Vestibulopathy, Imbalance, and Gait Disturbances in Parkinson Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: University of Michigan

 
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Study Title: Vestibulopathy, imbalance and gait disturbances in Parkinson disease 
PI: Fay Pongmala, PhD 
Study ID: HUM00192613 
NCT#: NCT05446194 
Protocol Version IRB Approval Date: 5/15/2025 

 
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Vestibulopathy, imbalance and gait disturbances in Parkinson disease 
Principal Investigator: Nicolaas Bohnen, MD, PhD and Fay Pongmala, PhD 
Funding Agency: VA - Rehabilitation R&D 
 
 
 
 

 
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Abstract 
 
Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by resting tremor, slowness of movement, rigidity 
as well as postural instability and gait difficulties (PIGD) motor features. Nigrostriatal dopaminergic denervation is a key pathological 
factor in PD. Advancing PD is associated with disabling PIGD motor features, in particular freezing of gait (FoG) (3, 4). Progressive 
Supranuclear Palsy (PSP) is a neurodegenerative disorder that is characterized by increased falls, postural instability, FOG, and 
vertical ocular motor dysfunction. FoG is an important trigger for falls and resulting in reduced functional abilities and that greatly 
affects quality of life in people with PD and PSP. This is further complicated by fear of falling resulting in pervasive sedentariness 
where avoidance of physical activity leads to deconditioning, thereby aggravating a downward functional spiral. Effective management 
of FoG represents an unmet clinical need (gap in clinical practice). The dopaminergic medication-refractory nature of PIGD motor 
features in advancing PD implicates non-dopaminergic brain pathologies.  
We have novel preliminary data showing that non-acute vestibulopathy may be another important factor contributing to PIGD motor 
features, in particular FoG in PD and PSP. Unlike sporadic intermittent vestibular disorders with a more acute onset, chronic bilateral 
vestibular dysfunction of older age (recently defined by the Bárány Society as presbyvestibulopathy, PVP) is also common in PD (5-7). 
Our preliminary data suggest that PVP may be a critical determinant of FoG in PD (scientific premise). Furthermore, we found that 
absence of PVP was associated with a very low frequency of FoG suggesting a specific effect of PVP on FoG in PD. However, these 
preliminary observations need to be confirmed in a larger study using more dedicated assessment methods (knowledge gap). Closing 
this gap is important because of the potentially high clinical translational impact if our preliminary findings can be verified. The 
overarching goal of this study is to test the hypothesis that the presence of PVP is an important risk factor for FoG in subjects with PD 
and PSP while accounting for nigrostriatal dopaminergic denervation.  
 
 
 

 
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Contents 
Protocol Title: ............................................................................................................................. 1 
1.0 
Study Personnel .............................................................................................................. 4 
2.0 
Introduction ..................................................................................................................... 4 
3.0 
Objectives ......................................................................................................................10 
4.0 
Study Procedures ...........................................................................................................10 
4.1 Study Design ...................................................................................................................10 
4.2 Recruitment Methods.......................................................................................................15 
4.3 Informed Consent Procedures ....................................................................................... 117 
4.4 Inclusion/Exclusion Criteria ...................................................................................... 117100 
4.5 Study Evaluations .......................................................................................................... 118 
4.6 Data Analysis ..................................................................................................................20 
4.7 Withdrawal of Subjects ....................................................................................................23 
5.0 
Reporting ........................................................................................................................23 
6.0 
Privacy and Confidentiality .............................................................................................23 
7.0 
Communication Plan ......................................................................................................24 
8.0 
References ...................................................................................................................25 
 

 
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Protocol Title:   
 
1.0 
Study Personnel 
 
Principal Investigators:  
University of Michigan: Fay Pongmala, PhD 734-998-8400 
Ann Arbor VA: Nicolaas Bohnen, MD, PhD 734-998-8400 
 
2.0 
Introduction 
 
i) Motor impairments, dopamine responsive and progression in PD: The hallmark pathology of PD is loss of dopamine in the striatum 
secondary to progressive degeneration of dopaminergic cells in the substantia nigra pars compacta, due to the formation of Lewy 
bodies (8). A variable combination of tremor, rigidity, and bradykinesia symptoms may present along with PIGD motor features. 
Because of primary involvement of the basal ganglia in PD, it has often been asserted that these motor features are mainly attributable 
to nigrostriatal dopaminergic losses. A study by Vu et al., however, showed that L-DOPA potency was lowest for PIGD motor features 
compared to other cardinal motor features in PD (4). In the Sydney Multicenter Study of PD, patients were followed for about two 
decades. Results of this study indicate that dopamine non-responsive problems dominate 15 years after initial assessments and 
include frequent falls occurring in 81% of patients (9). Similar findings were reported by López et al. after following de novo PD patients 
for 10 years (3). López et al. reported good responses to dopaminergic treatment in the first year with a progressive decline becoming 
more manifest after 3 years of treatment. Significant PIGD motor disabilities arose at 10 years in 71% of patients that were mainly 
caused by non-dopamine-responsive features, such as FoG (3). FoG is usually manifested as transient but abrupt cessation or 
reduced of leg movement during walking leading to episodic experience of being ‘frozen’ or ‘glued’ to the ground often resulting in 
falling. This phenomenon may occur during gait, gait initiation, or most frequently during turning. FoG and falls are major contributors to 
decreased quality of life and impaired functional abilities in people with PD(10-12). Dopaminergic medication-resistance of 

 
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parkinsonian PIGD motor features has been proposed to result from the extension of the degenerative process to extra-striatal regions 
(13).  
 
