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American Parkinson Disease Research Grants 2017


American Parkinson Disease Association is using its 2017 distribution to fund:

Validation of Smartphone-Based Sensory Augmentation Technology for Home-Based Balance Training of People with Parkinson’s Disease

Functional investigation of rare genetic variants in Parkinson’s disease

Cracking the code of Chromosome 17q21 for Parkinson’s: From GWAS to Novel Drug Targets 


PROJECT TITLE:  Validation of Smartphone-Based Sensory Augmentation Technology for Home-Based Balance Training of People with Parkinson’s Disease

Investigator/Author:  Beom-Chan Lee, PhD

Objective:  Development of a smartphone-based system, called the Smarter Balance System (SBS) and its usability for physical therapists’ recommended balance exercises performed by people with PD.

Background:  Postural instability, a cardinal symptom of PD, can result in loss of balance and risk of falling, thus reducing independence in daily activities. Although existing dopamine replacement therapies do not treat postural instability effectively, Dr. Lee and his team have demonstrated in laboratory settings that balance training assisted with biofeedback technologies decreased body sway and increased a range of motion for people with PD. Lab-based biofeedback technologies are impractical for use in the home due to size, weight, calibration procedures, cost, and fragility. They also lack user-friendly interfaces and simplified displays.  APDA initial funding of this work through a 2016-2017 Research Grant was instrumental in the development of a smartphone-based system, called the Smarter Balance System (SBS) and its usability for physical therapists’ recommended balance exercises performed by people with PD over one unsupervised training session in a laboratory setting.

Methods/Design:   The first four months will focus on more SBSs, and the second eight months will focus on the systematic in-home studies. 22 people with idiopathic PD having bilateral symptoms with impaired postural reflexes (i.e., Hoehn and Yahr stage classification of between 2 and 4) will participate in the study. All participants will be randomly assigned to one of two groups of 11 (intervention group vs. control group). Both groups will use SBSs and Fitbits. Only the intervention group will complete in-home balance exercises with SBS. The control group will not perform in-home balance exercises with SBS, but will use only the SBS’s smartphone paired with the Fitbit. All participants will undergo quantitative and qualitative assessments of their static/dynamic balance performance before, after, and one month after their in-home use of the SBS and Fitbit.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  Improvements in balance performance that are retained for time periods of weeks to months after extended balance rehabilitation training with the SBS will improve quality of life (more confidence in performing daily tasks and decreased fall risk) for people with PD. The SBS’s user-friendly and wearable characteristics will eventually reduce the need for assistance by family members and other caregivers while people with PD perform balance exercises at home This study will assess the impact on long-term rehabilitative training for people with PD who receive in-home balance exercises with assistive guidance via SBS and quantitatively and qualitatively analyze the carry-over effects of long-term rehabilitative training with SBS on balance performance, daily physical activities, and confidence in less fear of falling.

September 2018 Project Update:

Dr. Lee and his research team developed a new smartphone-based balance training system, called the Smarter Balance System (SBS), and assessed SBS’s usability with physical therapists’ recommended balance exercises performed by people with PD at home. Sixteen people with idiopathic PD and symptoms of impaired postural stability (i.e., Hoehn and Yahr stage classification of between 2 and 4) were recruited and randomly assigned to one of two groups (intervention and control group). The intervention group completed physical therapist-recommended balance exercises guided by SBS (20-30 minutes each including rest periods 3 days per week for 6 consecutive weeks). The control group did not perform in-home balance rehabilitation training. The major findings were: 1) the intervention group showed greater improvements in range of motion and static/dynamic balance performance at the post-assessment; 2) the intervention group had higher confidence and less fear of falling than the control group at the post-assessment; and 3) observed improvements were retained for one month. These findings have significant implications for improving balance and gait performance of PD patients with the use of this new smartphone-based balance rehabilitation technology.

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PROJECT TITLE:  Functional investigation of rare genetic variants in Parkinson’s disease

Investigators/Authors:  Isabel Lam, PhD

Objectives: The objective of this research is to understand the function of rare genetic variants in Parkinson’s disease.

