Protocol study

1. 1
PT. B. D. SHARMA UNIVERSITY OF HEALTH SCIENCES, ROHTAK
Protocol of thesis to be submitted towards partial fulfillment of the requirement
for the degree of MD (RADIODIAGNOSIS) examination.
1. Name of the Candidate : Dr. Keerthan
2. Father's Name : Sh. Harish Nayak
3. Address of the candidate : Department of Radiodiagnosis
Pt. B.D. Sharma PGIMS, Rohtak
4. Name of the University from
which graduated
: Rajiv Gandhi University of Health
Sciences , Bengaluru
5. Year and month of passing
MBBS examination
: December 2019
6. Date of joining MD course : 25th February, 2022
7. Proposed subject of thesis : To evaluate role of Diffusion
Tensor Imaging in the diagnosis of
Parkinson's disease and Parkinson
plus syndrome-A Case Control
study.
8. Facilities for work on the subject : All facilities exist at Pt. B.D. Sharma
PGIMS, Rohtak
9. Detailed scheme according to
which candidate proposes to work
: Plan attached
10. Name and Address of the
Supervisor
: Dr. Shalini Agarwal
Professor,
Department of Radiodiagnosis,
Pt. B.D. Sharma PGIMS, Rohtak.
11. Name and Address of the Co-
Supervisor
: Dr. Surekha Dabla
Senior Professor,
Department of Neurology,
Pt. B. D. Sharma PGIMS, Rohtak.
Total no. of pages : 27
Signature of candidate
CERTIFICATE OF SUPERVISORS

2. 2
I certify that facilities for study on the subject of thesis entitled "To evaluate role of
Diffusion Tensor Imaging in the diagnosis of Parkinson's disease and Parkinson
plus syndrome-A Case Control study" exist in PGIMS, Rohtak and these shall be
provided to the candidate in pursuance of his plan of thesis. I shall guide the candidate
in his work and shall ensure that the data being included in the thesis are genuine and
that the work is being done by the candidate himself.
Dr. Shalini Agarwal
Professor,
Department of Radiodiagnosis ,
Pt. B.D. Sharma PGIMS ,
Rohtak.
(Supervisor)
Dr. Surekha Dabla
Senior Professor ,
Department of Neurology,
Pt. B.D. Sharma PGIMS ,
Rohtak.
(Co-supervisor)

3. 3
ETHICAL JUSTIFICATION
The proposed study entitled "To evaluate role of Diffusion Tensor Imaging in the
diagnosis of Parkinson's disease and Parkinson plus syndrome-A Case Control
study." Informed written consent will be taken from all the subjects. No drugs will be
administered during the study. No invasive procedures will be done on the subjects.
All the procedures used in the study do not carry any harmful effect on the patients.
Thus the present study is well within the ethical norms and is ethically justified.
Signature of Candidate
(Dr. Keerthan)
Dr. Shalini Agarwal
Professor,
Department of Radiodiagnosis ,
Pt. B.D. Sharma PGIMS,
Rohtak.
(Supervisor)
.
Dr. Jyotsna Sen
Senior Professor and HOD,
Chairperson ,PG Board of studies
Department of Radiodiagnosis,
Pt. B.D. Sharma PGIMS, Rohtak.
Dr. Surekha Dabla
Senior Professor ,
Department of Neurology,
Pt. B.D. Sharma PGIMS ,
Rohtak.
(Co-supervisor)

4. 4
DECLARATION BY THE POSTGRADUATE STUDENT
I hereby declare that:
1. The study will be done as per Institutional protocol and guidelines.
2. Study shall be initiated only after clearance from institutional ethics committee.
3. Written, Informed consent of the patients/control (volunteers) will be obtained.
4. In case of children and mentally handicapped both patients/control (volunteers)
written informed consent of the parents/care givers will be obtained.
5. The probable risks involved in the study will be explained in full to the
subjects/parents/care givers in their own language.
6. I will terminate the study at any stage, if I have probable cause to believe, in the
exercise of the good faith, skill and careful judgment required for me that continuation
of the study/experiment is likely to result in injury/disability/death to the subject.
7. Disclosure:
i. Financial/ funding None
ii. Conflict of interest None
iii. Association None
Date :
Signature of PG Student
Department of Radiodiagnosis,
Pt. B.D. Sharma PGIMS, Rohtak

