2010 Grants

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Funding from The Parkinson Alliance helped to finance the following Parkinson's research. Grantees were selected by scientific review committees of participating organizations. Updates will be posted, when available.


Project Title:  Neuroimaging Repetitive Transcranial Magnetic Stimulation Effects in Patients with Parkinson’s Disease

Grant Awarded to:  Principal investigator: Allan D. Wu, MD, Co-investigator:  Janice Lin, PT, PhD, TMS Fellow / Study Coordinator:  Choi Deblieck, PhD

Objective:  Our objective is to determine the effects of daily repetitive transcranial magnetic stimulation (rTMS) on task-related brain activity in Parkinson’s disease (PD) patients.
 
More specifically, we want to know how rTMS stimulation of the motor cortex (which is related to making voluntary movements) will change the brain activity of tasks that require the motor cortex.  We also want to know how rTMS stimulation of the prefrontal cortex (part of the brain related to mood and cognition) will change brain activity in tasks that require cognitive effort. 

Background:  The UCLA Transcranial Magnetic Stimulation (TMS) Laboratory is in the 2nd year of a multi-center clinical trial testing repetitive TMS (rTMS) for the treatment of mood and motor symptoms in Parkinson’s disease (PD) patients, the MASTER-PD trial.

Repetitive TMS is a non-invasive and relatively painless way of stimulating the brain.  This is the first multicenter clinical trial of rTMS in PD patients in North America and the first one which will test to see if rTMS can help both movement problems and mood problems (like depression).  This is a growing and exciting concept, particularly since rTMS is now an FDA approved therapy for certain types of major depression.  In depression, rTMS is applied for 4-6 weeks over a part of the brain within an area called the prefrontal cortex.  After 2 weeks, patients who receive rTMS show an significant improvement in depression compared to patients who receive a placebo (sham-rTMS).

In our MASTER-PD trial, we study the effects of 2 weeks of rTMS on motor and non-motor symptoms of Parkinson’s disease.  The motor symptoms we aim to improve include walking, freezing of gait, imbalance, rigidity, loss of dexterity, and slowness of movement.  The non-motor symptoms we aim to improve are those related to depression (lack of motivation).
 
In our study, we are seeing if rTMS of the motor cortex will help the motor symptoms and if rTMS of the prefrontal cortex will help the depression symptoms.  The study is a blinded, sham-controlled study with 4 conditions.  Patients who are eligible for the study will have both depression symptoms and movement symptoms in spite of medical treatment.  Each patient will then be randomized to receive real or sham-(placebo)-rTMS over the motor cortex (part of the brain controlling movement symptoms) and real or sham-rTMS over the prefrontal cortex (part of the brain responsible for depressed mood) for 10 sessions over 2 weeks. Patients will be followed up to 6 months after rTMS to see how long effects of rTMS may last.

The study involves 5 academic centers across North America (Beth Israel Deaconess Medical Center, Boston; Cleveland Clinic; University of Florida, Gainesville; Toronto Western University; and UCLA) with the goal of 120 patients over 4 years.  When the study is complete in another 2 years, we feel that the results will tell us whether rTMS will help PD patients with their symptoms.  However, this clinical trial will not tell us how rTMS works on the brain.  Understanding how rTMS might work (or not work) will be important in figuring out how to best use rTMS treatment for PD symptoms and how to make rTMS a better or more specific treatment for PD.
    
Methods/Design:  To address this issue of how rTMS works, at UCLA, we used pilot funds from Team Parkinson to add a functional imaging component to our MASTER-PD trial.  We offer every MASTER-PD patient the opportunity to have a functional MRI (fMRI) scan done at the beginning and at the end of their 10 sessions of rTMS.  Functional MRI scans allow us to see which parts of the brain are active when we ask patients to perform movement and cognitive (thinking) tasks while they are being scanned.  We will obtain fMRI scans before and after the 2 weeks of rTMS treatment for each patient in the MASTER-PD clinical trial.  When we compare the brain activity before and after rTMS treatment, we can find out what nearly 2 weeks of daily rTMS does to modulate (change) the activity of brain networks needed to perform the movement and cognitive (thinking) tasks.
 
The movement task that patients perform is a sequential finger movement task where patients push sequences of 4 buttons each, guided by visual cues in the scanner.  There are several sequences of 4 buttons which repeat in random order.  This task is designed to test the brain activation patterns used by PD patients to make these complex sequential movements.  Even though PD patients have difficulty in making complex sequential movements, this task was designed to be easy to perform while lying in the MRI scanner.

