained her Ph.D from the University of Mysore in 1981. In 1986, after completing her post-doctoral training at the National Institutes of Health, USA, she joined the Department of Neurochemistry at National Institute of Mental Health and Neurosciences, (NIMHANS) Bangalore. In 1999, the Dept. of Biotechnology (DBT), Government of India sought her out to help establish the National Brain Research Centre (NBRC), an autonomous institution of DBT, Ministry of Science and Technology as a centre of excellence and to co-ordinate and network neuroscience research groups in the country. She continued as Founder Director, NBRC till May 2009, when she returned to Bangalore at the Indian Institute of Science (IISc) as Professor and Founder Chair of the newly created Centre for Neuroscience. She is currently Founder Director, Centre for Brain Research (CBR) at Indian Institute of Science.

During her tenure as Director of NBRC, she provided visionary leadership at NBRC, which in a very short period attained a position of being an internationally acclaimed centre of excellence. NBRC was granted “Deemed University” status in May 2002 to help promote human resource development in an inter-disciplinary manner. She networked 45 institutions around the country with NBRC with a goal to share resources and promote neuroscience. She then established the Centre for Neuroscience at IISc leveraging the expertise at IISc in mathematics, computation and engineering. The newly established Centre for Brain Research is a unique public-private partnership between IISc (a public funded institution) and Pratiksha Trust (a philanthropy) that funds CBR. Research at CBR is focused on aging brain and a large, prospective longitudinal study of 10,000 againg individuals has been initiated for the first time in India. In addition, she has received generous funding from Tata Trusts, which has paved the way for starting a longitudinal study in an urban cohort.

Dr. Vijayalakshmi Ravindranath is elected Fellow of all the 3 science academies in India, namely Indian National Science Academy, Indian Academy of Sciences, National Academy of Sciences, India. She is also a Fellow of the National Academy of Medical Sciences, India, Indian Academy of Neurosciences and Third World Academy of Sciences. She is a recipient of the prestigious S.S. Bhatnagar award (1996), Omprakash Bhasin Award (2001) and the J.C. Bose National Fellowship (2006), S.S. Bhatnagar Medal, INSA (2016) and the civilian honour, Padma Shri (civilian honor, 2010). She is also a fellow of American Academy of Advancement of Science, USA (2019).

YLOPD Study