Research > Grants Archive

The 2011 Parkinson's Unity Walk Funds Research Grants

Through the generous support of its corporate sponsors, 100% of all donations made to the Parkinson's Unity Walk are distributed among the major U.S. Parkinson's disease foundations for Parkinson's disease research. The foundations include: (1) the American Parkinson Disease Association; (2) the National Parkinson Foundation; (3) the Parkinson's Action Network; (4) the Parkinson's Disease Foundation; (5) The Michael J. Fox Foundation for Parkinson's Research; (6) The Parkinson Alliance; and (7) The Parkinson's Institute and Clinical Center.

We are excited to share with you information about the following grants —all of which are made possible from 2011 Parkinson's Unity Walk distributions. We will update the grants with progress reports as they are made available to us.

Grants with progress reports from previous years are also available.


1. American Parkinson Disease Association is using its distribution to fund:

Project title: Identifying risk and protective factors for Parkinson’s disease
using data from the California Teachers Study: Reproductive Factors and PD

Investigators: Beate Ritz, MD, PhD, UCLA

Objective: To identify risk and protective factors for PD using data from a unique cohort for which a host of information about reproductive health is available.

Background:
Most epidemiologic studies have found that PD is more prevalent in men than in women at an approximate ratio of raising the possibility that female hormones, namely estrogens or progesterone, may play a protective role.  Animal studies suggest several mechanisms by which estrogen could be acting neuroprotectively, including through anti-oxidative, anti-inflammatory, and anti-apoptotic pathways.  Such studies documented that estrogen increases dopamine concentrations in the brain and influences dopamine receptor density and sensitivity.  Estrogen can also reduce oxidative stress, upregulate neurotrophic factors, and protect dopaminergic neurons against apoptosis.
 
The majority of epidemiologic studies that have examined the role of hormonal factors in PD have included small numbers of mainly prevalent cases and used varying diagnostic criteria to verify the diagnosis of cases.  Results from these studies have been somewhat inconsistent. Some studies suggest that conditions resulting in a shorter lifespan with high physiologic estrogen levels increase PD risk in women, while others report that treatment with estrogens decrease risk.  However, there are also reports to the opposite and studies that failed to find any association between estrogen and PD.  An increased risk of PD was reported for post-menopausal hormone use in a case-control study of Kaiser Permanente members in Northern California and in the Cancer Prevention cohort study, but negative associations were found in three case-control studies.  The Nurses’ Health Study pointed specifically to progesterone only formulations as being associated with increases in PD risk.   Early age at menopause increased PD risk in two studies, but was protective in another. Results for age at menarche, parity and type of menopause have generally been inconsistent or null. The conflicting findings from existing studies underscore the importance to further elucidate potential effects of reproductive hormones and the reproductive cycle on PD in human populations. 

The California Teachers Study (CTS) is a unique and powerful resource to address hypotheses pertaining to reproductive factors in PD, given that it provides arguably the most comprehensive data with which to examine these factors.  The most recent CTS questionnaire (years 2005-2006) identified 403 women (out of 69,527 responders) who responded ‘yes’ to a PD screening question (“Were you ever told by a health professional that you have Parkinson’s disease?”  If yes, “At what age?”). 

Methods/Design:
In summer of 2009, we obtained data from the CTS consortium for the “Reproductive History” section of the baseline CTS questionnaire for 403 self-reported cases of PD and for 4,045 controls selected from the cohort; controls were frequency matched (1:10 ratio) to cases based on year of birth (5-year categories) and race.  The data included age at menarche and menopause, oral contraceptive use (OC) and hormone therapy (HT), parity, breast feeding and surgical menopause. We also obtained data on potential confounding factors including age, race, type of employment/job title, socioeconomic status, smoking history, caffeine intake, and pesticide exposure.  We started analyses of this case-control sample nested within the CTS cohort to investigate the role of reproductive factors in PD, and specifically to test whether exposure to estrogens is associated with a lower risk of developing PD. 

Results: In July 2010, we presented preliminary results to the CTS Steering Committee at a meeting conducted at USC.  Of the 404 self-reported PD cases, 58 (14.3%) reported having been diagnosed before study entry in 1995 (“prevalent cases”), 208 (51.4%) reported having been diagnosed between baseline and follow-up (“incident” cases) and 138 (34.1%) did not provide an age of onset (“unknown onset” cases), not allowing a classification as either incident or prevalent cases. Preliminary analyses of the data suggested a significantly increased risk of PD with older age at menopause, with estrogen + progesterone or progesterone only post-menopausal HT and with five or more years of OC use. 

Given the importance of having an accurate diagnosis and reporting of PD, in fall of 2010, we proposed and received permission from the CTS to conduct a follow-back investigation to achieve the following objectives, a) obtain missing age of diagnosis data for the 138 (34.1%) unknown onset cases and verify age at diagnosis for the other 266 (65.8%); b) request permission to contact treating neurologists to confirm PD diagnosis in all cases either by completing a brief diagnostic questionnaire similar to the one used in the Harvard Nurses Health cohort study or by sending UCLA a copy of the medical records; and c) to collect saliva samples from women for DNA extraction and storage for future studies of gene-environment interactions.

Working with collaborators at USC, we developed the procedures for the follow-back study of the 404 self-reported incident PD cases. Since due to IRB restrictions CTS cohort participants are only allowed to be contacted by the original investigators, all contacts with patients have to be initiated by USC. Thus, CTS staff is responsible for sending cases a brief questionnaire and medical record release and HIPAA authorization forms, consent forms for the spit sample, and Oragene kit and for follow contacts to ensure they return the signed forms and spit sample. UCLA staff contacts neurologists asking them to complete a diagnostic questionnaire or to send us a copy of the patient’s medical records.

The follow-back study was initiated on June 1, 2011.  As of July 28, 2011, initial invitation letters had been sent to the random sample of 200 cases. For 40 cases, data forms and HIPAA authorizations for medical records have already been received; and we also received 30 saliva kits. Five women returned incomplete data and are being followed-up; one has a new mailing address; seven letters were undeliverable and these women are now being traced; 14 refused; five were found to be decease; 52 reported not having PD, and for 76 there was no initial response yet. A second invitation letter was sent to all non-responders and USC has also initiated a telephone follow-up.

