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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:
Results: Dopamine transporter knock-down in mice: dopamine neuron loss and susceptibility to pesticide exposure; Franziska Richter, DVM, PhD, Assistant Researcher: A study in rural Californian counties conducted by Dr B. Ritz from UCLA has shown increased risk for PD in individuals with variations in the gene coding for the molecule that regulates dopamine recapture into nerve terminals (“dopamine transporter”). PD risk was increased up to 4.5 fold if the individuals were also exposed to two widely used pesticides, maneb and paraquat. These data further support a link between environmental exposure, genetic predisposition and PD risk. In the pilot project supported by the PUW-APDA award, Dr Richter demonstrated that mice with low levels of the dopamine transporter were born with less dopaminergic neurons, and lost more dopaminergic neurons when exposed to paraquat and maneb than mice with normal levels of the transporter. Dr Richter went on to show that mice with low dopamine transporter who were exposed to paraquat and maneb also had increased accumulation of iron in their substantia nigra; iron is known to cause oxidative stress and this could contribute to an increased risk of developing PD.
The results suggest that individuals with genetic variations in their dopamine transporter may be at greater risk of developing PD because they already have a lower number of dopaminergic neurons at birth, which makes them more susceptible to additional insults. This validates a hypothesis that the risk of developing PD may be linked not only to insults that occur during life but also to the number of neurons an individual is born with. The reproduction of a greater loss of dopamine neurons in animals exposed to factors known to increase the risk of developing PD in humans provides a new model to understand mechanisms that lead to PD, develop better treatments based on this understanding, and a more relevant model to test these new treatments in animals before using them in the clinic.
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.
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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.
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.
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