ii) Vestibular functions in PD and PSP: Appropriate postural control is essential for the coordinated control of locomotion. Peripheral 
sensory feedback from the vestibular, somatosensory (i.e., proprioception), and visual systems is centrally integrated and evaluated to 
prepare for an appropriate reactive motor response when postural instability may occur. There is increasing evidence that impaired 
integration of sensory feedback contributes to PIGD motor features in PD (14). Vestibular system function is multi-faceted and can be 
defined as the integration of both peripheral vestibular labyrinth and central vestibular system functions. For decades it has been 
speculated that PD is associated with dysfunction of the vestibular system (esp., given that postural instability is one of the major 
symptoms of this disorder) but clear evidence of such a connection has been slow to emerge (see Smith, 2018, for review (15)). 
Studies examining the specific contribution of vestibular sensory functions to PIGD motor features in PD are, however, inconsistent. 
For example, Reichert et al. carried out bithermal caloric tests and electronystagmography in PD patients and controls (16). Results 
showed that significantly more PD patients had reduced or absent vestibular responses than controls. Importantly, decreased or 
absent vestibular responses in patients with PD were associated with postural instability. More recent research by de Natale et al., 
found that vestibular-evoked myogenic potentials (VEMPs) were significantly altered in PD patients and with the severity of these 
alterations progressively increasing with disease severity (17, 18). These alterations in VEMPs were correlated with greater postural 
instability, suggesting that impaired vestibular activity may play an important role in postural instability in PD (17). However, there are 
also conflicting reports. For example, findings by Pastor et al. concluded that vestibular dysfunction could not clearly explain postural 
deficits in PD patients (19). A study by Chong et al. examined sensory processing function in PD patients and compared this to age-
matched normal controls (20). Results of their study suggested that there was no difference in sensory processing efficacy between 
these two groups. Results of their study also showed no difference in parameters of vestibulo-ocular (VOR) and optokinetic nystagmus 
(OKN) reflexes between the control and PD group. It should be noted, however, that key short-comings of the existing literature 
on the effects of vestibulopathy on motor impairments in PD is the absence of adjustment for the degree of nigrostriatal 
dopaminergic denervation, the key pathobiology in PD (knowledge gap). We propose to assess vestibular dysfunction as it 
relates to FoG in subjects with PD while taking into account the severity of nigrostriatal dopaminergic denervation. 
 
Disturbance of gaze is a distinct clinical feature in PSP which is often characterized by slower vertical saccades and an inability 
to utilize linear vestibular ocular reflex (tVOR) to determine distance (66-68). These clinical features of PSP negatively impact the 
ability to integrate visual stimuli which may contribute to postural instability (67). Loss of vestibular nuclei and impairment of central 
otolithic pathways inhibit tVOR, which in turn may explain postural instability and increased fall rates in PSP (67,68). Individuals with 
PSP experience higher fall rates and FOG rates compared to idiopathic PD (69). Rezvanian et al. found that 45.6% out of 349 PSP 
patients experience FOG further demonstrating the prevalence of FOG in PSP (69). Rezvanian et al. also distinguishes FOG is present 
during the early stages of PSP disease progression with severity increasing over time compared to PD (69). The research findings 
suggest that falls and FOG are clinically significant features of PSP which may require targeted treatment options.  
Age-associated vestibular impairment is a significant contributor to imbalance and falls in older US adults. Unlike sporadic intermittent 
vestibular disorders with a more acute onset, chronic bilateral vestibular dysfunction of older age is common in the elderly (recently defined 
by the Bárány Society as presbyvestibulopathy, PVP).  For example, about 50% of community-dwelling older adults were found to have 
evidence of PVP resulting in higher risk of imbalance and gait disturbances (1). Even older individuals without a history of dizziness but who 

 
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had abnormal findings on the clinical PVP test (i.e., the modified Romberg test, a postural control test with sensory conflict) also had 
significantly increased risk of falling (21). This suggests that the age-associated sub-clinical vestibular dysfunction is clinically relevant. PD 
predominantly affects the older population and, expectedly, more chronic bilateral vestibular dysfunction of older age is also 
common in PD (5-7) and lack of PVP assessment in controls may explain some of the inconsistencies in studies of vestibular 
differences between PD and older controls. Although the prior literature has been inconclusive about group differences in the 
frequency of vestibular changes between PD and older non-PD adults (see (15) for review), the possibility of intrinsic PD-related 
vestibular changes exists. However, if these may be present these would further augment the effects of age-associated vestibulopathy 
and thereby lower the symptomatic threshold for symptomatic presentation. Therefore, any presence of PD-specific vestibular changes 
beyond age-associated changes would further emphasize the potential therapeutic importance of pursuing vestibular rehabilitation 
strategies in the PD population suffering from treatment-refractory PIGD motor features. 
 
iii) Vestibular sensory processing changes in FoG in PD: The inability to integrate postural sensory inputs may play a role in the 
pathophysiology of FoG (22). For example, FoG can be provoked under sensory conflict situations that challenges postural control but 
can also be alleviated by various sensory cues (23). Prior studies using postural sensory conflict tasks, such as the sensory 
organization test, have demonstrated that postural sensory deficits involving specific sensory modalities are strongly associated with 
FoG in PD and PSP (24).  A common example is visual sensory processing where providing visual cues may help to attenuate freezing 
motor behaviors (23). However, there is limited literature on vestibular sensory processing in FoG (25). A recent study using a sensory 
conflict testing paradigm found that PD freezers had greater difficulties processing vestibular sensory information than non-freezers 
(24).  Importantly, relative effects of vestibular processing were greater than visual and somatosensory effects. These data 
show that the inability to integrate vestibular information may be highly relevant for PD patients with PIGD motor features. Vestibular 
feedback becomes even more critical when initiating walking or turning (26). Gait initiation and turning are motor activities where visual 
and somatosensory feedback becomes more unreliable and thereby resulting in higher reliance on effective vestibular processing for 
postural control (27). This is also consistent with the clinical observations that gait initiation and turning are well-known risk factors for 
FoG and consequently these triggers are used clinically to provoke motor freezing (23). Assessment of postural vestibular sensory 
deficits in PDpatients with FoG may provide a better understanding of pathomechanisms of FoG and may accurately identify 
suitable patients for rehabilitative interventions.  
 
 
  
INNOVATION 
Our approach and subject cohort are unique in several ways by investigating new concepts. First, there are no prior published studies 
of vestibular dysfunction in PD that have also assessed the degree of dopaminergic nigrostriatal denervation with in vivo dopaminergic 
nerve terminal brain PET or SPECT imaging. Second, there are no published studies on the relationship between PVP and FoG in PD.  
 