The cognitive task is based on the difficulty PD patients have in controlling movements.  The prefrontal cortex is associated with control of movement by inhibiting (preventing) inappropriate actions. In this task, patients are asked to respond with a button press to every letter shown on the screen except for a given target letter.  When the target letter is shown, patients are asked to not respond (to inhibit or prevent the default action of pressing the button). This task tests the brain activity required to monitor the letters shown and to inhibit (prevent) the inappropriate action.  This task is called the “go-nogo” task and is known to activate a network of brain regions related to the prefrontal cortex and was designed to also be easy to perform in the MRI scanner.

September 2011 Project Update:

Results:  At UCLA, we enrolled 5 patients in the MASTER-PD study in the last year. Four patients underwent MRI scanning at the beginning and end of their rTMS.  One was claustrophobic and elected not to undergo MRI scanning.  All 4 patients who performed two sets of MRI scan sessions were able to successfully complete both motor and cognitive tasks.  One patient had too much head motion from dyskinesia.  With data from 3 patients and being still early in the study recruitment process (we have not unblinded Dr Lin as to what type of rTMS each of these patients received), no conclusions as to rTMS effects at this point can be drawn.

For our motor task, we found that the sequential key pressing task activated a consistent set of brain regions associated with a motor execution network including bilateral motor cortex, premotor cortex, supplementary motor area, and parietal regions.  The overall pattern remains visible after 6-9 days of daily rTMS but an analysis of real or sham-rTMS associated change cannot be made. This confirms the robust nature of this task in activating a motor network and provides a good basis for later comparison after rTMS.

In the cognitive “go-nogo” task, we found more variability in the inhibitory control network than in the motor task among our 3 patients.  In general, when patients are monitoring for and stopping inappropriate responses, we see more brain activity in inferior frontal, inferior parietal, and prefrontal brain regions.  However, 1 patient showed this pattern on the left side of the brain and the other two showed this on the right side of the brain.  Overall, the patterns confirm an expected dependence of this task on the prefrontal cortex in all patients, but not all patients showed the same pattern.  Differences in the individual pattern are apparent after rTMS, but at this point cannot be interpreted because we have not unblinded the type of rTMS each patient received.
     
Relevance to Parkinson's disease:  It remains too early to say anything definitive about the results from this project.  The main results are practical issues that are being solved with how to obtain and collect data from PD patients in a rTMS study.  We have tested two tasks for use in the MRI scanner on normal control subjects without PD and have successfully run the MRI scans before and after daily rTMS on 4 PD patients who were able to complete and tolerate the tasks.

The motor task appears highly promising as its pre-rTMS results are consistent across patients.  The cognitive (go-nogo) task is consistent with activation of the prefrontal network, but since results are more variable, we are considering further testing of other prefrontal fMRI tasks in non-PD patients.  We have also collected additional MRI data in all our PD patients to date (not task-related) in our routine scan protocol.  These MRI data permit additional analysis of resting-state brain activity, functional connectivity, and brain structure before and after rTMS.  These analyses require more data from additional patients and are anticipated to yield additional information about effects of rTMS on different aspects of brain structure and function in PD patients. 

We have been pursuing this pilot project with the knowledge of the other sites involved in the multicenter clinical trial.  In fall 2011, the protocol we used has attracted attention from Beth Israel Deaconess Medical Center (BIDMC), the coordinating site for the MASTER-PD study, who has expressed in collaborating on adding functional MRI imaging to their patients as well.  As such, we will be sharing our scanning protocol and data with BIDMC.  This will likely double the number of patients we can image with our MRI protocols and improve our ability to draw pilot conclusions on the effects of rTMS within the rigor of a randomized sham-controlled clinical trial.  We anticipate that the pilot data from these imaging studies by the 4th year of this project will be sufficient to be used as pilot data in larger grant applications aimed at understanding the rationale of how daily application of rTMS achieves its hopefully beneficial clinical effects.  It is also noteworthy that this is an example of how pilot ideas and projects that were supported and started at UCLA can spread to other sites in larger clinical trials.

December 2012 Project Update:

We continue to study the effects of repetitive transcranial magnetic stimulation (rTMS) on motor (movement) control problems and depression symptoms in Parkinson’s disease (PD) patients.     