We are now completing the follow-back for all CTS PD cases and will then perform final data analyses. We expect to be able to submit a manuscript describing the results of this study to a peer-reviewed journal in early 2012.

Conclusions/Relevance to Parkinson’s disease: When completed with the final follow up this study will provide unique information on the role of female hormones and reproductive history on the risk of developing PD and help clear up uncertainties from previous studies based on less informative cohorts. This is important because it may help identify protective factors for PD that can be exploited to develop new protective therapies for the disease.

September 2012 Project Update:

In the California Teacher Study (CTS) cohort, we conducted a study of female hormones and Parkinson's disease risk. First we identified all teachers who had reported a PD diagnosis between 1995 and 2005 in order to confirm the diagnosis via medical records. Using the National Death Index, we found that 77 of the 404 women who had self-reported a PD diagnosis were already deceased and could not be contacted.

We then attempted to contact all surviving potential PD cases (n=327) by telephone or by mail and invited them to participate in this study and provide permission to contact their neurologist or primary care physician for a confirmation of their PD diagnosis. Through these efforts, we were able to diagnostically validated 102 cases and we also developed an algorithm based on record information that allowed us to accept another 128 as possible or probable PD cases. We then included a total of 230 PD cases and 3,349 age-and race-matched unaffected controls from the CTS in our analyses of lifetime female hormones and PD. Based on the data these study participants had provided to the CTS in 1995 and 2000, we found that cases and controls did not differ in having ever been pregnant, age at first pregnancy, total number of pregnancies and full-term pregnancies. There was however a suggestion that three or more pregnancies may reduce PD risk. While age at menarche was not associated with PD risk, compared to women with menopause at age 50-52 years, women with menopause at both younger (

September 2013 Project Update:

The work on this study was completed and provides some support for the hypothesis that higher lifetime estrogen levels may be protective against PD. The manuscript has been completed and is pending submission for publication.

 

Project Title:  APDA Advanced Center for PD Research at Washington University in St. Louis

Name of Organization:  Washington University in St. Louis (WUSTL)

Investigators:  Joel S. Perlmutter, M.D. Center Director

Objectives:  To develop biomarkers for cognitive impairment that occurs in people with PD.

Background:  The WUSTL APDA Advanced Research Center for PD has supported a wide variety of exciting new PD research projects over the last 10 years.  This “see funding “ has produced a many peer-reviewed publications and provided the pilot data for a large number of subsequently externally funded PD research studies.  These programs have focused on multiple areas including Mechanisms of Deep Brain Stimulation; Caroxyfullerene treatment of MPTP-induced parkinsonism; Validation of Biomarkers for Nigrostriatal Neurons; and Investigations of Dementia in PD.  We will now focus on the PD dementia studies which use clinical, PET, cognitive, genetic, and biochemical measures to investigate the pathophysiology of dementia.  After collecting pilot data with APDA support, we just obtained an RO1 to support ongoing longitudinal studies.  The initial studies found that dementia related to Parkinson disease is associated with abnormal alpha-synuclein deposition in cortex in all subjects, additional abnormal amyloid deposition in about 2/3 and only rarely abnormal tau deposition.  PET scans with the amyloid radiotracer PIB revealed positive scans that we initially thought would predict Alzheimer’s pathology on subsequent postmortem evaluation.  However, we were surprised to find that a positive PIB scan did predict abnormal amyloid deposition but not necessarily Alzheimer’s pathology sufficient to contribute to dementia.  Those with positive PIB scans had abnormal alpha-synuclein deposition throughout cortex as well as abnormal amyloid but did not have pathological deposition of tau.  Thus, Alzheimer’s disease pathology did not contribute to their dementia.  The role of amyloid remains unknown.  We are now focusing on developing biomarkers of these different pathologic groups and further exploration of the role of amyloid.

Methods/Design: 
We will use these PUW funds to leverage the support from our new RO1 in this area.  Our planned study includes longitudinal assessments over 5 years in 290 people (people with PD with and without cognitive impairment as well as healthy controls).  Each participant has an initial evaluation including cognitive testing, clinical evaluation for dementia, MR for structure and BOLD measures, PET PIB (for amyloid measures), genetic testing and spinal tap for biochemical analysis.  Follow-up includes periodic cognitive testing and clinical evaluations as well as planned postmortem evaluation of the brain.  We would like to enhance this research by collecting additional follow up resting state functional connectivity MR studies, developing additional PET radiotracers (such as PET tracers for dopaminergic pathways (like D3 receptor radioligands, alpha-synuclein radiotracers and radioligands for vesicular acetylcholine transport sites), beginning biochemical studies of transmitter systems in postmortem brain tissues form these subjects and coordinating the activities of the subjects through these different components of the research.

Relevance to Parkinson Disease:  These research projects will provide key insights into the pathophysiology of cognitive impairment in people with PD.  Development of biomarkers that predict the pathophysiology of cognitive impairment in PD is critical to identify proper categorization of participants for clinical studies.