5. 1
INTRODUCTION
Parkinson's disease (PD) is a complex progressive neurodegenerative disease
described by James Parkinson in his 1817 publication," Essay on the Shaking Palsy." 1
PD is the second most common neurodegenerative disorder following Alzheimer's
disease (AD).2
It is characterized by the loss of dopaminergic neurons in the substantia
nigra.3 The atypical causes of Parkinsonism that mimic Idiopathic PD include multiple
system atrophy (MSA), Progressive supranuclear palsy (PSP), Cortico-basal syndrome
as well as drug-induced Parkinsonism, and others. 2
They are characterized by very
similar motor symptoms, making them difficult to distinguish in the early stages,
despite having distinct molecular pathology.4
Globally, disability and death due to PD are increasing faster than for any other
neurological disorder. The prevalence of PD has doubled in the last 25 years. Global
estimates in 2019 showed over 8.5 million individuals with PD. Current estimates
suggest that, in 2019, PD resulted in 5.8 million disability-adjusted life years and
caused 3,29,000 deaths.5
The diagnosis is clinical, made in the presence of at least one motor symptom such as
bradykinesia, rest tremor, rigidity, and postural instability. Pathological studies
describe that synuclein is first found in the lower brainstem and/or olfactory bulb,
corroborating the idea that brain affection goes beyond the motor system and that
nondopaminergic neurons are also involved. PD is mainly known for its motor
symptoms; however, nonmotor symptoms have a significant impact on a patient's
quality of life. Cognitive impairments are common in PD patients and can be present at
initial diagnosis, though they are more frequent at late disease stages. 6
In PD, the loss of dopaminergic neurons and the accumulation of Lewy bodies are
typically accompanied by damage of neuroglial cells and demyelination of axons with
increasing microglia concentration in extracellular spaces. It is, therefore, plausible
that the detection of extracellular microstructural abnormalities in brain regions with

6. 2
dopaminergic neurons and along dopaminergic pathways might be a biomarker of
incipient PD.2 The development of a neuroimaging biomarker for early PD diagnosis is
critical and might have a high impact on a patient's quality of life. 6
A range of Magnetic Resonance Imaging (MRI) techniques have been used to identify
regions of brain pathology in parkinsonian syndromes.4
T2-weighted MR images,
proton density-weighted spin-echo images, short inversion time inversion-recovery
images, or multi-shot diffusion-weighted imaging have been used previously. The
paramagnetic effect of increased nigral iron content in PD patients by measuring T2
and T2* relaxation times has found significant differences between Parkinson's
patients and control subjects within the substantia nigra. The T1-related contrast
between the neuro-melanin-containing dopaminergic cells of the SNc and the
surrounding brain tissue has been used to demonstrate reduced SNc signals in PD
patients. Despite these developments for visualization of the SN by employing T1-
sensitive imaging techniques, all aforementioned approaches suffer from long
acquisition times. As a consequence, to keep scanning time within a clinically useful
range while sustaining a high signal-to-noise ratio (SNR), data acquisition has to be
limited to small volumes and relatively thick slices (approximately 3 mm thickness),
which is problematic especially for the investigation of smaller nuclei in the brain such
as SN.7
The acquisition of multi-averaged DESPOT1 driven equilibrium single pulse
observation of T1 maps (DESPOT1) has furthermore been proven to allow for visual
discrimination between the major nuclei of the thalamus. This finding suggests that
DESPOT1 could also be a suitable tool for investigating the substantia nigra. Apart
from having an impact on transverse and longitudinal relaxation times in affected
brain regions, the neurodegenerative process that occurs in PD is also likely to alter
measures that can be detected by diffusion tensor imaging (DTI). 7
Recent neuroimaging methods make it possible to investigate the anatomy and
impact of brain alterations on the basis of functional, structural, and diffusion data

