Smell, Voice and Nasal Swabs as Markers for Neuro-degenerative Disorders
Phase: NA
Conditions: Alzheimer Disease, Neurodegenerative Diseases
Sponsor: University of Arkansas

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 1 
 
Study Title: 
Smell, voice and nasal swabs as markers for 
neurodegenerative disorders 
 
Principal Investigator:  
Rohit Dhall, MD, MSPH 
 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 500 
Little Rock, AR 72205 
Telephone:  602-503-3193 
Email:  rdhall@uams.edu 
 
 
Co-Investigator: 
Ozlem Tulunay-Ugur, MD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 543 
Little Rock, AR 72223 
Telephone:  501-686-5140 
Email: OETulunayugur@uams.edu 
 
 
Sub-Investigator (s): 
Tuhin Virmani, MD, PhD 
 
University of Arkansas for Medical Sciences 
 
4301 W. Markham Street, Slot # 500 
Little Rock, AR 72205 
Telephone:  501-686-7235 
Email:  tvirmani@uams.edu 
 
 
Mitesh P Lotia, MD 
 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 500 
Little Rock, AR 72205 
Telephone:  501-686-7236 
Email: mplotia@uams.edu 
 
 
Sue T Griffin, PhD 
 
University of Arkansas for Medical Sciences 
Geriatrics Research, Reynolds Center for Aging 
Little Rock, AR 72205 
Telephone:  501-526-5801 
Email: GriffinSueT@uams.edu 
 
Study location: 
 
University of Arkansas for Medical Sciences.Table of Contents 
 
List of Abbreviations ........................................................................................................ 3 
Background and Rationale .............................................................................................. 4 
Specific Aims ................................................................................................................... 6 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 2 
Study Population ............................................................................................................. 6 
Inclusion Criteria .......................................................................................................... 6 
Exclusion Criteria ......................................................................................................... 7 
Study Design and Procedures ......................................................................................... 7 
Screening Procedures ................................................................................................. 7 
Informed Consent ..................................................................................................... 7 
Demographics .......................................................................................................... 8 
Medical History......................................................................................................... 8 
Review Eligibility Criteria .......................................................................................... 8 
Study Procedures ........................................................................................................ 8 
Otolaryngology Elements ......................................................................................... 8 
Neurological Elements ........................................................................................... 10 
Gaze Tracking While Reading ............................................................................... 11 
Risks and Benefits......................................................................................................... 11 
Compensation ................................................................. Error! Bookmark not defined. 
Data Handling and Recordkeeping ............................................................................... 11 
Data Analysis ................................................................................................................ 12 
Ethical Considerations ................................................................................................... 13 
Dissemination of Data ................................................................................................... 13 
References .................................................................................................................... 14 
 
 
 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 3 
List of Abbreviations 
AD: 
Alzheimer’s Disease 
AE: 
Adverse Event 
CBD:  
Corticobasal degeneration 
CNS:  
Central Nervous System 
CSF:  
Cerebrospinal fluid 
DAT:  
Dopamine Transporter 
DLB:  
Dementia with Lewy Bodies 
ENT 
Ear, Nose, and Throat 
FTLD:  
Fronto-temporal dementia 
IHC:  
Immunohistochemistry 
IL-1:  
Interleukin 1 
MCI:  
Mild Cognitive Impairment 
MoCA:  
Montreal cognitive assessment  
mRNA:  
Messenger ribonucleic acid 
MSA:  
Multiple systems atrophy 
OM:  
Olfactory Mucosa 
PD:  
Parkinson’s disease 
PDD:  
Parkinson’s Disease with Dementia 
PSP:  
Progressive supranuclear palsy 
UPDRS:  
Unified Parkinson’s Disease Rating Scale 
UPSIT:  
University of Pennsylvania Smell Identification Test 
 