September 2012 Project Update:

Results:   The WUSTL APDA Advanced Research Center for PD has supported a wide variety of exciting new PD research projects over the last 11 years.  This “seed funding” has produced a many peer-reviewed publications and provided pilot data for several subsequently externally funded PD research studies. This past year, we focused the resources of our Advanced Research Center on developing biomarkers for PD and cognitive impairment that frequently occurs in people with PD.  We now have support from an NIH RO1 “Investigations of Dementia in Parkinson Disease” and have continued to recruit more than 140 participants in this longitudinal study. We just published a paper in the Archives of Neurology based on postmortem examination of 32 people with PD that had dementia that clarifies the underlying brain changes.  All 32 had alpha-synuclein (the abnormal protein associated with PD) deposits in cortex and 60% also had abnormal deposits of Abeta42 – one of the two proteins (the other is tau) found in people with Alzheimer’s disease.  However, only one had abnormal tau.  Thus, co-existing Alzheimer’s disease is not a likely contributor to most people with PD that have dementia.  However, the Abeta42 deposits seemed to confer a higher risk for shorter survival, but this needs confirmation.  We also found that the pattern of the PET PIB (the PET marker that indicates abnormal Abeta42) seems to be different in people with PD from those with Alzheimer’s disease. We are preparing this for publication.  We have collected specialized MRI scans from all participants that permit assessment of patterns of brain activity while subjects like quietly in the scanner.  This allows us to examine changes in the ways different brain regions are connected with each other. One paper describing these findings is now in press in a journal called Brain.  We also have made progress in developing new PET tracers to measure brain alpha-synuclein in living people and submitted a paper for publication describing a our preliminary findings.  We also have submitted an RO1 proposal to NIH to further support that work.  In addition, we have continued testing how well three different types of PET markers to measure dopamine nerve cells (those that die in PD).  We have made substantial progress in determining how these PET measurements reflect the actual number of nerve cells in the brain.  We have published three papers on this in the past year  and a fourth is now in revision for Annals of Neurology. These studies are critical for permitting measures of PD progression and testing new therapies to slow disease progression. We just received another 5-year RO1 to continue support of this biomarker work (“Validation of Biomarkers for Nigrostriatal Neurons”).

In summary, we have substantial progress this past year.  The funds from the Parkinson Unity Walk that supported our APDA Advanced Research Center have permitted us to continue these studies and collect new preliminary data to extend the currently NIH funded research.  
 
Relevance to Parkinson disease:  These research projects have provided new insights into the mechanisms that contribute to cognitive impairment that afflicts many people with PD.  We also have made substantial progress in developing and validating neuroimaging biomarkers to apply to these studies.

September 2013 Project Update:

Working with 190 recruited participants, we have utilized Positron Emission Tomography (PET) brain imaging for principal components analysis (a statistical approach to identify patterns) of A-beta and found it differs in PD patients from that in people with Alzheimer disease (AD).  This provides additional evidence that A-beta, an abnormal protein in AD, plays a different role in PD.  

We also studied utilized MRI-based measures of brain networks demonstrating specific changes that relate to cognitive impairment in PD.  We also published a paper in Brain revealing changes in networks between striatum and the back of the brain including brainstem and cerebellum.  We will soon submit spinal fluid analyses of our PD participants that demonstrate differences between AD and PD in the amount of tau protein, which is elevated in AD and not in PD.  We have also collected brains from 23 of 24 participants that have died and continue biochemical measurements in these brain tissues to determine specific relationships to types of cognitive problems that people had in life.

2. National Parkinson Foundation is using its distribution to fund the following:

Project Title:  Sleep Disordered Breathing and its Impact on Neuro-Cognitive Performance and Quality of Life in Parkinson’s Disease

Investigators/Organizer:  Carlos Singer, MD

Objectives:  To determine the prevalence of sleep disordered breathing (SDB) and poor sleep quality in a diverse ohort of idiopathic PD patients. To determine the association between SDB and impaired cognition in PD patients. To evaluate, prospectively, changes in cognition and sleep quality at 4 months follow-up in all study patients.

Background:   Sleep and sleep quality impact physical health, emotional well being, and quality of life.  Sleep disturbances are one of the most common non-motor complications in patients with Parkinson’s disease with a reported prevalence of up to 90%.  Sleep disordered breathing (SDB), a syndrome that includes obstructive sleep apnea, has been associated with impaired cognition, increased risk of stroke, hypertension, atrial fibrillation, coronary artery disease, and worsening diabetes. There is a growing awareness that SDB is a significant problem in PD yet the study of sleep disorders in patients with PD remains in its infancy.  SDB is likely to be an important determinate of poor sleep quality in PD. Data on the prevalence and clinical correlates of SDB in PD are limited and contradictory; but some studies report SDB prevalence to be as high as 60%. Importantly, little is known of the impact of SDB therapy on neuro-cognitive measures and sleep quality in PD.  In a disease, where curative therapy has remained elusive, interventions that may improve quality of life, daytime functioning and cognition are of paramount importance.

Methods/Design:
  During the two-year project, investigators will prospectively enroll 200 patients with idiopathic PD. All patients will undergo a baseline polysomnography (PSG) to diagnose SDB and will be asked to complete validated questionnaires to measure poor sleep quality (SQ), SDB risk, insomnia severity, daytime sleepiness, presence of restless leg syndrome (RLS), anxiety/depression, and quality of life.  Medical records will be reviewed to determine co-morbidities and medication use.  Each PD participant will undergo a full neurological examination, including the Unified Parkinson’s Disease Rating Scale (UPDRS), the Hoehn & Yahr stage and a battery of neuro-cognitive measures at baseline.  Patients with SDB will be offered PAP titration and treatment for 4 months.  All patients (SDB [PAP compliant, non-compliant], and no SDB [controls]) will complete repeat neuro-cognitive evaluation, questionnaires, neurological evaluation and UPDRS assessment at 4 month follow-up.  Although participants will understand the general purpose of the study, they will be blinded to the major study hypothesis. Neuropsychological examiners and the neurologist conducting the neurological exam will be blinded to the SDB status of the patient.

Relevance to Diagnosis/Treatment of Parkinson’s disease: This study will be the first trial evaluating the effectiveness of PAP in improving cognition and sleep quality in PD patients with SDB.

Projected Results:
  This is a two-year grant and results are not anticipated until the end, but the grant requires an interim report after one year.

September 2012 Project Update:

This is a two-year grant and results are not anticipated until the end. However, up to date, we can report that the study has enrolled 40 patients of whom 83% are male and 60% Hispanic. Twenty one base line in lab sleep studies, 5 positive airway pressure titrations and 21 base line neuro-cognitive assessments have been completed. Interim analysis will be performed after enrollment of 100 patients.