7. 3
acquisitions.Based on this, three complementary techniques to assess brain changes
related to neurodegenerative diseases like PD have been developed. While fMRI
allows the study of functional connectivity by assessing neuronal dysfunction related
to PD, structural MRI adds information regarding anatomical changes, mainly cortical
lesions involved in the disease progression. Functional and structural MRI data
contribute to a substantial but still partial understanding of PD pathophysiology. To
enhance this knowledge, DTI allows the study of white fiber integrity, which is also
impacted by the neurodegenerative processes.8
DTI is an MRI technique that can indirectly evaluate the integrity of white matter
tracts by measuring water diffusion and its directionality in three dimensions. The
magnitude (diffusivity) and directionality (anisotropy) of water molecular
displacement by diffusion in the brain can be quantified by the mean diffusivity (MD)
aka apparent diffusion coefficient (ADC) and fractional anisotropy (FA), respectively. 9
DTI has been employed to measure white matter microstructural integrity in
neurodegenerative diseases, as well as to visualize brain fiber connections via
Tractography. Many quantitative DTI indices could be derived from a clinical DTI
sequence. FA, radial (RD), axial (AD), and mean diffusivity (MD) have been most
commonly used to describe the degree of random motion of water molecules on a
microscopic scale. Specifically, FA, which measures the directionality of random water
motion, has been used to probe nerve fiber arrangements, axonal integrity, and the
degree of axonal myelination.2 Anisotropy refers to a non-uniform diffusion of water
molecules in tissues. The closer to 1 the FA value is, the more anisotropic this diffusion
is. Conversely, for an FA value close to 0, the movement of water molecules would be
isotropic, suggesting damaged tissue when measured in white matter. 8 FA is clinically
useful to deduce the microstructural integrity of brain tissues, especially preferred for
oriented tissues, such as white matter and fiber-tract architectures. MD measures the
magnitude of water diffusion.2 Increased MD can be problematic since it indicates that
the tissues do not retain water molecules, possibly because of an enlargement of the
extracellular space, suggesting degeneration of the tissue.8 FA and MD make it
possible to measure demyelination as a sign of white matter alteration. 8

8. 4
AD measures the magnitude of diffusion along the main axis, and RD measures the
magnitude of transverse diffusion. In animal studies, increased RD appears to describe
myelin pathology-induced myelin thinning, while decreased AD indicates acute axonal
injury but does not correlate with chronic axonal damage.2
The diagnosis of PD in the early stages can be challenging because symptoms often
overlap with other movement disorders, such as the parkinsonian variant of multiple
system atrophy (MSAp), progressive supranuclear palsy (PSP), and essential tremor
(ET). Advances in neuroimaging have led to a greater understanding of which brain
regions are affected in these movement disorders, with the basal ganglia and regions
of the cerebellum commonly implicated. Using DTI several laboratories have
confirmed that FA in the substantia nigra is reduced in subjects with PD compared
with control subjects. ET and PD subjects have different FA patterns in the dentate
nucleus and superior cerebellar peduncle. DTI has also shown promise for
differentiating PD from atypical Parkinsonism. Diffusion-weighted imaging has been
used to discriminate MSAp from PD and healthy controls on the basis of putaminal and
pallidal diffusion coefficients. However, in other studies, this same technique has
shown mixed results for distinguishing subjects with PSP from MSAp. In a recent study,
regional ADCs calculated from multiple brain regions, including the basal ganglia,
thalamus, brainstem, and cerebellum, were shown to differentiate MSA (primarily the
cerebellar subtype), PSP, PD, and healthy control subjects. 10
Studies utilizing FA, MD
and other diffusion measures in PSP have described abnormalities in the superior
longitudinal fasciculus, corpus callosum and superior cerebellar peduncles, whilst in
MSA white matter abnormalities have been identified in the putamen and middle
cerebellar peduncles. In non-demented PD, white matter is thought to remain largely
normal; however, there have been reports of corpus callosum, superior cerebellar
peduncles, cingulum, and uncinate involvement.4
However, the clinical utilities of these DTI metrics have to consider several limitations.
Despite the limitations, the decreased FA and increased MD have been found to

9. 5
correlate with neuronal degeneration and degeneration caused by dopamine loss.
Further, previous studies reported that abnormal FA values are detected in PD prior to
atrophy, suggesting the usefulness of DTI measures as a biomarker of PD in clinical
studies.2
This study is an attempt to evaluate the utilities of DTI as a biomarker in the early
diagnosis of PD as well as a tool to differentiate PD from its variants, thus enabling
appropriate timely therapeutic and interventional measures and hence might become
a useful tool in reducing the overall morbidity of PD and its variants.