 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 4 
Background and Rationale 
Degenerative dementias including Alzheimer's Disease (AD), Parkinson’s Disease with 
Dementia (PDD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementias 
(FTLD), Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) 
constitute a significant, and growing burden with an estimated cost to the US healthcare 
system for 2016 of $236 Billion (1).  Definitive diagnosis of these dementias is based on 
pathological criterion upon autopsy, which presents a significant challenge to establish 
diagnosis in living patients.  Although clinical diagnostic criteria have been developed 
for several of these disorders, including for AD by the NINCDS-ADRDA (2,3), PD by the 
United Kingdom Parkinson Disease Brain Bank Diagnostic Criteria (UKPDBB) 
diagnostic criteria for Parkinson Disease(4) and others, the currently available tests, 
including the use of imaging markers and CSF biological markers do not provide a 
definite diagnosis since this requires the observation of characteristic neuropathological 
changes in specific regions of the brain.  As an example, the presence of senile plaques 
and neurofibrillary tangles in mesial temporal structures is required for the diagnosis of 
AD, loss of nigral dopaminergic neurons with presence of intracellular Lewy Bodies 
being the hallmark of PD. 
This difficulty with ante-mortem definitive diagnosis for degenerative neurological 
disorders leads to several challenges pertaining to patient care and counseling, as well 
as recruiting the appropriate population of subjects for disease modifying therapies.  
Functional neuroimaging markers are being evaluated for improving the diagnostic 
certainty, including imaging amyloid, and phosphorylated tau (p-tau), as well as 
DATScan (r), but these add cost to the diagnostic process, and access is limited due to 
the need for nuclear imaging facilities and technical expertise. 
The inability to establish a diagnosis is even more relevant in early stages of the 
disease, when specificity of establishing a diagnosis using the clinical diagnostic criteria 
is lower.  As evidence, 16% of patients identified by PD experts as having PD for a 
longitudinal cohort study funded by the Michael J Fox Foundation for development of 
biomarkers for PD did not have a deficit in dopamine transporter (DAT) binding, 
suggesting that they did not indeed have PD (5).  Similarly, in a large neuropathology 
study of patients diagnosed with mild to moderate AD at AD centers funded by the 
National Institute for Aging, 12.5% met neuropathological criteria for non-AD dementias 
(6).  There is a clear need to develop diagnostic markers, yet blood, peripheral tissue 
and CSF markers have all lacked specificity to be of practical use in the clinic.  
A common, early marker of several degenerative dementias is impaired smell sensation 
and changes in voice.  Indeed, olfactory impairment has been reported in PD (7), FTLD 
(8), and AD (9).   Voice changes appear early in many parkinsonian disorders (10), and 
language changes have been assessed as a marker of disease progression in 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 5 
Alzheimer’s Disease (11).  Pathological involvement of the olfactory bulb has also been 
demonstrated with disease specific pathological changes (12).  These changes are 
hypothesized to appear early in the pathological process, and olfactory neurons provide 
us a unique opportunity to evaluate disease specific pathological changes 
representative of dysfunction within the CNS in a non-invasive fashion, since these can 
be sampled using simple nasal brushings or swabs.   Voice changes appear early in 
may parkinsonian disorders, and language changes have been assessed as a marker 
of disease progression in Alzheimer’s Disease. 
Techniques for nasal swabs for evaluating of rapidly progressive dementia in prion 
diseases have been published previously.  Indeed, for prion diseases, olfactory mucosal 
brushings or swabs provide a very high sensitivity and specificity of diagnosis (13). 
Previous evaluation of the nasal epithelium have shown increased levels of A-beta and 
p-tau in AD compared to controls, and a correlation between A-beta plaque frequency 
and p-tau in olfactory epithelium and brain in post-mortem examinations (although the 
correlation coefficient was 0.37) (14). 
In spite of the low risk, relative simplicity of sampling, and the ability to test for 
characteristic pathological changes on CNS tissue directly, thus far, nasal mucosal 
swab or cytobrush techniques have not been used broadly for diagnosis of degenerative 
dementias (except for rapidly progressive dementias). 
We propose this pilot study for evaluation of olfactory and vocal cord function, and nasal 
mucosal swabs of patient volunteers with neurodegenerative disorders or at risk of 
neurodegenerative disorders (identified as either having changes of presbylarynx on 
examination of laryngeal function, or with single or multi-domain mild cognitive 
impairment (MCI)) on standard neuropsychometric evaluations at the Psychiatric 
Research Institute for evaluation of cognitive symptoms.  Neuropsychometric 
evaluations and cranial imaging (with or without olfactory evaluation) form the existing 
standard of care for patients considered at risk for neurodegenerative disorders. 