September 2013 Project Update:

To-date the investigators have enrolled 81 patients, mean age 64 +/- 10 years.  Participants are 75% male and 62% Hispanic.  Recruitment was delayed by the initial requirement that subjects receive an in-clinic sleep study.  After 21 subjects were evaluated in-clinic, the protocol was updated to allow for at home polysomnography using portable device.  To date, 60 subjects have been evaluated using the portable device.  Of these 81 subjects, 21 (25%) were assessed to have SDB and were treated with positive airway pressure (PAP) devices.  Twelve subjects have received their 4-month follow-up evaluations and nine subjects have returned for their one-year follow-up evaluations.  Total enrollment will be stopped at 86 subjects.

Enrollment was limited because many patients were medically unstable and not suitable for recruitment and additional patients who were approached for PAP titration refused treatment.

The investigators filed for a no-cost extension, which was granted to allow them to complete analysis of the data.  Despite not achieving their enrollment target, the investigators feel that they have gathered enough data to be able to show significant new insight into the prevalence of SDB in Parkinson’s disease and the impact of treatment.

Results/Conclusions:  This study is not yet complete.  Baseline subject characteristics were presented at the 2013 American Academy of Neurology conference in San Diego.  The investigators are currently finalizing the data analysis to present results on sleep, SDB, Parkinson’s status and cognition to show associations between sleep status and each subject’s Parkinson’s disease.  These results will be published over the next year.


Project Title:   Targeting Non-Motor Symptoms: A National Parkinson Foundation Symposium on Parkinson’s Disease

Investigators/Organizer:  Ariel Deutch, PhD, Professor of Psychiatry and Pharmacology, Vanderbilt University, Nashville, Tennessee.

Objectives:  To bring together scientists from multiple fields who are researching the biological pathways that result in non-motor symptoms in order to identify key targets for translational development.

Background: With medications for Parkinson’s disease effectively controlling many of the motor symptoms, people with the disease now often report that non-motor symptoms are the ones that most limit the quality of their lives.  These motor, cognitive, and mood-related symptoms that are not well managed by dopamine-replacement therapy are often the cause of disability in patients.   Recent research has found commonalities among the biochemical mechanisms and anatomical manifestations that lead to symptoms across several neurological conditions.  Many of these common pathways are currently in the early stages of understanding.  Organized by symptom, this symposium will be tailored to focus the conversation on translation of basic science to clinical therapy.  With a focus on fundamental biology, the program will draw on investigators who target pathways to disease that may be common across conditions.

Methods/Design:
  This symposium will be used to discuss many of the commonalities among different neurological conditions to advance science in PD.  It will take place as a day and a half pre-meeting to the Society for Neuroscience annual meeting in November 2011.  The conference will consist of four symptom-specific sessions, each lead by a chairman who is a respected leader in translational research.  Day one will consist of four sessions, each 105 minutes, consisting of an introduction by the session chair and five 15-minute presentations by researchers in the field followed by discussion.  The four sessions will be on autonomic dysfunction, depression, cognitive impairment and psychosis.  Day two of the symposium will consist of reflections by the four session chairs of day one presentations followed by a round-table discussion with audience participation on the promising avenues for research.  Close to 200 participants are expected.

Relevance to Diagnosis/Treatment of Parkinson’s disease: NPF and the symposium chair will prepare a memorandum summarizing the conference and the discussion which will be distributed among the participants and sponsors. This memorandum could be used to steer grant funding to the areas identified as promising targets for therapy development. In addition, it will be presented to the advisory boards of organizations such as the Massachusetts Translational Research Fund, the Cures Acceleration Network, and organizations that support pharmaceuticals development.

September 2012 Project Update:

Results: On November 10 and 11, 2011, over 50 neuroscientist from different academic institutions in the United States met to discuss the latest advances made in understanding the pathophysiology of four non motor PD symptoms including autonomic dysfunction, depression, cognition and psychosis . Four panels covered these symptom domains with speakers who were experts in these symptoms as they occur in other disorders but who were not experts in PD. Speakers presented very new data, which lead to interesting discussions about different lines of work including potential targets for Parkinson’s treatment. The conference was successful in bringing specialists in specific neural systems together with clinical experts in Parkinson’s pathology to link Parkinson’s disease to brain biology. The conference concluded with the four session chairs forming a panel with the conference chair, the chairman of NPF’s scientific advisory board Ariel Deutch, Ph.D. The group agreed that additional basic research is necessary to develop new therapies to specifically target Parkinson’s-specific problems, but that much progress could be achieved through better application of existing therapies or clinical trials of medications approved for other conditions to establish benefit in Parkinson’s. Our hope is that this initiative and others will raise awareness among investigators who are not focused on Parkinson’s disease to consider the impact on Parkinson’s of new developments in their respective fields.


Project Title:   Smartphones for Ambulatory Monitoring of Gait Disturbances in PD

Investigators: Mark Shapiro, PhD, Kondrad Kording, PhD

Objectives:

1. To demonstrate validity of using smartphones to quantify parameters of the Timed Up and Go (TUG) test
2. To demonstrate the validity of using smartphones for ambulatory monitoring to quantify freezing of gait and falls

Background:  Cardinal signs of Parkinson’s disease include postural instability and gait disturbances (PIGD) that are associated with increased risk of falls and limit patient mobility.  While tremor, rigidity, and bradykinesia can be successfully managed by pharmacological and surgical interventions in most cases, PIGD symptoms and in particular freezing of gait (FOG) are refractory to medical and surgical management.  Timed Up and Go (TUG) is the most commonly used clinical test which provides a global picture of functional mobility.  Measurements of acceleration of the trunk and limbs enhance utility of the TUG test and allow clinicians to relate specific movement parameters to previously validated tests.
 
It is well known among neurologists that the most effective therapy for FOG is the presence of a neurologist: patients who complain of constant freezing will commonly walk without hesitation in the clinic.  Because FOG is one of the major symptomatic targets for new pharmacological and rehabilitation interventions and FOG is difficult to assess, a new tool for this assessment is an important unmet need in the Parkinson’s research community. This is particularly problematic considering variability of gait and freezing leading to failure to capture these symptoms in the clinic setting.  The proposed research is designed to address this issue. It promises to integrate current approaches and make them cheaper and easier to use.  It will improve our understanding of the PIGD symptoms in PD patients.