10. 6
REVIEW OF LITERATURE
Parkinson's disease is a disorder of the extrapyramidal system which includes motor
structures of the basal ganglia and is characterized by the loss of dopaminergic
function resulting in cholinergic over-activity leading to characteristic clinical features
of the disease. The role of imaging particularly MRI has been evaluated in the
detection of regional alterations, white matter integrity, etc. The decreased FA and
increased MD have been found to correlate with neuronal degeneration and
degeneration caused by dopamine loss. Previous studies reported that abnormal FA
values are detected in PD prior to atrophy, suggesting the usefulness of DTI measures
as a biomarker of PD in clinical studies. Studies also demonstrated cortical atrophy in
PD patients in different region of interest(ROI). This review of literature provides an
insight into the findings of previous studies, thus directing our study to come to a
conclusion that may validate or negate the previous findings, which may help in the
early diagnosis of PD as well as to differentiate it from Parkinson's variants thereby
helping to reduce the overall morbidity of the disease.
Authors
Journal
Year
Objective Design Characteristics
of the
participants
Sample size
Results
Chan et al
J neurol
neurosurg
psychiatry(2007)
to determine:
(1) If FA and ADC
values on DTI in
the basal ganglia
and SN are
different
between patients
with PD and
healthy controls
(2) The predictive
value of these
parameters and
their clinical
utility
Prospective
study
151 subjects (73
PD patients, 41
men, 32 women;
mean age 63.6
years) and 78
age and sex-
matched control
subjects
The FA value in
the substantia
nigra on DTI
was lower in
PD compared
with healthy
controls and
correlated
inversely with
the clinical
severity of PD
Yu Zhang et al
Movement
disorders
Test whether DTI
measures along
the nigrostriatal
Case-control
study
50 drug-naive
PD patients and
27 healthy
FA of the
nigrostriatal
tract was, on

11. 7
(2014) tract differ
between PD
patients and
Healthy Control
(HC) subjects
control subjects average,
markedly
reduced in PD
patients (α
<0.05)
Yu Zhang et al
PLoS one
(2016)
To determine the
degree and
regional
distribution of
microstructural
integrity decline
in PD relative to
healthy aging
Cohort study 122 de-novo PD
patients (age =
60.5±9) and 50
healthy controls
(age =60.6±11)
PD was
associated
with higher
rates of FA
reduction,
increased RD
and AD
predominantly
in the
substantia
nigra,
midbrain, and
thalamus.
Atkinson
–Clement et al
Neuroimage
clinical
(2017)
To provide a
whole brain meta
-analysis for DTI
in PD
Meta-
analysis
included 39
studies: 14 used
fractional
anisotropy (FA),
one used mean
diffusivity (MD),
and 24 used
both indicators.
The studies
comprised 1855
individuals, 1087
with PD, and
768 healthy
controls.
decrease of FA
-DES and an
increase of MD
-DES in the SN,
the corpus
callosum, the
cingulate, and
the temporal
cortices except
for the
corticospinal
tract, which
showed
opposite
changes
in PD
Guimarães et al
Frontiers in
Neurology
(2018)
To assess white
matter
abnormalities in
PD
Cross-
sectional
study
132 patients
with PD (mean
age 60.93 years;
Average disease
duration 7.8
years) and 137
healthy controls
(mean age 57.8
years)
Lower FA
(p<0.01) in
patients in
different ROI's
as compared
to healthy
controls

12. 8
Yu Zhang et al
Frontiers in
Neurology(2020)
To prove the
utilities of DTI as
a marker of
diagnosing PD,
correlating
clinical
symptomatology,
tracking
disease
progression, and
treatment effects
Systematic
review
44 young PD and
176 old PD
patients;15
young and 60
old healthy
controls
FA increase is
pronounced in
the young
onset PD and
in the earliest
years of PD.
Chan et al (2007) conducted a prospective case control study on 151 subjects (73 PD
patients, Male:Female: 41:32; mean age 63.6 years) and 78 age and sex matched
control subjects. DTI imaging was carried out in patients with PD and controls. FA and
ADC values were obtained from various brain structures on the DTI scan using the
diffusion tensor task card. The structures studied were: caudate, putamen, globus
pallidus, thalamus, and substantia nigra. The FA value of the substantia nigra in
patients with PD was lower compared with controls (0.403 vs. 0.415; p = 0.001). For
the ADC, there was a trend towards a higher value in the substantia nigra of PD
compared with controls (7.342 vs 7.157; p=0.13). However, no significant differences
were demonstrated for FA or ADC values of other structures. Multiple regression
analysis revealed that the clinical severity of PD (measured by the H & Y scale )
correlated inversely with the FA value in the substantia nigra in patients with PD
(regression coefficient -0.019). No single FA value had both a high positive and
negative predictive power for PD. They concluded that the FA value in the substantia
nigra on DTI was lower in PD compared with healthy controls and correlated inversely
with the clinical severity of PD.9
Yu Zhang et al (2014) studied 50 drug-naive PD patients and 27 healthy control
subjects from the international multicenter Parkinson's Progression Marker Initiative
and concluded that Tractography consistently detected the nigrostriatal fibers,
yielding reliable diffusion measures. Fractional anisotropy and RD and AD of the
nigrostriatal tract showed systematic abnormalities in patients. On average, the
nigrostriatal tract's FA was markedly reduced in PD patients (F 2,150=12.7; P=0.0007),