We will obtain buccal and nasal mucosal swabs which will be used for standard 
immunohistochemistry (IHC) evaluations for neuronal, disease-specific and 
inflammatory markers.  We will correlate olfactory dysfunction (measured by the 
University of Pennsylvania Smell Identification Test (UPSIT), performance on 
neuropsychometric testing including evaluation of anxiety and depression and quality of 
life measures, and cranial imaging results with the nasal mucosal cells obtained through 
swabs.  We will also evaluate the functioning of the vocal folds during voice production 
(phonation) and closure of vocal folds, as well as any structural abnormalities in the 
vocal folds, hypopharynx, pharynx (throat) and larynx (voice box), as well as measuring 
the quality of sound produced, including breath control during speech, intelligibility of 
voice and its pitch and loudness through specific speech measures. 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 6 
Specific Aims 
The specific aims of the study are: 
• Aim 1:  Determine if smell, voice or vocal cord dysfunction serves as a reliable 
markers to distinguish between neurodegenerative disorders or among subjects 
with and those without neurodegenerative disorders. 
• Aim 2:  Determine if nasal swabs can provide an adequate sample for evaluation 
using cytology and immunohistochemistry for alpha-synuclein, A-beta and p-tau 
staining. 
• Aim 3:  Measure cellular levels of IL-1 a/b protein and mRNA levels and 
genotyping of apo-E4 alleles on the nasal mucosal swab samples. 
• Aim 4:  Evaluate if IHC and neuro-inflammatory marker levels correlate with 
severity of impairment in various cognitive or motor domains based on 
neuropsychological and motor scores, or olfactory impairment based on UPSIT 
scores. 
Study Population 
This is a prospective cross-sectional study of subjects with, or at risk of 
neurodegenerative disorders.  Initial recruitment goal is for 60 subjects: 
• Twenty people with Parkinson’s Disease requiring evaluation of voice dysfunction 
by an Ear, Nose, and Throat (ENT) doctor 
• Twenty people with other neurodegenerative disorders requiring evaluation of 
voice dysfunction by an ENT doctor. 
• Twenty people with voice tremor and/or presbylarynx, but no evidence of 
Parkinson’s other neurodegenerative disease, requiring evaluation of voice 
dysfunction by an ENT doctor. 
Subjects will be recruited from the population of patients with neurodegenerative 
disorders (seen in the UAMS Neurology Clinic) or presbylarynx and/or voice tremor 
patients scheduled to undergo routine voice and laryngeal assessments as part of 
required clinical care for problems with voice and swallowing in the UAMS ENT Clinic. 
Inclusion Criteria 
• Diagnosed with idiopathic Parkinson’s disease, progressive supranuclear palsy, 
Alzheimer’s disease or Mild Cognitive Impairment based on consensus criteria, 
or suspicion of presbylarynx based on clinical evaluation. 
• Require evaluation of voice dysfunction by an ENT doctor given symptoms of 
impaired voice volume or quality 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 7 
• Age ≥ 18 years-old to ≤ 90-years old. 
• Ability to understand and the willingness to sign a written informed consent. 
Exclusion Criteria 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
• Active nose bleeds, or abnormal anatomy of the nose that prevent safe nasal 
swabs, or active oropharyngeal disease that prevents laryngoscopy or voice 
assessments. 
Study Design and Procedures 
Screening Procedures 
Informed Consent 
Informed consent will be obtained by one of the investigators after discussing the 
rationale, study procedures and the risks and benefits of participation in the study with 
potential subjects. The consent process will take place in a dedicated research space at 
Translational Research Institute (TRI). The voluntary nature of participation and 
subjects’ ability to (and process of) withdraw from the study will also be discussed 
during the informed consent discussion.  Consent to participate will be documented by 
the person obtaining informed consent according to required procedures. 
Some of the participants with neurodegenerative disorders will, by definition, have at 
least mild impairment of cognitive function (e.g., subjects with Alzheimer's Disease). 
One of the neurologists on staff (Drs. Dhall, Lotia or Virmani) will determine capacity to 
consent (determine if subject is able to understand the information relevant to 
participation in the study, and the completely voluntary nature of study participation, as 
well as appreciate the reasonably foreseeable consequences of participation, including 
the risks of participation) using unstructured subject and caregiver interview at the time 
of obtaining informed consent. 
Additionally, a structured neurological examination including a Montreal Cognitive 
Assessment (MoCA) will be performed as a part of the study before the 
laryngoscopy/stroboscopy and sampling of olfactory mucosa for subjects with 
neurodegenerative disorders (including Parkinson's Disease). The (MoCA) will take 
place in a dedicated research space at Translational Research Institute (TRI). If the 
MoCA score is less than 21/30, or neurological examination shows moderate language 
or executive impairments, subject assent in addition to informed consent by a legally 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 8 