SIGNIFICANCE 
The significance of this project is that it addresses an unmet need in clinical practice, i.e. there is currently no effective treatment for 
FoG in advancing PD or in PSP. Our preliminary data suggest that PVP may be a critical determinant of FoG. Assessment of postural 

 
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vestibular sensory deficits in PD patients with FoG and patients with PSP may provide a better understanding of pathomechanisms of 
FoG that may inform therapeutic management.  
IMPACT & FUTURE DIRECTIONS 
New knowledge from this project may provide important clues about the pathophysiology of motor freezing behaviors and associated 
risk of falls in PD. Such clues may inform novel therapeutic interventions for this unmet clinical need. Falls and postural instability are a 
major clinical dilemma in patients with PD. These issues get progressively worse and more difficult to treat as the disease progresses. 
New therapies to reduce FoG and imbalance in patients with PD and PSP may reduce fall risk and drastically improve functional 
abilities and quality of life of these patients. 
Preliminary Studies 
We present novel preliminary findings of a significant association between presence of FoG and PVP clinical status and evidence of an 
independent relationship between abnormal VOR function, PIGD motor features and postural control that cannot be explained by other 
PD specific features such as bradykinesia or rigidity.  
i) Association between clinical presence of FoG and PVP in persons with PD. We investigated the relationship between the 
clinical presence of FoG and PVP in persons with PD. Methods: 92 patients with PD (M70/F22; mean age 67.67.4 years, mean motor 
disease duration 6.0±4.6 years, mean Hoehn and Yahr stage 2.40.6) completed detailed clinical assessment. FoG status was defined 
by direct observation of motor freezing behavior by an experienced neurologist while performing the UPDRS motor examination. 
Clinical screening for PVP was performed using the modified Romberg sensory conflict test (1). A time to fall < 20 seconds while 
standing on foam surface with eyes closed was used for the presence of PVP as previously reported (1), and validated in a prior study 
of patients with vestibular disorders (34). Our findings showed a substantially higher frequency of FoG in PD persons with PVP 
(33%) compared to PD persons without PVP (3.3%; Likelihood ratio χ2=15.6; P<0.0001), see table 1. Furthermore, PVP was 
present in the majority (84.6%) of PD persons with FoG.  
[11C]DTBZ dopaminergic brain PET imaging was available in 29 patients. Logistic regression analysis of this subset showed that the 
PVP effect remained highly significant (Likelihood ratio χ2=10.3; P=0.0013) independent from the degree of nigrostriatal 
dopaminergic losses. Similar independent significant effects for the PVP effect (Likelihood ratio χ2=7.1; P=0.0070) was seen when 
adjusting the model for effects of age or the severity of parkinsonian motor impairments. These preliminary data suggest that PVP may 
be an important factor contributing to FoG independent of the degree of disease-specific confounders.  
 
 
 
Table 1. Contingency table of FoG vs. clinical PVP status in PD 
(Likelihood ratio χ2=15.6; P<0.0001) 

 
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No PVP 
PVP 
Total 
No FoG 
57 
22 
79 
FoG 
2* 
11** 
13 
Total 
59 
33 
92 
 
 
 
 
*FoG was present in 3.3% in PD persons without PVP 
 
 
 
 
**PVP was present in 84.6% of PD freezers 
 
ii) VOR and PIGD features in PD and PSP. VOR was assessed in 29 PD patients (9 female, 67.8 ± 6.9 years of age, 5.9 ± 3.2 years 
of motor disease duration) using the active head rotation (AHR) protocol of the VORTEQ™ module of the VisualEyes™ VNG system. 
The two main outcome parameters were gain (ratio of slow component eye velocity and head velocity) and phase (offset in eye 
movement time relative to the head movement). All subjects underwent the MDS-UPDRS clinical examination for assessing PD 
severity. Separate sub-scores were calculated for PIGD, bradykinesia, tremor, and rigidity features. We dichotomized phase into 
“normal” and “abnormal”, with -5° ≤ normal phase ≤ 5°. PIGD sub-score was dichotomized into “low” and “high” based on a median 
split (score of 6). Chi-square analysis was performed to test for difference in proportion normal/abnormal phase between the two PIGD 
groups (see Table 2). Near significant analysis (2=3.1, p=0.077) showed that there were disproportionally more PD subjects with 
abnormal VOR phase in the group with high PIGD sub-scores (see also Figure 1).  
Linear VOR has been assessed in PSP to determine whether abnormal VOR contributes to frequent falls. Liao et al. analyzed linear 
VOR in 9 individuals with PSP and 9 age-matched controls (66). The findings revealed individuals with PSP were unable to utilize 
linear VOR to adjust vergence on near objects. In the same study, VEMPs were measured from 10 PSP participants, which revealed 
decreased VEMP responses, suggesting abnormalities in otolith-spinal reflexes. The research suggests that a combination of 
abnormal linear VOR and otolith-spinal reflexes may contribute to increased falls and PIGD symptoms.   
 
Table 2. Contingency table for the dichotomized PIGD sub-
score (“low” and “high”) and “normal” and “abnormal” 
VOR phase 
 
Figure 1. Scatterplot of VOR phase versus MDS-UPDRS 
PIGD sub-score. PD patients with “abnormal” phase (≤ -5° 
or ≥ 5°) and “high” PIGD sub-score are in solid black dots. 
Subjects within the boundaries of the two vertical lines 
(around phase 0°) have a normal phase. Subjects above 
the horizontal line (median PIGD sub-score split) have high 

 
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PGD sub-scores. 
 
 
 
We performed additional binary logistic regression to examine whether other PD motor features such as bradykinesia or rigidity or any 
other parkinsonian motor feature as captured by the total motor disease duration variable had a confounding effect on VOR phase. The 
near significant model (2=9.3, p=0.053) showed independent prediction of VOR phase for the PIGD sub-score (Wald = 4.6, p = 0.032), 
while controlling for bradykinesia, rigidity, or motor disease duration (all n.s.). These preliminary findings provide supportive 
evidence that abnormal VOR phase is associated with PIGD features in PD and cannot be explained by other features such as 
overall slowness of movement (bradykinesia) or rigidity (e.g. stiffness of the neck musculature). 
 