13. 9
regardless of the side of motor symptom onset (F 1,75=0.1, P=0.7). The RD was
increased in PD patients (F2,150=5.6, P=0.02), regardless of the side of symptom onset
(F1,75=0.2, P=0.6). The AD was also increased in PD patients (F 2,150=4.0, P=0.049), again
with no side interaction(F1,75=1.1, P=0.3). The significance level was α<0.05 in all tests.
In addition, variations in FA and RD of the nigrostriatal tract were associated with the
degree of motor deficits in PD patients, specifically after controlling for age and sex,
per unit increase in UPDRS-III corresponded with a 0.40% (90% confidence interval
[CI]:0.11%-0.68%) decrease in contralateral FA and a 0.30% (CI: -0.17%, 0.44%)
decrease in ipsilateral FA. The RD increased on average 1.05% (CI: 0.47%-1.64%) as per
UPDRS-III unit increase, without significant differences between the contralateral and
ipsilateral side. The AD was not significantly correlated with UPDRS- III (P=0.2).
Similarly, per unit increase in total UPDRS corresponded with a 0.25% (CI: 0.08%-
0.42%) decrease in contralateral FA and a 0.01% (CI:-0.17%, 0.20%) decrease in
ipsilateral FA. The RD increased 0.51% (CI: 0.13%-0.89%) as per total UPDRS unit
increase, with no difference between the contralateral and ipsilateral sides. The AD
had no significant correlation with total UPDRS (P=0.2). Hence the findings imply that
the DTI characteristic of the nigrostriatal tract is potentially an index for detecting and
staging early PD.11
Yu Zhang et al (2016) conducted a study to identify the utility of DTI in measuring the
regional distribution of abnormal microstructural progression in patients with
Parkinson's disease who were enrolled in the Parkinson's progression marker initiative
(PPMI). 122 de-novo PD patients (age = 60.5±9) and 50 healthy controls (age
=60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image
processing included an intra-subject registration of all time points and an inter-
subjects registration to a brain atlas. Annualized rates of DTI variations, including FA,
RD, and AD, were estimated in a total of 118 white matter and subcortical regions of
interest. A mixed effects model framework was used to determine the degree to
which DTI changes differed in PD relative to changes in healthy subjects. Significant
DTI changes were also tested for correlations with changes in clinical measures,
dopaminergic imaging, and CSF biomarkers in PD patients. Compared to normal aging,
PD was associated with higher rates of FA reduction, and RD and AD increased

14. 10
predominantly in the substantia nigra (ipsilateral: 3.5±1.4%/year, PFDR = 0.03;
contralateral: 3.6±1.4%/year, PFDR =0.02), midbrain and thalamus. The highest rates of
FA reduction involved the substantia nigra (3.6±1.4%/year from baseline), whereas
the highest rates of increased diffusivity involved the thalamus (RD: 8.0±2.9%/year,
AD:4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated
with increasing dopaminergic deficits as well as with declining α-synuclein and total
tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus
correlated with progressive decline in global cognition in PD. The results suggested
that higher rates of regional microstructural degeneration are potential markers of PD
progression.12
A meta-analysis was performed by Atkinson-Clement et al (2017), which included 39
studies: 14 used FA, one used MD, and 24 used both indicators. The studies comprised
1855 individuals, 1087 with PD, and 768 healthy controls. Regions of interest were
classified anatomically (subcortical structures; white matter; cortical areas;
cerebellum). The analysis considered the disease effect size (DES) as the main
variable; the heterogeneity index (I2) and Pearson's correlations between the DES and
co-variables (demographic, clinical, and MRI parameters) were also calculated. At the
clustering level, significant differences in FA-DES and MD-DES were found between PD
patients and healthy controls in subcortical and cortical areas. In white matter, this
was the case for FA-DES only, and no significant differences were found in the
cerebellum. MD-DES was highly heterogeneous in all significant clusters except in
cortical areas (I2 = 34.5%). At the anatomical level, five regions demonstrated
significant differences between PD patients and healthy controls for both FA-DES and
MD-DES. Four of these regions showed a decrease in FA-DES and an increase in MD-
DES: the SN, the corpus callosum, the cingulate, and the temporal cortices. The
remaining region, localized in the corticospinal tract, showed an opposite change. All
regions were heterogeneous for the FA-DES, but only the corpus callosum was
heterogeneous for the MD-DES (I2 = 52.1%). A single region with a significant
difference between PD patients and healthy controls was found for FA-DES only in the
caudate nucleus (increased FA-DES). For the MD-DES only, four areas (the putamen,
the pallidum, the internal and external capsules, and the olfactory cortex) displayed