In the last year, UCLA recruited 5 more PD patients into the MASTER-PD study with no significant adverse events and excellent tolerance of 2 weeks of rTMS.  Three of these 5 patients were scanned in the MRI scanner during their rTMS sessions without incident.  In total, we have scanned 7 out of 10 PD patients recruited at UCLA.  One patient showed too much dyskinesia (head movement) to make scans interpretable.  The remaining 6 patients completed two sets of MRI scan sessions.  

These functional MRI (fMRI) scans allow us to see which parts of the brain are active when we ask patients to perform movement and cognitive (thinking) tasks while they are being scanned.  We obtain fMRI scans before and after the 2 weeks of rTMS treatment for each patient in the MASTER-PD clinical trial.

We also have been obtaining scans of the brain at “rest,” when patients just lay quietly in the scanner.  This allows us to do “resting-state” analysis, a measure of how different parts of the brain are connected to each other.  It is thought that different PD symptoms (such as movement or mood symptoms) are due to different functional connections between movement or mood brain networks. Since the MASTER-PD protocol applies rTMS to either movement networks or mood networks, this resting-state analysis provides another potential means to understand how rTMS may be working. This resting-state fMRI protocol has been shared with a second MASTER-PD site (Beth Israel Deaconess Medical Center, Bosoton) and both sites are now pursuing data collection for resting-state fMRI before and after rTMS jointly.

The MASTER-PD project is a multicenter one involving 5 academic centers across North America (Beth Israel Deaconess Medical Center, Boston; Cleveland Clinic; University of Florida, Gainesville; Toronto Western University; and UCLA).  Recruitment of eligible patients for this project has been challenging and we have recently added a 6th site in Oregon.  Eligible patients must show both signficant depression and motor symptoms, both of which had been adequately treated medically with insufficient benefit, – and be willing to travel to UCLA for treatments daily for 2 weeks.  This issue is not been unique to UCLA and all sites have increased our support group and recruitment efforts. UCLA continues to be the second highest recruiting site among the group.  Nevertheless, all sites are committed to bringing this rTMS project to a successful close.

The MASTER-PD study will close later this year.  Then, work will begin to consolidate the data across 6 sites to see if rTMS can help PD patients with their motor (movement) or mood (depression) symptoms.  When the study closes, we will have completed pilot fMRI scanning in PD patients here at UCLA and jointly at BIDMC in Boston.  These functional imaging data are anticipated to yield some novel insights into how rTMS may work on the brain and generate new hypothesis for the design of more effective brain stimulation therapies for PD.


Project Title:  Cortical Mapping of Pathology in Early versus Later Stage Parkinson Disease

Grant Awarded to: 
Yvette M. Bordelon, MD, PhD, Liana Apostolova, MD, Kristy Hwang, Hans Bogg, UCLA

Objective:  This proposal seeks to define the cortical distribution of pathology in later stages of Parkinson disease as a marker or correlate of the Braak PD pathologic stages 5 and6 using FDDNP-PET imaging.

Background:  The Braak staging system describes the progression of Lewy body pathology from brainstem (stages 1 and 2)  to subcortical structures (stages 3 and 4) to cortical areas (stages 5 and 6). We have investigated the utility of a positron emission tomography (PET) molecular imaging probe, 2-(1-{6-[(2-[F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene) malononitrile or [18F]FDDNP, as a biomarker of Lewy body pathology in living subjects with Parkinson disease.  FDDNP binds misfolded proteins in the brain that assumes an amyloid conformation.  This probe has been shown to label Lewy bodies in tissue sections from PD brains

Methods/Design:  FDDNP binding in the brains of subjects with varying  PD duration will be compared.  This proposal began a detailed analysis of cortical  [18F]FDDNP uptake in these patients to better define the load and distribution of pathology in early versus later stage PD using state-of-the-art quantification techniques.

September 2011 Project Update:

Results:  During the study period data continued to be collected with enrollment goal (total subjects=20) being met in mid-2011.  Dr. Apostolova’s lab began the proposed analysis as the data collection continued through late 2010 and 2011.

The first and more complicated phase of analysis involved preparation and processing of the structural MRI data.  The interim analysis of the structural data were on a total of 12 PD subjects.

Variable (SD) PD (N=12)
Age (years) 63.85 (8.08)
Gender (M:F) 6:6
UPDRS (Part III, motor evaluation) 16.54 (9.72)
Duration of disease (years) 5.96 (4.46)


Although not statistically significant, we recognized a trend of global cortical atrophy associated with the duration of Parkinson’s disease. Linear regression analysis of patient disease duration and grey matter density showed several areas of strong negative correlation, including the left anterior cingulate (r>-0.6), left inferior temporal (r>-0.6), right temporal pole (r>-0.7), bilateral precuneus (r>-0.6), and bilateral lateral occipital cortices (r>-0.6).