 

 
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iii) VOR and biomechanical parameters of posture. In an exploratory manner 
we correlated the VOR parameters and biomechanical parameters of posture. 
Biomechanical data was available for a subgroup (n=17) of the same PD subjects 
described above. Posture was assessed using 6 OPAL accelerometer sensors (APDM Mobility Lab) during normal stance with eyes 
open. Results showed that VOR gain correlated in a linear fashion with sway velocity (Spearman r = -0.587, p = .013), a measure of 
overall sway (Figure 2). We performed post-hoc linear regression analysis to examine the independent prediction of VOR gain on 
sway velocity while accounting for bradykinesia, rigidity and total motor disease duration. Near significant regression (F(4,12) = 2.50, 
p=0.098) showed significant effect of VOR gain on (t=-3.0, p=0.011) sway velocity, however, not of bradykinesia, rigidity, or disease 
duration. These preliminary findings provide supportive evidence that there is an independent relationship between VOR and 
postural control that cannot be explained by other PD specific features such as bradykinesia or rigidity. 
3.0 
Objectives 
 
Specific Aim: To perform detailed clinical assessments and dopamine transporter (DAT) [11C]PE2I brain PET imaging in subjects with 
PD.  
Hypothesis: The prevalence of FoG is higher in subjects with PD and PSP who also have evidence of PVP compared to those without 
PVP independent of nigrostriatal dopaminergic losses. 
Exploratory Aim: To complete follow-up assessment with PD subjects to determine whether vestibular dysfunction is progressive in 
PD. 
Exploratory hypothesis: Follow-up assessments will demonstrate progressive vestibular dysfunction in PD subjects. 
Long-term goals: Finding will help to answer the current knowledge gap regarding whether vestibular dysfunction is progressive in this 
population. This is relevant as it may inform future treatments for people with PD and PIGD motor features. 
4.0 
Study Procedures 
 
4.1 Study Design 
Figure 2. Scatterplot of VOR gain versus sway velocity 
during quiet stance with eyes open. 

 
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Approach: The overarching goal of this study is to test the hypothesis that the presence of PVP is an important risk factor for FoG in 
subjects with PD and PSP while accounting for nigrostriatal dopaminergic denervation. For the main aim of the study, subjects with PD 
(gross recruitment n=64) and PSP (n= up to 20) will undergo brain DAT PET and MR imaging, followed by a baseline clinical test day. 
All participants will complete a 6-month prospective fall diary. PD subjects will be asked to return for optional visits at 3 years (±1 year) 
from their last visit and again 2 years (±1 year) after the previous follow-up for a limited test battery.  
Design & subjects: Our main aim will be a cross-sectional study in 84 subjects (gross recruitment) with 64 subjects with a  PD 
diagnosis following the UK Parkinson's Disease Society Brain Bank Research Center (UKPDSBRC) criteria (35) and presence of 
abnormal striatal denervation pattern on DAT PET scan and up to 20 subjects with a PSP diagnosis following the Movement Disorder 
Society Revised 2017 diagnostic criteria for PSP across a spectrum of severity of disease (modified Hoehn & Yahr stages 1-4) (69). 
Participants meeting the diagnostic criteria for probable PSP, as determined by a clinician, will be eligible. Our second exploratory aim will 
be to complete follow-up assessments to explore the progressive nature of vestibular dysfunction. PD subjects that previously 
participated in the study will be asked to return for a limited test battery at 3 years (± 1 year) from their last visit. A second follow-up 
visit for this exploratory aim will occur 2 years (± 1 year) from the previous visit. 
 
General methods 
After obtaining informed consent and screening for study eligibility, study participants will undergo DAT PET and MRI imaging, followed 
by a baseline clinical evaluation day. The clinical testing will consist of a clinical test battery (see table 3 below). The motor component 
of the test battery will be performed in the dopaminergic medication 'off' state in the morning after overnight withholding of their 
dopaminergic medications.  The remainder of the test battery will be performed in the medication 'on' state. Qualified personnel who 
have been trained in the use of the instruments and have undergone inter-rater reliability evaluations will perform the assessments. 
The DAT PET study will also be performed in the dopaminergic medication 'off' state in the morning. 
 
Table 3: Components of the clinical test battery 
Limited motor test battery* 
Main outcome parameter: 
Administration 
time: 
Parkinsonian ratings: Movement Disorder Society-revised Unified PD Rating 
Scale (MDS-UPDRS) (36) 
UPDRS parkinsonian PIGD motor 
sub-score 
15 min 

 
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FoG: Freezing of gait clinical provocation protocol (37) 
Examiner-based FoG assessment 
15 min 
Clinical PVP test: Modified Romberg test (1)* 
Clinical PVP: Modified Romberg test (1) (ON) 
Time to fall < 20 seconds when 
standing on foam with eyes 
closed (For participants taking 
oral dopamine replacement 
therapies, will be done both OFF 
and ON dopaminergic 
medication) 
10 min 
[Optional[ APDM sensor-based walking and postural tests (iTUG, iWalk, 
iSAW, iSWAY)) 
Sensor-based outcomes 
15 min 
(Optional) Mini-BESTtest  dynamic balance test 
Total scores 
15 min 
 
 
Total motor:  
35-65 min 
Non-motor tests 
 
 
Ankle sensation: Biothesiometer (Bio-Medical Instrument Co., Newbury, 
OH, USA) (38). 
Vibration perception threshold at 
the medial malleoli 
5 min 
Motion Sickness Susceptibility Questionnaire  
Total score 10 items  
10 minutes  
FoG rating: New Freezing of Gait Questionnaire (NFOG-Q) (39). 
Sum of part II & III questions 
5 min 
Cognition: The PD Cognitive Rating Scale (40). 
Total PDCRS score 
20 min 
Function: The PD Cognitive Functional Rating Scale (41) 
Total PDCFRS score 
10 min 
Quality of life scale: Short Form 36 health survey questionnaire: SF-36 (42) 
Total SF-36 scores 
10 min 
Dizziness & vertigo: Dizziness Handicap Inventory (43), Vertigo Symptom 
Scale (44)  
Total score (25 items) 
8-10 min 
Vestibular testing: Video head impulse test, OVRT-C *, rotary chair, calorics 
Bárány Society diagnostic criteria 
45 min  

 
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for PVP (45) 
 
 
Total non-
motor: 105 min 
Measures to be collected at home by the participants 
 
 
Fall diary (6 months)  
 
 
Number of falls during 6 months  
mail with 
biweekly 
monitoring 
phone call 
 
 
Total: 155 min 
*Will be performed in the dopaminergic medication 'off' state 
General clinical assessment: Clinical assessment will consist of a general medical and neurological examination, the measurement of 
visual acuity, orthostatic vital signs, general hearing assessment, weight and height in all subjects. General clinical information, such as 
duration of disease, age of onset, and medication use will be recorded. L-DOPA equivalent dose (LED) of dopaminergic medications 
will be calculated (51). We will use the Dizziness Handicap Inventory and Vertigo Symptom Scale to assess self-perceived handicap as 
a result of vestibular system disease (43, 44). 
 