authorized representative will be required for continued study participation.  Since 
subjects with voice tremor and presbylarynx are expected to be cognitively normal, for 
this comparison group, neurological examination and MoCA can be performed after 
their ENT and speech therapy assessments (see below). 
Demographics 
Routine demographics, e.g., age, gender, race, ethnicity, will be collected. 
Medical History 
A routine medical and surgical history will be collected with a recent history of infections 
or nose and/or throat-related problems.  Previous and concomitant medications will also 
be reviewed and recorded. 
Review Eligibility Criteria 
Documentation of subjects having an established diagnosis of Parkinson’s Disease, 
other neurodegenerative disorders, or a voice tremor or presbylarynx will be reviewed at 
the time of screening. 
In order to stratify subjects with appropriate diagnostic certainty of the underlying 
diagnosis of neurodegenerative disorder, subjects will undergo comprehensive 
neurological assessments (described under the study procedures section below) and 
review of previous assessments to ensure that they meet the current consensus criteria 
for neurodegenerative disorders (e.g., United Kingdom Parkinson Disease Brain Bank 
Diagnostic Criteria for Parkinson Disease, NINCDS-ADRDA diagnostic criteria for 
Alzheimer’s Disease) after screening is completed.   
This review will be done during the study-related neurological assessments, and will 
include review of imaging, neuropsychological data (if available), neurological history 
and examination performed during their study-related visit with the neurologist. 
Study Procedures 
Logistically, this study involves a routine otolaryngology clinic visit and a research-
related neurology visit that are likely to occur over separate days. The research-related 
neurology visit and consent will take place in a dedicated research space at 
Translational Research Institute (TRI). The study visits will occur within 1 year of the 
providing informed consent, otherwise the subject will be deemed lost to follow up.  
Otolaryngology Elements 
Physical Exam (routine clinical care) 
A general physical examination will be performed as part of routine care. 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 9 
Laryngeal evaluation (routine clinical care) 
An examination of the oropharynx and nose will be performed as part of routine care by 
the laryngologist. 
Once nasal swabs have been obtained, the fiberoptic laryngoscope will be advanced 
through the already anesthetized nasal passage and threaded to the throat.  This is to 
allow direct visualization of the larynx (voice box) and pharynx and hypopharynx (throat) 
region to assess its structure and function.  A built in strobe light that allows for 
controlled, high speed flashes of light (stroboscopy) will allow the physician to see the 
voice box activation with the patient producing sound, with assessment of vocal fold 
vibration and vocal fold closure.  Laryngoscopy and stroboscopy are routine 
assessments performed by the laryngologist in the office for evaluation of voice and 
swallowing function, which may be affected in the aging of the larynx (presbylarynx) and 
in degenerative disorders like Parkinson Disease and other dementias.  The procedure 
is generally safe and carries very few side effects, other than soreness of throat or 
soreness of the nose. 
Speech Assessment (routine clinical care) 
A trained speech and language pathologist will perform assessments of speech function 
including measuring the quality of sound produced, including breath control during 
speech, intelligibility of voice and its pitch and loudness through specific speech 
measures. 
Smell Testing (only for research purposes) 
We will use the smell identification Test [UPSIT] for evaluation of smell sensation.  
UPSIT is a 40 item test of smell function with established age based normative data.  
The test is a simple scratch and sniff test which comprises of four booklets each 
containing 10 micro-encapsulated odors printed onto a section of the page.  Forced-
choice responses accompany test item on the same page of the booklet as the scratch 
and sniff component. The test will be administered by the patient's under guidance of 
the investigator or coordinator.  It usually takes about 10 to 15 minutes to self-
administer the test. To evaluate if there is asymmetry of smell identification when using 
left and right nostril, a subset of participants will be administered the test twice, at the 
beginning and then at the end of their physical and neurological exam, and instructed to 
use one and then the other nostril while occluding the opposite nostril with their finger 
when inhaling. The smell test will take place in a dedicated research space at 
Translational Research Institute (TRI). 
Buccal Swabs (only for research purposes) 
Sample Collection.  Oral mucosa samples from subjects will be obtained using two 
cotton swabs, and a board certified physician (RD or OTU) will obtain the swabs by 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 10 
scraping the inside of the cheek of the subject firmly with the swab, with the swab being 
placed in saline solution in two test tubes labeled with subject ID.   
Nasal Swabs (only for research purposes) 