Also using linear regression analysis, UPDRS III scores were shown to have a negative correlation with grey matter density in the bilateral sensorimotor (r>-0.5) and medial occipital cortices (r>-0.6). This matches previous examinations of PD structural pathology, which have found atrophy in similar cortical regions.

Conclusion/Relevance to Parkinson's disease:  The extent of gray matter atrophy in the PD patients imaged in this study parallels the duration of their pathology, agreeing with a common sense hypothesis that atrophy will increase over the course of disease progression.  Our results show decreased grey matter density in the occipital cortices.  Considering that visuospatial difficulties arise in Parkinson’s, manifested in difficulty recognizing faces or the orientation of lines, it is entirely possible that the cortical atrophy witnessed in the occipital cortices is to blame for the loss of function.

The next phase of this study will use these structural images to map FDDNP signal onto them to determine whether the Lewy body pathology also has more cortical signal with advancing disease with earliest signal in the occipital lobe (initial analysis shows this trend).

October 2012 Project Update:

A total of 20 subjects were enrolled with 10 classified as early PD and 10 determined to be later PD according to these critieria. All subjects completed neurologic, imaging and neuropsychologic assessments which included UPDRS, brain MRI, [18F] FDDNP-PET, FDG-PET, UPDRS, MMSE and cognitive measures.  However, 2 subjects were eventually excluded from analysis as they met criteria for dementia upon review of their detailed testing.  Thus, a total of 18 subjects were included in the final analysis: 9 subjects with early PD and 9 subjects with later PD. One subject from each category did not have a full motor UPDRS at the time of the scan and one early PD subject did not have an MMSE performed at the time of scanning.

Image analysis included motion correction for [18F] FDDNP-PET scans and generation of the parametric images using a modified Logan plot approach with cerebellum as the reference region.  Region of interest (ROI) analysis of [18F] FDDNP parametric images was performed by manually selecting regions on axial sections to include: midbrain, right and left striata, right and left frontal cortices, right and left temporal cortices and right and left occipital cortices.  

Higher [18F] FDDNP binding levels were appreciated in almost all brain areas in subjects with later stage PD as compared to early PD with the right occipital lobe being the only region reaching statistical significance.  

Conclusions: Our PET imaging results have revealed that [18F] FDDNP uptake is present in PD subjects and is greater in the cortex of patients with later stage PD compared to early PD, particularly the occipital cortex.  This correlates with known progression of Lewy body pathology to involve the cortex through later PD stages according to Braak and colleagues.  We continue to work to refine the cortical mapping techniques of FDDNP binding.  We feel that FDDNP-PET may serve as a useful marker of progression of the cortical pathology in PD and hence as a potential therapeutic biomarker for interventions in early PD aimed at slowing or preventing PD progression.


Project Title:  Brain and Behavioral Effects of Exercise in Patients with Parkinson’s Disease

Name of Organization: University of Southern California

Principal Investigators: Beth E. Fisher, PhD, PT & Giselle M. Petzinger, MD
Investigators: Quanzheng Li, PhD; Michael Jakowec, PhD; Peter Conti, MD, PhD

Objective:  To better understand changes in dopamine regulation with exercise and how they influence behavior in individuals with Parkinson’s disease.

Background:  While a number of studies have shown that exercise is beneficial in improving motor function in Parkinson’s disease (PD), the brain mechanism(s) by which this happens is poorly understood. Parkinson’s disease is a problem of dopamine neurotransmission that results in hyperexcitability (i.e, too much activation) of the cortex. There is compelling evidence that this hyperexcitable state underlies the very motor dysfunction associated with Parkinson’s disease including gait and balance impairments, slowness and stiffness. Acting principally through an important receptor on neurons of the basal ganglia, the D2 receptor, it is thought that dopamine can influence hyperexcitability. Treatments that can restore dopaminergic signaling at D2 receptors can attenuate the hyperexcitable state and lead to improved motor function. Our preliminary data using intensive treadmill exercise in both animal models of PD and humans suggests that exercise facilitates dopaminergic signaling of the dopamine D2 receptor, decreases cortical excitability and improves motor function.