Background: A substantial component of Parkinson’s disease is inherited, but most of this heritability is currently unexplained. Advances in genome sequencing promise to uncover genetic variants that account for this “missing heritability.” However, human genomes contain many genetic variations, and distinguishing variants that are relevant to disease from those that are neutral remains a major challenge.

Methods/Design: This study implements a high-throughput cross-species experimental platform to enable functional interpretation of rare variants found in patients with Parkinson’s disease. This platform provides information on the effect of the genetic variant on the molecular interactions of the protein it encodes, as well as its genetic interactions in cellular models, thereby allowing us to gain insight into the biological relevance of rare genetic variants.

Relevance to Diagnosis/Treatment of PD: The knowledge gained from this study promises to uncover genetic risk factors for Parkinson’s disease. Additionally, insights gained into the genetic and molecular underpinnings of the disease will ultimately help uncover therapeutic targets and assist in precision medicine diagnosis.

September 2018 Project Update:

 As described in the project proposal, we sought to study the functional consequences of genetic variants found in patients with Parkinson’s disease (PD). So far, we identified 475 variants in 105 genes. Two hundred and fifty of these variants are now available to us in the lab for future studies. We are investigating whether these genetic variants have an effect on how proteins interact with each other in the cells and whether they affect how toxic alpha-syuclein is to cells.

For approximately 18 of the identified variants, the genetic alteration was in a section of the gene that is the same in the human and yeast. When a section of the gene is conserved across species, this suggests that that section is functionally important. We therefore tested whether these conserved portions of the gene were important in cell function, by introducing the identified alteration into our yeast model and determining whether there was any effect on the toxicity of alpha-synuclein. Results indicate that two of the identified variants decreased the toxicity of alpha-synuclein. This will need to be confirmed in further experiments.

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 PROJECT TITLE:  Cracking the code of Chromosome 17q21 for Parkinson’s: From GWAS to Novel Drug Targets

Investigators/Authors:  Xianjun Dong, PhD

Objectives: Dr. Dong’s research interest is to use both computational and experimental methods to understand how the human genome is regulated in the brains of healthy people and patients with neurodegeneration diseases.

Clinical trial failure rates, including those for Parkinson’s disease, are extremely high. The increasing number of failures due to lack of efficacy indicates that the current preclinical pipeline is failing to correctly identify good drug targets.

Methods/Design: One of the recent breakthroughs in Parkinson’s genetics is to identify a list of genomic loci (the position on a chromosome) whose mutations significantly associate with different risk of Parkinson’s disease (PD). However, most of these genomic mutations do not alter protein sequence; it’s unclear how these genomic loci link to the drug target. So, finding their functional consequences in PD-vulnerable dopamine neurons is critical to translating this breakthrough in genetics into novel medications for PD. In this proposal, Dr. Dong’s team will identify the putative causal mutations and their regulated genes in a PD risk locus located on chromosome 17q21 via fine-mapping eQTL analysis specifically in dopamine neurons. In short, they will sequence both DNAs and RNAs from the region in 86 postmortem brains available to his lab and determine if any (and which) DNA mutations are significantly associated with the expression level of genes in the region. In addition, they will evaluate the effect of the putative causal variant in iPSC-derived (induced pluripotent stem cells) dopamine neurons.

Relevance to Diagnosis/Treatment of PD:
Drug targets that are clearly linked to genetic disease appear more likely to succeed in clinical trials than targets that lack a proven genetic link. Understanding the human genome regulation could lead to novel drug therapy for PD.

September 2018 Project Update:

We sequenced all of the RNAs (ribonucleic acid, that acts as a messenger carrying instructions from the DNA) from the dopamine neurons in 86 postmortem brains. We also extracted and sequenced a section of the DNA, chromosome 17q21, which has been implicated in causing Parkinson’s disease. Tens of thousands of genes were detected and quantified. Due to the long queue in the sequencing facility, we expect to receive the sequencing data in the coming month. A no-cost extension of six months has been filed and approved by APDA. New ending date is Feb 28th, 2019. We will continue our studies, correlating the mutation status of chromosome 17q21 with the RNAs that are produced, once the sequencing data is analyzed.

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