Methods/Design: The proposed research is driven by the realization that smartphones allow investigators to implement a number of important functions using the same device.  First, built-in accelerometers can be used to quantify movement parameters during the TUG test and better assess PIGD symptoms.  Second, movement tracking of patients in their home environment can be used to detect FOG episodes and falls.  Investigators will test the feasibility of using a smartphone to quantify gait disturbances in the clinic setting and home environment.  If successful, this will yield a new objective measurement for gait disturbances in PD patients with the potential to help not only validate a clinical observation, but to identify and track indications for changes in PD management strategies.

Projected Results:
  This is a two-year grant and results are not anticipated until the end, but the grant requires an interim report after one year.

Relevance to the diagnosis/treatment of PD: The impact of this study is that it demonstrates validity of using smartphones as a quantitative assessment tool for gait disturbances. Results also provide a foundation for further development of approaches for ambulatory monitoring and assessment of gait disturbances in PD.

September 2012 Project Update:

Results: After developing the smartphone app investigators recruited patients for the study and distributed smartphone’s with the app. Fourteen individuals were enrolled, 7 of whom had freezing of gait when off medication. After collecting and analyzing information these are the conclusions 1) smartphones can be used by PD patients to record data during everyday activities as long as it requires minimal input from the patient, 2) acceleration data recorded by the smartphone can be used to identify a number of activities in healthy individuals as well as PD patients, 3) acceleration parameters correlate with clinical scores and therefore potentially can be used to monitor the state of patients and progression of the disease, and 4) gait parameters, in particular step timing, can be extracted from the data recorded by smartphone during the TUG test as well as during walking in the home environment.

3. Parkinson's Action Network (PAN), founded in 1991, is the unified education and advocacy voice of the Parkinson's community, fighting for a cure. Through education and interaction with the Parkinson's community, scientists, lawmakers, opinion leaders, and the public at large, PAN works to increase awareness about Parkinson's disease and advocates for increased federal support for Parkinson's research.

PAN also provides the information and resources necessary to empower people with Parkinson's disease to act on their own behalf and gain a greater sense of control over their health and their future. For more information on PAN, please see its website at www.parkinsonsaction.org.

4. Parkinson’s Disease Foundation is using its distribution to fund the following: 

Project Title: Impact of Low- and High-Frequency Electrical Stimulation on the Inputs, Integrative Properties and Output of the Subthalamic Nucleus

Investigator: Mark Bevan, Ph.D., Northwestern University

Objective: To compare the effects of low- and high-frequency stimulation on the subthalamic nucleus and try to determine how the stimulation actually restores normal function.

Background: Nerve cells communicate by both chemical and electrical signals. In people with Parkinson’s disease, the loss of dopamine, a chemical signaling molecule, leads to overactive electrical signaling in an area of the brain called the subthalamic nucleus (STN). One therapy for Parkinson’s — deep brain stimulation (DBS) — delivers an electric current to the STN and helps restore normal patterns of signaling. But how this works at the level of individual nerve cells and their connections is still not well understood.

Methods/Design:  In laboratory studies, Dr. Bevan will use slices of brain tissue from mice that have dopamine loss and Parkinson’s symptoms. Then he will use electrophysiological techniques to study patterns of electrical signaling of STN neurons in the brain slices. He will compare the effects of low- and high-frequency stimulation on the STN and try to determine how the stimulation actually restores normal function.
Relevance to Parkinson’s Disease: A better understanding of the mechanisms underlying brain stimulation may lead to refinements in DBS therapy or to drug or gene therapies that mimic its effects.

Relevance to Diagnosis/Treatment of Parkinson’s disease:  He will compare the effects of low- and high-frequency stimulation (LFS and HFS) on the STN and try to determine how the stimulation actually restores normal function.

September 2012 Project Update:

The aim of this project is to understand the action of subthalamic nucleus high frequency stimulation (STN HFS) on STN inputs, integration and output. This knowledge may lead to the refinement of STN HFS in PD and/or the development of new therapies that mimic its actions through pharmacological or (opto)genetic approaches.

1. As predicted, we found that STN LFS (low frequency stimulation) more effectively and reliably drove inhibitory GABAergic and excitatory glutamatergic synaptic transmission than STN HFS. This observation suggests that STN LFS could worsen PD symptoms. In contrast, the reliability, rhythmicity and amplitude of inhibitory and excitatory signals were profoundly reduced by STN HFS. These observations suggest that STN HFS interrupts the synaptic patterning of neural activity (beta band) in the STN. The profound depression of GPe-STN synaptic transmission further suggests that GPe-STN inputs are unlikely to entirely suppress STN activity during STN HFS.

2. When STN LFS and HFS were applied in the absence of drugs that block neural transmission, complex, highly irregular and heterogeneous patterns of STN neural activity were evoked.  Thus, a major action of STN HFS appears be the generation of heterogeneous and irregular STN neuron activity. Presumably the precise orientation of STN inputs and STN neuron processes with respect to the electrical stimulation field are critical. Another possibility is that despite their apparently uniform electrical properties STN neurons like other neurons actually express highly variable patterns and densities of ion channels and synaptic inputs (Marder et al., 2011), which are only revealed through extreme perturbations like STN HFS.

Together our data suggest that STN HFS drives pre- and postsynaptic neuronal elements in the STN at a frequency at which transmission/activity cannot be sustained. As a consequence the level and reliability of transmission/activity are reduced leading to irregular activity and desynchronization. We therefore postulate that STN HFS replaces the low 13-30 Hz beta band transmission and activity in the STN with an irregular, noisy pattern of neural activity and output that is presumably less deleterious to motor function.