Methods/Design:  For this proposal, participants with early stage untreated Parkinson’s disease will be randomized to one of two groups: high-intensity treadmill (fast walking to jogging), and no-exercise standard of care group. Participants in the exercise groups will exercise, one hour, three times per week for eight weeks (24 sessions). Participants will be examined at baseline and one week following exercise termination using Positron Emission Tomography (PET) to determine changes in D2 receptor changes.

September 2011 Project Update:

Results: We are in the process of submitting the manuscript entitled: ‘Exercise Effects On Dopamine D2 Receptor Expression in Early Parkinson’s Disease’ for publication in a Parkinson’s Journal.

In this paper, we provide evidence using Positron Emission Tomography that exercise leads to neuroplasticity in dopaminergic signaling and contributes to improved function in individuals with early PD (within one year of diagnosis).
 
Our data below demonstrates that in our subjects with PD, intensive exercise led to a 98% and 81% INCREASE in D2 receptor binding potential (BP) for Subject 1 (S1) and S2, respectively supporting an EXERCISE-INDUCED INCREASE IN THE D2 RECEPTOR EXPRESSION. In contrast, in our subjects with PD that did NOT undergo exercise there was either relatively no change (3% decrease in S3) or a decrease of 23% (S4) in D2 BP. Finally, in our healthy control subject (S5) there was a modest exercise-induced increase of 9% in BP.

Relevance to Parkinson’s disease:  The results of this study could have an immediate and substantial impact on the management of individuals with PD by demonstrating the need for exercise intervention to be prescribed immediately upon diagnosis. This is a critically important study that supports the possibility that intensive exercise may delay the need for dopamine replacement therapy given the fact that the signal of dopamine may be magnified by the increase of the dopamine D2 receptor itself. This published study would be a significant first step in revealing the potential for exercise in modifying disease.


Project Title:  The Role of Context-Specific Learning in Motor Skill Acquisition in Individuals with Parkinson’s Disease

Name of Organization:
University of Southern California

Investigators/Authors:
Principal Investigators: Beth E. Fisher, PhD, PT & Giselle M. Petzinger, MD

Investigators:
Ya-Yun Lee, MS, PT; Michael Jakowec, PhD; Carolee Winstein, PhD, PT.

Objective: 
To determine the affected brain areas associated with the set-shifting deficits seen in individuals with Parkinson’s disease (PD) and to determine whether set-shifting deficits leads to context-specific learning in PD.

September 2011 Project Update:

Results: During the past year, the main focus of this study was to develop a paradigm that enables us to test context-dependent learning in both people with and without Parkinson’s disease (PD). The most robust results were observed utilizing a paradigm that involved key press learning of 3 numerical sequences with both hands under a random practice schedule.

The participants were given a total of 324 trials (36 blocks of 9 trials) to practice the three sequences. Twenty-four hours after practice, the participants are asked to return to the lab and complete a retention test under two conditions: SAME and SWITCH conditions. The SAME condition is when the number sequence and the associated contexts are the same as what was practiced, while the SWITCH condition is when the original sequence-context associations are changed from those in the practice condition.

To date, 9 participants with PD and 8 healthy age and gender matched participants have completed the final version of the task.  An additional 52 subjects have been tested with various other forms of the paradigm. Our preliminary results show that while both PD and healthy participants are slower in executing the sequences during the SWITCH condition compared to the SAME condition, people with PD are much slower and made more errors than healthy individuals. This indicates that people with PD may have greater difficulty generalizing what they learned across different contexts when compared to healthy individuals. Using a correlation analysis to investigate the relationship between set-shifting ability (using a Trail Making Task, frontal lobe function) and the amount of context-dependency, we found a positive (r = 0. 67) relationship between set-shifting and context-dependency  in individuals with PD.  In the next year we plan to finish our recruitment for the study and prepare a manuscript for publication

Relevance to Parkinson’s disease:
Our study indicates that individuals with PD may have a greater dependency on context related cues for motor learning than individuals without PD.   This dependency may be related to frontal lobe changes observed in PD and emphasize its role in basal ganglia circuitry and motor function.   This study suggests that individuals with PD have difficulty “carrying over” or “translating” physical therapy practice in the gym to walking at home or outside because of PD related changes in the frontal lobe that are necessary for generalizing the benefits of their gait practice to different environments/surroundings.    These findings support the utility of compounds that facilitate frontal lobe function in combination with physical therapy that would train individuals with PD under a variety of contexts to restore motor function and quality of life.

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