Determination of imbalance and FoG status: Imbalance will be defined as abnormal performance on the retropulsion test, presence of 
falls or FoG or subjective loss of balance functions. FoG classification will be based on the New Freezing of Gait Questionnaire, 
NFOG-Q (39) and/or direct observation of obvious FoG episode with ineffective stepping (52) by experienced clinicians during the 
Snijders et al. FoG provocation protocol. For example, non-FoG PD subjects (based on the NFOG-Q) who show specific evidence of 
FoG during the FoG provocation protocol will be reclassified as FoG (37). The gait assessment will be videotaped and FoG episodes 
will be scored by an unaffiliated VA movement disorders neurologist for blinded clinical judgment.  
 
Presbyvestibulopathy (PVP) status assessment: Clinical testing for PVP will be performed using the modified Romberg test (1, 53). 
The modified Romberg Test is designed to test vestibular function exclusively where participants have to maintain balance on a foam-
padded surface (to obscure proprioceptive input) with their eyes closed (to eliminate visual input). A time to fall < 20 seconds while 
standing on foam surface with eyes closed will be defined as clinical evidence of PVP (1), as previously validated in a prior study of 
patients with vestibular disorders (34). The modified Romberg test is similar to the Sensory Organization Test (SOT) where falls on the 
modified Romberg test corresponds to falls on the SOT5 subtest, which has been found to have high sensitivity (80%) and high 
specificity (80%) to diagnose a vestibular disorder (54).  
 

 
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Fall assessment: All subjects will participate in a prospective study assessing the risk of (near-) falls over a 6-month fall diary study. 
We will define a fall according to ICD criteria (ICD 9: E880A-E889A) as an unexpected event where a person falls to the ground from 
an upper level or the same level. We will define a near-fall as an occasion on which an individual felt that they were going to fall but did 
not actually fall (55). Falls and near-falls during follow-up will be ascertained with a set of monthly fall diaries, where subjects will be 
asked to fill out incidents of (near-) falls each week and document the circumstances (esp. indoor vs. outdoor and turn or not turn 
related) and consequences using standardized scoring forms (56).  Monthly calendars will be returned by mail at the end of each 
month. Subjects will be called every 2 weeks to maintain compliance.  
 
Dedicated vestibular testing: This will be based on evaluation of VOR based on a) air or water caloric irrigator (Air Fx (AFX), Aquastim, 
Micromedical Technologies, Inc. Chatham, IL), b) rotary chair (System 2000, Micromedical Technologies, Inc. Chatham, IL), and c) 
Video Head Impulse Testing (VORTEQ, Micromedical Technologies, Inc. Chatham, IL). All eye movements will be recorded with the 
VisualEyes Video Nystagmograph system (Micromedical Technologies, Inc. Chatham, IL). This device has lightweight high-speed 
binocular video goggles (110Hz) that allow for analysis of VOR in addition to pursuit tracking, saccade and optokinetic oculomotor 
tests. Vestibular response will be assessed utilizing patterns of oculomotor, vestibular, reaction time and cognitive (OVRT-C) functions 
in patients with PD and PSP. Participants will use a non-invasive FDA-cleared device, the Neurolign Dx 100, which will administer an 
OVRT-C test battery to evaluate visual and neurological deficits in patients with PD. Subjects with excessive earwax build up will be 
referred to their primary care physician for removal of the earwax prior to assessment. Our neuro-otology co-investigator Dr. Kevin 
Kerber will be in charge of the vestibular testing protocol.  
Magnetic resonance imaging (MRI) will be performed on a 3 Tesla Philips Achieva system (Philips, Best, The Netherlands). A 3D 
inversion recovery-prepared turbo-field-echo was performed in the sagittal plane using TR/TE/TI=9.8/4.6/1041ms; turbo factor=200; 
single average; FOV=240x200x160mm; acquired Matrix = 240x200x160 slices and reconstructed to 1mm isotropic resolution.  
 
PET imaging will be performed in 3D imaging mode on a Biograph 6 TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., 
Knoxville, TN), which acquire 63 transaxial slices (slice thickness: 2.4 mm) over a 15.2 cm axial field-of-view. Images were corrected 
for scatter and motion.  Subjects will be scanned in the dopaminergic medication 'off' state. [11C]PE2I will be prepared as described 
previously (50). 
[11C]PE2I PET imaging will be obtained using a 70-min dynamic imaging acquisition following a 15 mCi i.v.  tracer injection. [11C]PE2I 
PET imaging will be analyzed using a Logan plot and using the cerebellar hemisphere as reference region.  
The PET imaging frames will be spatially coregistered within subjects with a rigid-body transformation to reduce the effects of subject 
motion during the imaging session (57). Statistical parametric mapping (SPM) software (SPM12; Wellcome Trust Centre for 
Neuroimaging, University College, London, England will be used for PET-MRI registration using the cropped T1-weighted MR 
volumetric scan. Freesurfer software will be used to define cortical and subcortical MR gray volumes-of-interest (VOI).  

 
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MRI-based PET partial volume correction: We will use the Müller-Gärtner partial volume correction technique, which is based on the 
assumption that white matter uptake is homogeneous and uses gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) to 
correct the partial volume effect in GM tissues (58). Using the segmented images and the assumed PET resolution, the method 
calculates the spill-out from WM to GM and subsequently subtracts it from the GM. Similarly, it also calculates the spill-out from the GM 
to the surrounding tissues and compensates for the difference to the GM. The result is a grey matter image with corrected activity 
values in all voxels.  
 