15. 11
significant differences between PD patients and controls. None of these regions was
associated with any significant heterogeneity of DES. In addition, it also demonstrated
that MD-DES was particularly sensitive to clinical and MRI parameters, such as the
number of DTI directions (the studies considered in the meta-analysis used directions
between 6 and75) and the echo time within the white matter.8
Guimarães et al (2018) conducted a study on 132 patients with PD (mean age 60.93
years; Average disease duration 7.8 years) and 137 healthy controls (mean age 57.8
years) who underwent the same MRI protocol. Patients were assessed by clinical
scales and a complete neurological evaluation. Tract Based Spatial Statistics (TBSS)
analysis was performed to compare patients and controls, and patients were divided
into mild PD (H&Y =1-1.5), moderate PD (H&Y=2-3), and severe PD (H&Y=4-5) and
performed an ROI analysis using Tractography. With TBSS the study found lower FA
(p<0.01) in patients in the corpus callosum, internal and external capsule, corona
radiata, thalamic radiation, sagittal stratum, cingulum, and superior longitudinal
fasciculus. Increased AD (p<0.01) was found in the corpus callosum, fornix,
corticospinal tract, superior cerebellar peduncle, cerebral peduncle, internal and
external capsules, corona radiata, thalamic radiation, and sagittal stratum. Increased
RD (p<0.01) was seen in the corpus callosum, internal and external capsules, corona
radiata, sagittal stratum, fornix, and cingulum. Regarding the ROIs, a general linear
model (GLM) analysis showed abnormalities in all tracts, mainly in the severe group,
when compared to HC, mild PD, and moderate PD (p<0.05). The study concluded that
since major abnormalities were found in the severe PD group, DTI analysis might not
be the best tool to assess early alterations in PD, and probably, functional and other
structural analysis might suit this purpose better. However, it also concluded that DTI
can be used to differentiate disease stages and as a surrogate marker to assess disease
progression. It is an important measure that could be used in clinical trials .6
Yu Zhang et al (2020) conducted a systematic review using a majority of clinically
employed DTI studies in PD, and its aim was to prove the utilities of DTI as a marker of
diagnosing PD, correlating clinical symptomatology, tracking disease progression, and
treatment effects. To address the challenge of DTI being a diagnostic marker for early
PD, this review provides a comparison of the results from a longitudinal, early stage,

16. 12
multicenter clinical cohort of Parkinson's research with previous publications. This
review provides evidence of DTI as a promising marker for monitoring PD progression
and classifying atypical PD types, and it also interprets the possible pathophysiologic
processes under the complex pattern of FA changes in the first few years of PD. The
review outlines the clinical utilities of the low-cost, noninvasive DTI MR as a biomarker
for diagnosing PD, correlating PD symptomatology, assessing PD progression, and
differentiating atypical types of Parkinsonism. The findings provide compelling
evidence that DTI may be a promising marker for monitoring PD progression and
classifying atypical PD types. Therefore, it provides outcome measures for clinical
trials and helps clinicians find better patient management. But it also concluded that
the utility of DTI for diagnosing early PD is still challenging. Together with the findings
on PPMI data, this review presents a divergent pattern of temporal FA changes in the
earliest stage of PD. In particular, FA increase is pronounced in the young-onset PD
and in the earliest years of PD. These observations help to improve understanding of
the pathophysiologic basis (e.g., the compensatory mechanisms, excitations of the
inhibitory circuits) during the earliest stages of PD.2
A growing body of literature suggests that some of the DTI parameters are altered in
Parkinson's disease and its variants with a significant difference from that of the control
group. It also suggests that DTI could be a potential biomarker for diagnosis of the
disease, grading its severity, and monitoring progression.

17. 13
RESEARCH QUESTION
Is DTI a really sensitive tool in the diagnosis of Parkinson's disease and Parkinson
Plus syndrome?

18. 14
AIM AND OBJECTIVES
AIM:- To evaluate role of Diffusion Tensor Imaging in the diagnosis of Parkinson’s
disease and Parkinson plus syndrome and compare them with healthy control.
OBJECTIVES:-
1. To determine neurodegeneration of both cortical and subcortical structures by DTI
MRI in patients suffering from PD and PD plus syndrome.
2. To determine the effects of severity of disease as per staging in Idiopathic PD with
neurodegeneration.
3. To determine the effects of severity of disease in patients with PD Plus syndrome.