Sample Collection.  Olfactory mucosa samples from subjects will be obtained using a 
flocked swab.  An absorbent disposable face mask will be used to cover the patient’s 
mouth to minimize dispersion of oral secretions in case of sneezing during the olfactory 
mucosal (OM) sample collection.  Mucosal swabs will be obtained by a board-certified 
otolaryngologist (OTU).  Subjects will not require sedation for the swab procedure.  After 
administration of a local vasoconstrictor (4% pseudoephedrine and 2% Tetracaine local 
anesthetic) with the use of a nasal pledget, a rigid fiberoptic laryngoscope will be 
inserted into the nasal cavity of the subject for inspection, and to locate the olfactory 
mucosa lining the nasal vault (at or above the level of the middle turbinate).  A sterile, 
disposable cytoswab will be inserted alongside the laryngoscope and will be rolled over 
the mucosal surface gently, then withdrawn and immersed in saline solution in a 15-ml 
conical centrifuge tube.  The procedure will be repeated for a total of 3-4 swabs.  Before 
removal of the scope, nasal mucosa will be inspected for any signs of trauma or 
irritation. 
Sample Processing.  Cellular material will be dissociated from the swab by means of 
vortexing.  The brush will be withdrawn and particulate matter will be pelleted for 
20 minutes at 2000xg at 4°C and frozen at -80°C until assayed. We will perform 
cytological and immune-cytochemical analyses to evaluate the quality of the OM 
sampling and the relative amount of olfactory neurons collected.  For western blot 
analysis, the OM cells will be lysed using a lysis buffer, and proteins separated in X% 
sodium dodecyl sulfate – polyacrylamide gel electrophoresis.  Appropriate antibody and 
secondary antibody probes will be utilized for detection of proteins of interest.  We will 
measure cellular levels of IL-1 a/b protein and mRNA levels and genotyping of apo-E4 
alleles, and evaluate the amount of aggregated alpha-synuclein, phospho-tau and beta 
amyloid through proteomic assays. 
Neurological Elements 
Neurological Evaluation (only for research purposes) 
A comprehensive neurological history and neurological examination, Unified 
Parkinson’s Disease Rating Scale (UPDRS), Schwab and England Activities of Daily 
Living scale, and the Montreal Cognitive Assessment (MoCA) as well as depression and 
anxiety scales (Hospital Anxiety and Depression Scale), quality of life scales (EQ-5D 
and Vision Function Questionnaire) as well as freezing of gait questionnaire (FOG-Q),  
will be performed by the neurologist for ensuring appropriate stratification based on the 
consensus criteria for various neurodegenerative disorders, or to ensure that subjects 
do not have incidental findings concerning for neurodegenerative disorders (if they are 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 11 
being recruited to the voice tremor/presbylarynx group). If there are any concerns for 
neurodegenerative disorders based on examination, the neurologist completing the 
examination will discuss this with the subject and may provide a referral for clinical 
assessment. 
Any prior neuropsychological evaluation results and imaging results (including those of 
functional imaging studies like Dopamine Transporter imaging (DATScan®) or PET 
Scans will be abstracted from the subjects’ medical records as part of the study 
procedures during the subjects’ neurology visits. 
Gaze Tracking While Reading (only for research purposes) 
We will use infrared oculography at 150- Hz to assess eye movements while the subject 
read aloud an English reading passages (Arial 36 point font, 5-8 words per line, 3-8 
lines per page, 8 pages total) at 8th grade reading level, which will be displayed on a 
desktop computer monitor. 
Risks and Benefits 
Risks associated with the research-related procedures include significant time burden 
associated with participation, with the neurological examination, smell identification test, 
and OM sampling which in total are expected to take 4 hours of subject’s time. 
There is risk of discomfort and irritation of the nose associated with sampling of the OM.  
A potential risk to study participants exists in the potential for loss of confidentiality.  
Measures to protect the confidentiality of study participants will be implemented as 
described in the Data Handling and Recordkeeping section below. 
This study also measures cellular levels of IL-1 a/b protein and mRNA levels and 
genotyping of apo-E4 alleles from the nasal mucosal swab samples.  The presence of 
apo-E4 alleles inform the risk of developing Alzheimer's disease, and possibly other 
neurodegenerative diseases.  A good proportion carries this genotype, so people can 
not be identified based on this alone.  The mRNA expression varies based on several 
factors and cannot identify subjects either. So loss of de-identification should not be a 
concern. 
There will be no direct benefits to the study participants; however, knowledge gained 
from the study could potentially benefit patients in the future. 
Data Handling and Recordkeeping 
The Principal Investigator (PI) will carefully monitor study procedures to protect the 
safety of research subjects, the quality of the data and the integrity of the study.  All 
study subject material will be assigned a unique identifying code or number.  The key to 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 12 
