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.
September 2019 Project Update:
Dr. Lee and his research team assessed the usability of a new smartphone-based balance training system, called the Smarter Balance System (SBS), for in-home use by people with Parkinson’s disease (PD). The SBS is a smartphone-based wearable biofeedback technology that incorporates visual and vibratory feedback and provides real-time error measures as patients are performing weight-shifting balance exercise (WSBE).
Seven participants were identified and randomly assigned to an intervention group or a control group. All participants were diagnosed with idiopathic PD and demonstrated bilateral symptoms with impaired postural stability. The study design included 1) laboratory-based balance assessments and 2) 6 weeks of in-home dynamic WSBE guided by the SBS. The intervention group performed in-home dynamic WSBE with the SBS for 3 days per week for 6 consecutive weeks, whereas the control group was not asked to perform any in-home balance exercises for 6 consecutive weeks. For both groups, laboratory-based balance assessments (i.e., pre-assessment (baseline at the beginning of week 1), post-assessment (at the end of week 6), and retention-assessment (1 month after week 6)) were conducted.
The results showed that only the intervention group significantly improved their static and dynamic balance control, after the six weeks of in-home balance exercises with the SBS. These improvements were retained for an additional month.
This is the first study to show the effects of in-home dynamic WSBE guided by the smartphone-based biofeedback technology on balance control in individuals with PD. Dr. Lee and his research team will continue their work on this project with additional subjects, supported by a recently awarded R21 NIH grant, obtained using the preliminary data from this APDA/PUW grant. The NIH grant period will run from August 2019 to July 2021.
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.
September 2019 Project Update:
For the funded project, I proposed to study the functional consequences of genetic variants found in patients with Parkinson’s disease (PD). A key question is whether these genetic variants that were found in PD patients are relevant to the disease, or whether they are benign variations in the genetic code. One of the approaches we use to evaluate the biological consequence of genetic variants is to examine whether the variant encodes a protein that still maintains its normal protein-protein interactions. Often, proteins need to interact with a set of other proteins in order to carry out proper cellular function. If a genetic variant results in the encoded protein not being able to interact with its normal cohort of proteins, this may have negative downstream consequences at the molecular, cellular, and organismal level.
Since the previous progress report, we have now recreated 266 genetic variants in DNA plasmids that can be expressed in cellular models. These variants were originally found in PD patients and encompass 79 genes. We are currently testing whether the variants exhibit altered protein-protein interactions compared to wild-type genes, and will soon start testing their effect on alpha-synuclein toxicity in cellular models. Genetic variants that demonstrate perturbations to protein-protein interactions and exhibit different effects on alpha-synuclein toxicity compared with the wild-type gene will be examined further in the alpha-synuclein human stem cell-derived neuron models currently being developed in our lab.
We are also re-running tests of the approximately 7000 variants found in our PD patient cohort, comparing them to new control cohorts from publically available datasets in order to make high-confidence calls of which variants are enriched in patients versus healthy individuals. Using these new analyses, we plan to generate a list of top candidate variants to test in the experimental pipeline described above.
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.
Background: 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.
September 2019 Project Update:
We sequenced all of the RNAs (ribonucleic acids that act as messengers 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. With both the DNAs and RNAs measured for these samples, we correlated the DNA mutation status of chromosome 17q21 with the RNAs present. We designed a computational strategy to identify various types of mutations, a technique more comprehensive than other available strategies. We detected five new non-coding RNAs (RNAs that are not translated into protein, but rather serve regulatory or other functions) which were associated with a high number of mutations on chromosome 17q21. By studying these RNAs and the DNA mutations that they are associated with, we hope to further understand the molecular underpinnings of the development of PD.