4.2 Recruitment Methods 
 
PD subjects will be recruited from the University of Michigan (U-M) Movement Disorder Center (MDC), which follows a population of 
about 2,000 clinically well-defined patients with PD. An additional source of subjects will be the VAAAHS Movement Disorders Clinic 
(directed by Dr. Bohnen). This clinic follows over 240 Veterans with idiopathic PD and this clinic serves as a tertiary referral center for 
more advanced PD subjects coming from the tri-state area (MI, north-western Ohio and eastern Indiana) resulting in a larger than 
average referral of new patients.  PD and PSP subjects from previous studies who have indicated interest (initials in informed consent 
form) in new studies at our laboratory will also be contacted. In case of unforeseen need, additional recruitment of subjects is possible 
via local Parkinson support groups and the Michigan Parkinson Foundation. Data Direct (https://datadirect.med.umich.edu/) will be 
used to recruit patients at Michigan Medicine to be study participants. A flyer will also be used to recruit subjects. 
 
Screening script: Screening script will be used if subjects do not wish to discuss the study further with a staff member or consent to the 
study in the clinic. In the past, subjects have expressed interest and discussed the study with staff members. However, they don't want 
to consent at that time and wish to go home and think about it. Study team members will follow-up with these subjects and use the 
screening script before subject comes in, to prevent wasted travel and time of the subject. Also, subjects recruited via other methods 
will be screened using the screening script. 
 
Timetable: The main study, to be conducted over a 4-year period, will include a gross total of n=64 patients with PD (allowing for a net 
recruitment of n=56 given possible attrition (10-12%)), due to imaging claustrophobia, unexpected brain imaging findings etc. 16 
subjects will be enrolled annually. Up to 20 PSP participants will be enrolled over the 4-year period to participate The study will 
continue after the main study portion is complete to allow for the collection of limited follow-up data at 3 years (±1 year) from last study 
visit and then again at 2 years (±1 year) post the previous follow-up visit.  
 
Compensation: Subjects will not be charged for their participation in this study. Subjects will receive $100 for the completed 
PET scan and $100 for the MRI scan. Payment for completion of the Screening/Baseline Visit will be $200. Subjects that 
participate in the additional optional follow-ups for the exploratory aim will receive $25 for each follow-up visit. Subjects will be 

 
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financially compensated for lost time and effort. We estimate that about 2/3 of PD/PSP patients will also need one night of 
overnight lodging to accommodate for “off state” requirements. Cost for overnight lodging and meals are estimated at $280 per 
night (3 nights per person). Subjects will receive a voucher for valet parking at the University Hospital. Parking at Domino's 
Farms is free. Subjects will be paid after their last study visit or, in case they decide to withdraw from the study, they will be paid 
for the parts that they have completed.  
 
4.3 Informed Consent Procedures 
Prior to any research procedures, IRB-approved written informed consent will be obtained from each subject followed 
by initial study eligibility screening. A study team member will obtain consent in a private location at the Functional 
Neuroimaging, Cognitive, and Mobility Lab, or Ann Arbor VA Movement disorders clinic. Remote electronic consent 
may be obtained using SignNow to reduce physical interaction between study staff and subjects. 
 
4.4 Inclusion/Exclusion Criteria 
Eligibility criteria:  
1. Diagnosis: 
• PD based on the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Research 
Criteria (n=64, gross; M/F, age 45 years or older), with duration of disease > 5 years and/or Hoehn & 
Yahr stages 1.5-4 and able to ambulate independently.  
• PSP following the Movement Disorder Society Revised 2017 diagnostic criteria for PSP across a 
spectrum of severity of disease (modified Hoehn & Yahr stages 1-4) (n=up to 20). PSP diagnosis will 
be verified by a clinician using the PSP-RS and other clinical information collected from the medical 
history. Participants meeting the diagnostic criteria for probable PSP, as determined by a clinician, will 
be eligible. (Investigator discretion). 
2. Dementia will be excluded by cognitive screening assessment and assessment of instrumental activities of 
daily living (PDCFRS). 
 
Exclusion criteria:  

 
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1. History of Meniere disease or recent onset of acute vestibular dysfunction, such as otolith disorders (BBPV etc).  
2. Other disorders which may resemble PD, vascular dementia, normal pressure hydrocephalus, multiple system 
atrophy (MSA), corticobasal ganglionic degeneration, or toxic causes of parkinsonism. Prototypical cases have 
distinctive clinical profiles, like early and severe dysautonomia (MSA) or appendicular apraxia, which may 
differentiate them from idiopathic PD and PSP. The use of the UKPDSBRC clinical diagnostic criteria for PD will 
mitigate the inclusion of subjects with atypical parkinsonism.   
3. Evidence of a stroke or mass lesion on structural brain imaging (MRI). 
4. Participants in whom MRI is contraindicated including, but not limited to, those with a pacemaker, presence of 
metallic fragments near the eyes or spinal cord, or cochlear implant. 
5. Severe claustrophobia precluding MR or PET imaging. 
6. Subjects limited by participation in research procedures involving ionizing radiation. 
7. Pregnancy (test within 48 hours of each PET session) or breastfeeding. 
8. Subjects with active and unstable mood or anxiety disorders 
9. Subjects with active ear infections or perforated eardrums 
 
4.5 Study Evaluations 
 
Table 4. Clinical test protocol for Participants: 
 
Screening 
Imaging 
Follow-up #1- OPTIONAL4 
Follow-up #2- OPTIONAL 4 
Visit No. 1 
V1 
V1 
V2 
V3 

 
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Visit description 
SCR 1  
OFF state for motor testing 
 
Imaging 
OFF state for PET 
 
Optional 3 years (±1 year) 
follow up 
Optional 2 year (±1 year) 
after follow-up #1 
Informed 
Consent 
X 
 
 
 
DAT PET2 
 
X 
 
 
MRI2 
 
X 
 
 
Demography 
X 
 
X* 
X* 
Medical History 
X 
 
X* 
X* 
MRI Screening 
Q. 
X 
 
 
 