the code will be kept in a locked file in the principal investigator’s office.  Only the 
individuals listed on the title page of this document will have access to the code and 
information that identifies the subject in this study. 
Paper data will be stored in a locked file cabinet in the PI’s office behind a locked door 
in a restricted access space of the in the Jackson T. Stephens Spine & Neurosciences 
Institute.  Digitized data be stored on a secure computer located in PI’s office with 
access permitted only to the PI, co-Investigators and other members of the research 
team after IRB approval. 
At the conclusion of the study, the paper and digitized data will be permanently de-
identified by the destruction of the key associating the unique study code with the 
subjects’ identity. 
Olfactory Mucosal (OM) samples will be similarly de-identified and stored in a-40°C or 
lower temperature freezer in Dr. Sue Griffin’s lab in the Donald W. Reynolds Institute on 
Aging. 
De-identified OM samples and linked accompanying study data (including diagnostic 
certainty, motor and cognitive scores as well as smell testing data from study related 
procedures) will be stored for future research, and may be shared, de-identified, with 
other researchers at or outside UAMS, provided the subjects have given their written 
informed consent.  Regarding the genotyping of apo-E4, results will not be shared with 
the study subjects.  There exist several uncertainties about the reliability of the small 
sample and we do not intend to validate the results against a traditional method since 
this is a proof of concept pilot study. 
Subjects can withdraw their consent and require destruction of their samples/data to 
prevent their use in future research by sending a written request to Drs. Dhall or 
Tulunay-Ugur. 
Data Analysis 
As a first pass, frequency distributions and cross tabulations will be obtained to look at 
the data.  Counts of missing data will be obtained.  The distributions will be looked at for 
heaping, skewness and general amenability to analysis.  We will compare the 
individuals with Parkinson’s disease to those with presbylarynx or other degenerative 
disorders to look for any demographic differences. Cross tabulations will be done 
between "independent" (diagnosis of Parkinson’s disease versus presbylarynx or other 
degenerative disorders) and "dependent" variables including abnormalities on 
laryngoscopy or stroboscopy, performance on smell identification test as both a 
continuous measure, and when classified into hyposmia and anosmia based on age 
and gender expected norms. 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 13 
Additionally, we will look at the presence of histopathological markers for inflammation 
and misfolded protein deposition by potential confounding variables like age, gender, 
duration of disease, treatment characteristics at baseline and performance on smell 
testing etc. If needed, analyses will be repeated using stratification to investigate the 
effect modification by age, gender and time since diagnosis of Parkinson Disease, etc.  
Since these are preliminary analyses to determine effect size estimates to help power 
future studies, a power sizes cannot be estimated at this time. 
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations 
and University of Arkansas for Medical Sciences research policies and 
procedures.  This protocol and any amendments will be submitted and approved by the 
UAMS Institutional Review Board (IRB) to conduct the study.   
The formal consent of each subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any study procedure.  All subjects for this 
study will be provided a consent form describing this study and providing sufficient 
information in language suitable for subjects to make an informed decision about their 
participation in this study. 
The person obtaining consent will thoroughly explain each element of the document and 
outline the risks and benefits, alternate treatment(s), and requirements of the 
study.  The consent process will take place in a quiet and private room, and subjects 
may take as much time as needed to make a decision about their 
participation.  Participation privacy will be maintained and questions regarding 
participation will be answered.  No coercion or undue influence will be used in the 
consent process. 
This consent form must be signed by the subject or legally authorized representative 
(LAR) and the individual obtaining the consent.  If the subject is determined to lack 
capacity to consent and a LAR provides consent, assent will be sought from the subject, 
and dissent will be honored. A copy of the signed consent will be given to the 
participant, and the informed consent process will be documented in each subject’s 
research record. 
Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
participant. 
 
 

Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 14 
References 
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Title: 
Smell, voice and nasal swabs as markers for neurodegenerative disorders 
PI: 
Rohit Dhall, MD. MSPH; Ozlem Tulunay-Ugur, MD 
Site: 
University of Arkansas for Medical Sciences 
 
Version #:  4 
 
IRB# 206829 
Date:  01/01/2019 
Page 15 
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