19. 15
FLOW DIAGRAM-I
To evaluate role of Diffusion Tensor Imaging in the diagnosis of
Parkinson’s disease and Parkinson plus syndrome-A Case
Control study
1. Patients of Idiopathic PD/ PD Plus syndrome of either gender.
2. Patients/legally authorized representative (LAR) willing to provide
written informed consent.
N=minimum 30
Data will be compiled and appropriate statistical test will be used to
obtain the results
Title of study
Patients to be
included
Secondary Parkinsonism by drugs or toxins.
Cerebrovascular diseases such as cerebral infarction and other central
nervous system (CNS) disorders.
Patients to be
excluded
Sample size
Patients will undergo diffusion tensor MR Imaging with calculation of
FA, MD, RD and AD values
Assessment
Analysis

20. 16
MATERIALS AND METHODS
STUDY DESIGN: Case-Control study.
STUDY PROTOCOL: This study will be conducted in the Department of
Radiodiagnosis in collaboration with the Department of Neurology, Pt. B. D. Sharma
PGIMS, Rohtak, in a minimum of 30 adult patients with Idiopathic PD, PD Plus each
and compare their healthy control over the period of 18 months. All the patients will be
asked for demographic details. Written informed consent will be obtained from all the
participants / LAR enrolled in the study . Approval will be taken from the Institutional
Ethics Committee, PGIMS/UHS, Rohtak before the commencement of the study.
STUDY POPULATION: All clinically diagnosed patients with PD, PD Plus
syndrome in the Neurology outpatient clinic or Idiopathic PD at Pt. B. D. Sharma
PGIMS, Rohtak will be screened and selected as per the inclusion and exclusion criteria
for the study.
ETHICAL CLEARANCE:
Ethical clearance shall be taken from the ethical committee of the institution. Informed
consent shall be taken from the patient or guardian of the study subjects. Investigations
done under this study are the usual investigations as per standard of care and no special
investigation purely for research purposes are planned.
INCLUSION CRITERIA:
1. Patients of Idiopathic PD/ PD Plus syndrome of either gender.
2. Patients/ LAR willing to provide written informed consent.
EXCLUSION CRITERIA:
1. Secondary Parkinsonism by drugs or toxins.
2. Cerebrovascular diseases such as cerebral infarction and other central nervous
system (CNS) disorders.
Diagnosis of PD and MSA-p will be performed using established diagnostic criteria.

21. 17
DETAILS OF IMAGING TECHNIQUE USED:
Magnetic Resonance Imaging of the brain will be performed on a three Tesla (3T)
MR system (GE Healthcare DISCOVERY MR 750W with GEM Suite Milwaukee US)
using 32 channel dedicated head coil. The MR protocol will be as follows,
● Noncontrast T1W sequences.
● Noncontrast T2W sequences.
● T2 FLAIR
● Diffusion-Weighted Imaging.
● Diffusion Tensor Imaging.
PARAMETERS T1WI T2WI DWI
FOV(cm) 22 22 22
SLICE
THICKNESS(mm)
5.0 5.0 5.0
SLICE
SPACING(mm)
1.5 1.5 1.5
TR(ms) 2671.1 11174 4000
TE(ms) 24 97 Min.
FREQUENCY 320 288 128
BANDWIDTH(kHz) 41.67 62.5 250
DTI imaging parameters will be: TR-6298ms ;b-value=1000s/mm 2 ;diffusion gradient
direction =30; frequency FOV -22cm; NEX -1; slice thickness-4mm; slice spacing -
0.0mm; slice number-30. Cortical and subcortical structures will be taken as ROIs (for
example, substantia nigra, corpus callosum, caudate, putamen, and middle cerebellar
peduncle to name a few). DTI parameters (FA, MD, RD and AD) will be calculated and
compared with that of healthy controls.

22. 18
STATISTICAL ANALYSIS
The data collected will be entered in MS-Excel. Appropriate statistical tests will be
applied using Statistical Package for Social Sciences [SPSS Inc., Chicago, IL, version
22.0 for Windows (India)] software and the inference will be drawn accordingly.