September 2013 Project Update:

We conclude that alterations in the intrinsic and connective properties of STN neurons that follow the loss of dopamine promote abnormal activity of STN neurons in PD leading to the expression of motor symptoms. We propose that STN HFS (subthalamic nucleus high frequency stimulation) disrupts the pathological activity of the STN induced by other brain regions through the generation of irregular, asynchronous activity in STN neurons and weakening the input from other brain regions. Thus, the abnormal activity of STN neurons in PD is replaced, using STN HFS, by activity that is more similar to the normal state and less profoundly disrupts motor function. Ongoing experiments in the laboratory are trying to uncover the mechanisms underlying the alterations in the properties of STN neurons that follow the loss of dopamine. This information may allow us to prevent these changes using gene therapeutic or pharmacogenetic approaches and thus improve motor function without surgery.  Data from this study were recently published in the Journal of Neuroscience (Fan et al., 2012; Atherton et al., 2013).
 

5. The Michael J. Fox Foundation for Parkinson's Research is using its distribution to fund the following: 

Project Title:  Discovery of mGluR4 Potentiators for Symptomatic and Disease-Modifying Treatment of PD

Principal Investigator(s):
P. Jeffrey Conn, C. David Weaver, Colleen Niswender, Craig Lindsley, Carrie Jones, Yoland Smith

Objective/Rationale:
  Surgical approaches to treatment of Parkinson’s disease (PD) using deep brain stimulation and corrective lesions provide valuable insights into novel approaches for treatment of this disorder by altering activity in brain circuits that control motor function.  This program seeks to develop a novel drug therapy for PD that provides sustained symptomatic relief and may slow progression of the disease by inducing changes in brain function currently achieved with surgical approaches.

Project Description:
   We have identified a neurotransmitter receptor that reduces activity of a brain pathway that is overactive in PD patients.  We used a library of 1.2 million drug-like molecules to identify molecules that increase activity of this neurotransmitter receptor.  We will now use a combination of medicinal chemistry, molecular biology, and animal studies to engineer these molecules so that they have all of the properties needed for use as a drug.  This requires an intense team effort by chemists, molecular pharmacologists, behavioral scientists, drug disposition scientists and engineers.   This team will use an iterative compound synthesis and testing approach to engineer a molecule that has all the properties required to be tested in humans as a new drug for treatment of Parkinson’s disease.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:   PD is treated with medicines that replace the neurotransmitter dopamine that is lost in Parkinson’s patients.  These medicines have severe adverse effects and lose reliable efficacy as the disease progresses.  This program endeavors to develop a new medicine that could provide sustained reliable symptomatic relief all stages of PD and may slow disease progression.  If successful, this could provide a transformative advance in treatment of PD.

Anticipated Outcome:  If successful, this program will deliver a drug candidate and backup compounds that can be tested for efficacy in treatment of PD.  In addition, the studies will provide valuable new information on the impact of regulation of transmission in an identified brain circuit impacted by PD on symptoms and progression of the disease.  This could provide a major advance in stimulating other treatment strategies that are focused on altering activity in this brain circuit.

September 2012 Project Update:

Project Update:  The team successfully developed a lead clinical development candidate and a backup molecule – developed for symptomatic (motor) benefit – that modulates mGluR4 and is showing promising results in animal studies. This is likely to be the first molecule against this glutamate target to go into clinical development for PD, with the anticipation that they will be tested in clinical trials sometime in 2013.

September 2013 Final Project Update:

Vanderbilt recently announced collaboration with Bristol Myers Squibb (BMS) to develop and commercialize the glutamate drugs for the treatment of Parkinson’s disease. The collaboration allows BMS to bring the pharmaceutical resources and expertise to move this project forward into clinical trials. Vanderbilt remains involved in the project to leverage their innovative team of scientists that have the experience of discovering and optimizing the molecules.

6. The Parkinson Alliance is using its distribution to fund the following:

Project Title: Analysis of Impedance Variations in a Large Population of Patients with Parkinson’s Disease Treated with DBS

Investigators/Authors: Michele Tagliati, MD and Tyler Cheung, MD, Cedars-Sinai Medical Center (Los Angeles, CA)

Objective:
To review impedance measurements in a large population of Parkinson’s disease (PD) patients treated with deep brain stimulation (DBS) and followed by a single center over multiple years.

Background: Two methods of delivering electrical energy are currently available for therapeutic DBS in humans: voltage control, almost exclusively used until now, and current control, featured on a number of new models approaching commercial availability.  The prevailing assumption is that impedance variations may make the therapeutic benefit of voltage-controlled devices more erratic, whereas current controlled devices by definition would not be affected.   However, there are no clinical trials comparing these two methodologies and very few studies have addressed impedance stability during long-term constant voltage stimulation in a significant number of patients.

Specific Aims:  We plan to answer the questions:
1. How much do impedances change over time during therapeutic DBS?
2. Do these impedances vary greatly between individual patients, and if so, how much?
3. Do impedances change only in the acute post-implantation period, or do they continue to show a degree of volatility even after the so-called “micro-lesion effect” of stereotactic surgery have resolved?

December 2012 Project Update:

Methods/Design:
 We reviewed impedance values from medical records of DBS patients with up to 5 years of clinical follow-up.  The standard deviation of data recorded in individual subjects and single contacts (on the DBS device) were used as measures of longitudinal impedance variability.  Note, a standard deviation shows how much variation exists from the average or expected scores (a low standard deviation indicates that points are close to the average/mean, whereas a high standard deviation indicates that the data points are spread out over a large range of values).  The generalized linear mixed model [statistical procedure] was used to determine if a number of effects had significant influences on impedance.  

Results: We analyzed 2863 impedance measurements from 94 subjects. Median variability was 194 Ohms for individual subjects and 141 Ohms for individual contacts, with a range spanning from 18 to over 600 Ohms (ohm is defined as a resistance between two points of a structure or object that conducts electrical charge).  Time was a significant predictor of impedance, along with a number of other factors including electrical activity, implanted target, contact position on the electrode and side of implantation.  Age and disease duration at surgery, gender or ethnicity were not significantly correlated with impedance variations.