PD/PSP History 
X 
 
 
 
Incl/Excl 
X 
 
 
 
Physical Exam3 
X 
 
X 
X 
Motor Testing/ 
UPDRS Pt III 
(dopaminergic 
medication 'OFF' 
state) 
X 
 
X 
X 

 
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UPDRS Pt I, II, IV 
X 
 
X 
X 
Modified Hoehn 
and Yahr (OFF) 
X 
 
 
 
Modified 
Romberg Test 
(OFF) 
X 
 
 
 
Modified 
Romberg Test 
(ON) (For 
individuals on 
dopaminergic 
medications) 
X 
 
 
 
Freezing of Gait 
Provocation 
Protocol (FOG) 
(OFF) 
X 
 
 
 
Optional: Postural 
Photograph 
X 
 
 
 
Optional: 
MiniBESTest (OFF) 
X 
 
X 
X 
APDM iTUG, 
iWalk, iSAW, 
iSWAY) (OFF) 
X 
 
 
 
Biothesiometer 
X 
 
 
 

 
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New-FOGQ 
X 
 
 
 
Short Form 36 
health survey 
questionnaire: 
SF-36 
X 
 
 
 
Motion Sickness 
Susceptibility 
Questionnaire 
X 
 
 
 
PD-CFRS 
X 
 
 
 
PD-CRS 
X 
 
 
 
DEXA Scan 
 
 
 
 
Dizziness 
Handicap 
Inventory 
X 
 
 
 
Vertigo 
Symptom Scale 
X 
 
 
 
VHIT vestibular 
testing 
X 
 
 
 
Oculovestibular/
Rotary Chair 
vestibular 
testing 
X 
 
 
 

 
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Caloric 
vestibular 
testing 
X 
 
 
 
OVRT-C 
Neurolign (OFF) 
X 
 
X 
X 
Ear exam 
X 
 
 
 
6-months Fall 
Diary 
X 
 
 
 
 
 
Foot notes 
1 order of assessments is flexible as long as “on” and “off” state requirement for assessments for each visit are followed. 
2 PET scan and MRI are considered part of V1 and can be done in any order with other assessments after informed consent is 
obtained. 
3 Physical Exam can be brief or focused on neurological (MDS-UPDRS Part III) depending on clinician’s determination, patient 
symptoms, and medical history. 
4The visit and/or individual test components are optional. 
*Abbreviated medical history and demographics forms will be used to assess changes since participants last study visit. 
Assessments that are unable to be obtained during visits will not be deemed protocol deviations unless they affect the data 
integrity/validity of the study. 
 

 
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4.6 Data Analysis 
 
Primary outcome measures and scientific rigor: Our primary outcome measure for Hypothesis 1 will be the New Freezing of Gait 
Questionnaire (NFOG-Q) (39).  The NFOG-Q is the current gold standard for assessment of FoG in PD research and clinical trials (46-
48). The diagnosis of PVP will be based on abnormal performance on the modified Romberg test (1). The modified Romberg test has 
high test-retest interrater reliability (each R=0.99) and has been validated in patients with vestibulopathy (34). The [11C]PE2I PET 
radioligand has the highest affinity and selectivity among DAT PET ligands that are currently in human use (49, 50).   
We propose to test the overall hypothesis that the prevalence of FoG is higher in subjects with PD and PSP who also have evidence of 
PVP compared to those without vestibulopathy independent of nigrostriatal dopaminergic losses. We will begin by calculating summary 
statistics (mean, median, SD, range, etc.) as well as plots of all data. This will allow us to examine the distribution of the data to ensure 
that assumptions of statistical models will be respected. All analysis will be performed using the R statistical software package. We 
predict that the prevalence of freezers will be higher in the PVP group compared to the non-PVP group. We will recruit a PD population 
enriched for the presence of FoG by requiring at motor disease duration of at least 5 years and exclude participants with early-stage 
Hoehn & Yahr disease. Given the prevalence of FoG in about 50% of patients in this group we expect to recruit about even groups of 
freezers and non-freezers. Our preliminary data showed that PVP was present in p1= 84.6% of PD freezers and p2=27.8% in non-
freezers. Given our net recruitment target of n=56 (half of whom will be freezers) PVP will be present in just over half of the total study 
population (56.2%). We plan to build a predictive model, such as logistic or probit, that links the binary FoG response to PVP (a binary 
variable) and the DAT PET scan (linear variable). Power is set at 0.8 with a significance level of 0.05 and the rejection region is one 
sided: p1 > p2. Sample size for PD is estimated based on preliminary data that yield estimates for p1 and p2 (as outlined above), and 
using the R-module statmod and calling the function power.fisher.test which simulates data sets – in our case we set its parameter 
nsim=1000 data sets -- to generate required sample sizes for given power and including the dopamine PET scan preliminary 
findings.  We will recruit up to 20 PSP participants to ensure an adequate sample size is used and to account for possible attrition.  
Specifically, we used the R command > power.fisher.test(.7,.3,24,24,nsim=1000,alternative="greater"), yielding a power .82 or greater. 
[Note n1=n2=24 is a conservative estimate in the sense that 0.7 - 0.3 < 0.84 - 0.28 (obtained in our preliminary data), and in that 0.7 
and 0.3 are symmetrically placed around 0.5]. Given these parameters and power simulations, the study requires a minimum sample of 
n=48 participants (about half freezers and half non-freezers) to achieve the stated goals, which is well within our recruitment target.  
If we find a significant association between the presence of PVP and FoG then we will perform a post-hoc confounder variables 
analysis using parkinsonian motor severity, cognition, age, gender, dizziness ratings or ankle sensation variables to investigate the 

 
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specificity of the main result in both the PD and PSP subjects. As FoG is an important risk factor for falls we will also evaluate whether 
the presence of FoG at baseline may predict subsequent fall risk prospectively in a secondary analysis.   
Missing data. Multiple imputation vs. single imputation via the mean, addresses the uncertainty in the missing values  
Pitfalls, problems and alternative strategies 
 
Possible scenario of falsification of primary hypothesis: If we fail to verify our primary hypotheses that vestibular dysfunction is a key 
determinant of FoG this would not preclude the possibility that a vestibular intervention may help to alleviate this mobility disturbance. 
For example, vestibular cerebellar compensation may play a role in PD to attenuate the effects of dopaminergic denervation on motor 
impairments, including gait functions (60, 61).  Furthermore, prior vestibular stimulation studies have found physiological effects across 
different brain regions, including the brainstem and basal ganglia (62, 63) that are relevant for PD pathophysiology. The recently 
published portable TNMTM intervention study also found positive clinical treatment effects in PD patients despite absence of screening 
for vestibulopathy in PD patients (64). 
 