Conclusions/Relevance to Parkinson’s disease: Our analysis suggests that a significant amount of impedance variability can be expected in chronically implanted DBS electrodes and indicates a number of factors may predict this variability. While further studies are needed to link impedance characteristics to clinical outcomes, such impedance variability is of great clinical interest due to its ramifications on the reliability and consistency of therapeutic DBS devices.

September 2013 Project Update:

The study was successfully completed, as outlined in the 2012 Progress Update, and initially presented at the 16th International Congress of Parkinson’s Disease and Movement Disorders in Dublin, Ireland.  A manuscript describing the methodology, results and conclusions of the study was submitted and accepted for publication in the peer-reviewed journal Brain Stimulation. The final version was published online on April 13, 2013.


Project Title:  Identifying Neural and Behavioral Risk Factors for Impulsive-Compulsive Disorders in Parkinson’s Disease

Investigator:  Susan Bookheimer, Ph.D., UCLA Medical School

Background:  A significant minority of patients with Parkinson’s Disease (PD) treated with dopamine agonists experience significant behavior changes including gambling, shopping and sexual addictions, and other impulsive-compulsive disorders, (ICDs), that can result in serious consequences to relationships, financial health and quality of life. This study proposes to use functional brain imaging and neurocognitive testing to identify risk factors that predict which individuals are more likely to develop these side effects, and to understand underlying brain mechanisms.

Objective:  While several studies have identified characteristics that co-occur with ICDs none have examined factors that predict response, nor have current studies examined characteristics that differentiate these patients after removal of agonist therapy and return to behavioral baseline. This study proposes collecting pilot data to fill this knowledge gap in preparation for a future, larger scale predictive study.

We propose a pilot study to use functional MRI in patients with Parkinson's disease with a history of ICD’s after taking dopamine agonists whose behavior improved after a medication shift, and in PD patients about to begin agonist therapy. Using paradigms that examine reward responsiveness, avoidance learning, and cognitive control, we will evaluate each individual's unique brain response to reward based decision making. Subjects will also receive neuropsychological evaluations that include measures of cognitive control, decision making, impulsivity, and will evaluate for signs of addiction, gambling risk, and behavioral disorders. The goal is to identify unique patterns of brain and cognitive performance that are associated with ICDs in comparison with those without ICDs, by recruiting  patients with a history of ICDs and  control subjects prior to agonist therapy.

Methods/Design:  We propose to recruit 25 Subjects with Parkinson’s Disease  through the UCLA Dept. Of Neurology Movement Disorders Program. We will target two groups of patients: the ICD group will be 12 patients identified by Dr. Bronstein as having had ICDs in response to agonist therapy, and were subsequently switched to L-dopa therapy with symptom resolution. A second group of patients will be matched for age, disease duration and gender, but will be agonist naïve and ready to initiate agonist therapy. Thus, both groups of patients will be taking the same class of medications at the time of study, and neither group will have current ICDs. This allows us to have a well-matched sample where the primary factor differentiating groups is whether the subjects have a known propensity for developing impulsive-compulsive behaviors. Subjects will participate in 2 sessions; The first session will test for behavioral and cognitive characteristics associated with ICD; in the second patients will undergo functional MRI.

Relevance to Parkinson’s disease:  The data generated will give us a framework for designing a more comprehensive longitudinal study to predict ICD risk in PD patients. Results of this study may help to prevent these problems and suggest alternative treatments in those at risk. In addition, the knowledge we will gain about the neural mechanisms for ICDs to identify at-risk patients, to evaluate prevention strategies and ultimately, to identify avenues for new pharmacological interventions.

December 2012 Project Update:

Our primary aims are to develop methods and preliminary data on the neural circuitry involved in Impulsive-Compulsive Disorders (ICD’s) in Parkinson’s disease. Many patients with Parkinson’s who are exposed to Dopamine agonist medications develop behavioral symptoms that in some cases can have serious personal consequences. It is unknown why some patients develop these and others do not, and whether these patients will be at further risk if they undergo Deep Brain Stimulation treatment. To begin to answer these questions, we proposed this pilot study, which we characterize in three phases. In Phase 1 we aimed to develop a computerized task to measure feedback-driven learning that could be used both during MRI and during DBS implantation; in Phase 2, we piloted this task behaviorally in normal volunteers; in Phase 3 we proposed to implement this task in patients with Parkinson’s disease during fMRI and during DBS surgery. With these pilot data, we hope to obtain sufficient preliminary data to justify an NIH-funded study on ICD’s in Parkinson’s patients that will allow us to expand our goals and obtain definitive data that will ultimately add to our understanding of the mechanisms of these disorders and help in optimizing treatments in PD. The funds spent have covered programming and scanning costs.

We completed phases 1 and 2, and are in the midst of the 3rd and final phase of data acquisition in subjects during fMRI and during DBS stimulation. For the fMRI study, we screened eight patients undergoing evaluation for DBS. All subjects were administered a clinical neuropsychological battery and the QUIP, a standardized test of impulsive-compulsive disorders in Parkinson’s. Four were identified as having had ICDs while on agonist therapy. Of these, one was eligible for and completed 4 fMRI scans; several additional patients participated in the task during DBS surgery. Data has been analyzed for all subjects receiving the reward task; analysis of fMRI data are ongoing and will be completed when recruitment is finished. We have agreed to broaden our recruitment criteria to include patients not scheduled for DBS surgery but who have a history of ICDs, as our inclusion criteria were apparently too strict to complete the study quickly.
 
While we cannot draw conclusions from so small a sample, the data thus far allow us to make some preliminary observations. Foremost, it appears that learning curves for reward vs punishment-feedback are different and independent. This suggests that are separate neural circuits for learning driven by reward receipt vs. learning to avoid a negative outcome. We hypothesize that agonist medications may differentially affect these circuits. If so, we should be able to evaluate the effect of different pharmacotherapies on reward vs. punishment circuits using fMRI. A second observation based on behavioral screening and neurocognitive testing of patients with ICDs is that there appeared to be a history of addictive disorders, particularly alcoholism, in the families of patients reporting ICDs. This suggests there may be a genetic pre-disposition to ICDs associated with addiction potential.  We believe that our task could potentially differentiate individuals with a higher risk for ICD’s by relating task performance and family history risk factors.

December 2013 Project Update:

Summary and Future Directions:

This study focused exclusively on PD patients with a history of ICDs in response to dopamine agonist therapy. The data suggest that thesepatients learn in response to rewards but have poor learning in response to punishments, i.e. impaired avoidance learning. The brain data suggest that there is a lack of frontal cortical engagement during reward-mediated learning, which may lead to increased impulsivity. This suggests a potential neural marker of propensity to develop ICDs in Parkinson’s patients.

To fully understand the relationship between reward circuitry and susceptibility to ICDs, we will need to conduct further studies on patient without ICD responses to agonist therapy. We have some remaining scan slots and plan to recruit these contrast subjects to confirm the specificity of these findings to patients with ICDs. With this comparison we hope to develop predictors that will help determine which patients are most likely to develop ICDs.

The results we obtained from this pilot study will be used as preliminary data for an R21 grant that we plan to administer in early spring to the NIH, in which we will expand to a large, 2-group study with outcome data. We are most grateful for this generous support which will further our understanding of this critical problem for Parkinson’s patients and their families.

7. The Parkinson’s Institute and Clinical Center is using its distribution to fund the following:

Project Title:  Gene correction in patient-derived induced pluripotent stem cells

Investigators/Authors:  J.William Langston, MD, Founder, CEO and Chief Scientific Officer Birgitt Schule, MD, Associate Professor, Clinical Molecular Geneticist

Objective:  The goal of this study is to correct genetic defects in induced pluripotent stem (iPS) cell lines derived from patients with genetic forms of Parkinson’s disease.

Background:  This project focuses on what is considered the next frontiers in medical genetics, and which is to actually repair mutations in cellular models genetic diseases.

Methods/Design:  The fundamental rationale underlying this proposal is that we can establish research tools to explore disease mechanisms and construct novel platforms for drug discovery by combining iPS cell technology with a novel approach (known as “zinc finger nuclease technology”) that allows for “gene correction” of known underlying mutations in PD.  This technology utilizes a “molecular scissor” that can enter the cell and cut the DNA at defined positions (from among the 3 billion base pairs that make up the human genome) so that genetic mutations can be edited and “repaired” in a human cell. We will merge these new technologies to develop a completely novel cellular tool consisting of genetically corrected iPS cell lines from patients with genetic forms of PD. We will then study these panels of edited iPS cell lines that have been differentiated into neuronal cell lines and test whether the gene correction shows a functional rescue of the underlying molecular pathology.  This proposal will supplement a current grant from the California Institute of Regenerative Medicine by supporting two new pieces of equipment which will be crucial for us to characterize the newly developed cell lines and validate their pathological changes.  The first is a flow cytometer which will enable us to purify and quantify these cells that have been repaired.  We will then be able to carry out functional assays on those cells.  The second piece of equipment is a quantitative PCR machine that will allow us to amplify gene message of these repaired iPS cells once they are differentiated into dopaminergic neurons.  Both are essential to the success of this research.

Relevance to Parkinson’s disease:
  These “corrected” cell lines will provide entirely new cellular tools to investigate the effects of specific mutations in patient-derived iPS cell lines that are only different by the disease-causing mutation and therefore represent “genetically virtually identical (or isogenic) control cell lines”, something that is of major importance for basic research.  Indeed, the absence of such isogenic stem cells is a significant bottleneck in the field. The ability to study the activity of either the normal vs. mutant gene products in cells derived from the same individual could be a critical tool for elucidating the function of disease-related mutations, especially in the context of late-onset and complex diseases such as PD. Furthermore, these cellular models could become important tools for drug screening approaches and perhaps gene repair in humans at some point in the future.

September 2012 Project Update:

With the generous funding of the Unity Walk, we are able to support the current program of stem cell biology and more specifically the gene correction of Parkinson’s disease (PD) associated mutations with equipment purchases such as an Accuri flow cytometer and a CFX96 real-time PCR detection system from Biorad.
           
Overall, the zinc-finger project to genetically correct patient-derived stem cells has been very successful. We have genetically corrected PD specific  mutations under support from the California Institute of Regenerative Medicine which we can further study and compare the molecular differences with respect to a PD phenotype.

September 2013 Project Update:

During the first year of the grant, we have successful derived patient-derived stem cell lines and genetically modified mutations in the LRRK2 gene as well as other mutations that are relevant to PD. This work is currently under peer review and we are excited to report that we developed cell lines that only differ by one DNA building block, thus generated ideal isogenic controls.  This should advance research in a major way, since scientists will have the perfect control cells for experiments.

Furthermore, we have now developed techniques to further fully characterize the neurons derived from the stem cell lines. First, we can now show that the neurons can release dopamine using high-performance liquid chromatography, thus showing that these are “functioning” dopaminergic neurons. Second, we have evaluated another characteristic of neurons, the fact that they are electrically active and can “fire” action potentials. We used automated patch-clamping to assess the channel composition of the neurons for firing action potentials and we are employing microelectrode arrays to assess the spiking patterns of these neurons. These are two important characteristics that validate the model of patient-derived stem-cell generated neurons in the culture dish. In other words, these neurons are functioning in a manner very similar to that if they were actually a human brain rather than just a culture dish.

Finally, to study the functional phenotypes that are relevant for PD in these cells, we have tested the function of their mitochondria –the power plants of the cell. Dysfunction of the mitochondria hasbeen described in sporadic PD, but we wanted to test them in our model of LRRK2 genetically modified neurons. We found that the PD lines show distinct changes in their mitochondrial function such as mitochondrial membrane potential, opening of the mitochondrial transition pore, and caspase activity.
 
In summary, we now have a cellular model for PD that is functional and has many similarities dopamine neurons in the brains.  These cells will be invaluable for studying disease mechanisms and for drug discovery.