Ineligibility and attrition rate: During the eligibility screening and course of the study we anticipate overall subject combined exclusion 
and attrition rate of approximately 10-15% (gross target n=64 and net target n=56). This is based on a typical 5% exclusion rate as the 
DAT PET scan may not confirm the diagnosis of idiopathic PD, either on absence of nigrostriatal denervation or evidence of atypical 
parkinsonism such as multiple system atrophy (MSA) based on the inspection of the PET post-injection K1 flow delivery images. There 
is also a small risk of withdrawal of subjects due to claustrophobia for the scanner despite appropriate pre-imaging screening and 
instructions. We will keep close documentation to register any missing data points, drop-outs and reasons for it. 
 
Medication use: Changes in dopaminergic medication use will be monitored throughout the study for post-hoc analysis when needed. 
 
Milestones of success:  
• 
IRB approval during the first 2 months of year 1.  
• 
A recruitment and completion target of 16 participants per year for the main aim 
• 
Interim data processing and analysis on a yearly basis to identify and correct potential dilemma early in the course of the study. 
 
The PI and the study coordinator will be in charge of the day-to-day operations of the study, oversee recruitment and monitor study 
completion to ensure successful accomplishment of the key milestones of this project.  
 
4.7 Withdrawal of Subjects 
 

 
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Subjects can withdraw their participation in this protocol at any time. 
5.0 
Reporting 
 
Ann Arbor VA IRB standard reporting guidelines will be followed.  
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in participants, users, or other persons, whether or not related to the study AEs 
will be collected starting from the time the participant signs informed consent until their participation is completed.  
A Serious Adverse Event (SAE) is an AE that has 
• 
Led to death, 
• 
Led to serious deterioration in the health of the participant, that either resulted in 
1.A life-threatening illness or injury, or 
2.A permanent impairment of a body structure or a body function, or 
3.In-patient or prolonged hospitalization, or 
4.Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure 
or a body function, 
• 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
All AEs will be recorded in the participants’ source documentation. For all AEs, sufficient information will be obtained as to 1) 
determine the severity of the event; 2) assess the casual relationship between the adverse event and the study; and 3) 
determine the outcome of the event. AEs will be followed until the event (or its sequelae) resolves or stabilizes at a level 
acceptable to the investigator. 
 
The investigator will promptly review documented AEs to determine 1) if there is a reasonable possibility that the adverse event 
was caused by the study and 2) if the adverse event meets the criteria for “serious.” If the investigator’s final determination of 
causality is “possible or probable relationship to the study,” the adverse effect will be classified as associated with the study for 
reporting purposes. If the investigator’s final determination of causality is “not related to the study,” this determination and the 
rationale for the determination will be documented. 

 
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6.0 
Privacy and Confidentiality 
 
All data collected under this research protocol will be coded data. The data linking file is stored on the Ann Arbor VA protected server. 
Only specific users with a login can access this file, and this file is password protected. PII information collected for recruitment are 
maintained in a file on the VA server. PHI information is reviewed for eligibility, and current medications may be acquired from medical 
records and become part of the research data.  
One participant will be tested at a time to protect the privacy of participants. If study participant sessions were to overlap then 
participants will be managed in separate rooms with the doors closed to protect the privacy of participants. VA data will be collected in 
paper workbooks. This data will be entered into a file maintained on the VA server and then a copy will be sent to the University of 
Michigan following a DUA. This data will be entered into electronic files maintained on the VA server and transferred to the University 
of Michigan using a VA approved USB storage device.  
The possibility of unintended disclosure of medical or research data is minimal, but not entirely impossible. We will employ stringent 
safeguards against unintended and inappropriate discovery and dissemination of personal medical and research data in our subjects 
by a multi-layered approach. All data bearing potential subject identifiers will reside securely on the VA server. Original data collection 
documents will be maintained in secure files under the control of the investigators and maintained at the Ann Arbor VA. Entries 
regarding details of the research project and its results will not be submitted to clinical medical databases. Data will be entered into an 
electronic database that will reside on the VA server. Electronic databases in the project will employ subject codes that cannot be 
linked directly to participants without a “key”, possessed only by the study investigators on the VA server, and maintained separately 
from the research data. Personal information that would directly identify study subjects will not be used in any publications or 
presentations resulting from this research study, unless separate written permission is given by the subject (or proxy). The data will be 
shared with the University of Michigan following the execution of a DUA. 
7.0 
Communication Plan 
 

 
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Science dissemination and communication plan. The current project aims to generate novel scientific insights into the comorbid 
presence of vestibular dysfunction and FoG in PD. Primarily, we aim to publish our results in top-level international clinically-oriented 
neuroscience journals (e.g., Annals of Neurology, Neurology, or Brain). This ensures that clinicians will take note of our results. 
Furthermore, we will present our results at (inter)-national conferences and symposia. We also envision that the results of this project 
will generate new knowledge on a new rehabilitation strategies to improve FoG and decrease fall risk in subjects with PD. We will 
communicate the project outcomes also in specialization courses for physical therapists involved in the Parkinson Care network. Direct 
communication to caregivers, patients and therapists by means of an information session on the outcome of this project will be 
organized in our lab for this purpose. In this way, participants will have the opportunity to be informed about the results of the ongoing 
studies and to discuss them with the researchers. Finally, we are already actively collaborating with Michigan Parkinson Foundation, a 
patient association that is committed to people afflicted with PD. This will give us the opportunity to inform a broader PD audience 
through their website, magazine, symposia and other organized activities.  
8.0 
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