23. 19
PATIENT CONSENT FOR INCLUSION TO STUDY
Patients have right not to sign this consent form; refusal to sign the form will not
affect their care in any way.
I .......................................................... hereby give my consent for inclusion in study
entitled "To evaluate role of Diffusion Tensor Imaging in the diagnosis of
Parkinson's disease and Parkinson plus syndrome-A Case Control study". I have
been told the details of study plan and I understand the methodology. I hereby give my
consent for clinical information and other details/investigation of my case that may be
published in any medical journal / medical books or online medical website by the
convener of this study. As a result, I understand that material may be seen by general
population. I understand that my name, initials and address will not be published but
that anonymity cannot be guaranteed. I am willing to participate in this study and
available for follow-up as needed. I can withdraw from this study at any time at my
willingness.
Name of Patient ------------------------------------
Signature ------------------------------------
Name of Witness ------------------------------------
Signature ------------------------------------

24. 20
अध्ययन के लिए प्रवेश के लिए रोगी सहमति
मरीजों को इस सहमति फॉर्म पर हस्ताक्षर नहीं करने का अधिकार है, फॉर्म पर हस्ताक्षर करने से इनकार करना किसी भी तरह से उनकी देखभाल क
प्रभावित नहीं करेगा।
मैं ................................................. ......... इसके द्वारा " : पार्किंसंस रोग और पार्किंसंस प्लस सिंड्रोम के निदान में डिफ्यूजन टेन्सर इमेजिंग
की भूमिका का मूल्यांकन- मामला नियंत्रण अध्ययन ।" नामक अध्ययन में शामिल करने के लिए मेरी सहमति दें। मुझे अध्ययन योजना का विवरण बताया
गया है और मैं कार्यप्रणाली को समझता हूं। मैं इस मामले में नैदानिक जानकारी और मेरे मामले के अन्य विवरण / जांच के लिए अपनी सहमति देता हूं जो
इस अध्ययन के संयोजक द्वारा किसी भी चिकित्सा पत्रिका / चिकित्सा पुस्तकों या ऑनलाइन चिकित्सा वेबसाइट में प्रकाशित किया जा सकता है।
नतीजतन, मैं समझता हूं कि सामग्री को सामान्य आबादी द्वारा देखा जा सकता है। मैं समझता हूं कि मेरा नाम, आद्याक्षर और पता प्रकाशित नहीं
किया जाएगा, लेकिन उस गुमनामी की गारंटी नहीं दी जा सकती। मैं इस अध्ययन में भाग लेने के लिए तैयार हूं और आवश्यकतानुसार अनुवर्ती कार्रवाई
के लिए उपलब्ध हूं। मैं अपनी इच्छा से किसी भी समय इस अध्ययन से हट सकता हूं।
मरीज़ का नाम ------------------------------------
हस्ताक्षर ------------------------------------
साक्षी का नाम ------------------------------------
हस्ताक्षर ------------------------------------

25. 21
PATIENT INFORMATION SHEET
STUDY TITLE: To evaluate role of Diffusion Tensor Imaging in the diagnosis of
Parkinson's disease and Parkinson plus syndrome-A Case Control study
Candidate : Dr. Keerthan
Supervisor : Dr Shalini Agrawal, Professor, Department of Radiodiagnosis, Pt. B. D. Sharma
PGIMS, Rohtak.
Purpose: To evaluate role of Diffusion Tensor Imaging in the diagnosis of Parkinson's
disease and Parkinson plus syndrome through a Case Control study.
Information: This study is only for research work. During this study, clinically stable
patients will be taken and relevant history pertaining to Parkinson's disease will be
asked. This will be followed by 3TMRI examination. This study may require one or
more than one meeting with each subject for discussion and data collection. There is no
risk to the patient in this study.
Confidentiality: The information in the study records will be kept confidential. The
data will be stored securely and will be made available only to persons conducting the
study and to the regulatory authorities. The data will not be made available to any
other individual unless you specifically give permission in writing. No reference will be
made in oral or written reports which could link you to the study. Result of the study
will not be communicated to the subject unless deemed necessary.
Participation: Your participation in the study is voluntary. You may decline to
participate at any time without penalty and without loss of benefits to which you are
otherwise entitled. You don't have to take part in this study if you do not wish to do so.
Refusing to participate will not affect your treatment. You will still have all the benefits
that you would otherwise have got at this hospital.
Whom to contact: If you have any question please ask them now. You may also ask
questions later. If you wish to ask questions later, contact:
Dr. Keerthan, PG Student, Department of Radio-diagnosis, Pt. B. D. Sharma PGIMS,
Rohtak (9164679295).
Dr. Shalini Agrawal, Professor, Department of Radio-diagnosis, Pt. B. D. Sharma
PGIMS, Rohtak (Supervisor).

26. 22
रोगी सूचना पत्र
अध्ययन का शीर्षक: पार्किंसंस रोग और पार्किंसंस प्लस सिंड्रोम के निदान में डिफ्यूजन टेन्सर इमेजिंग की भूमिका का मूल्यांकन-
मामला नियंत्रण अध्ययन ।
उम्मीदवार: डॉ।कीर्तन
पर्यवेक्षक: डॉ। शालिनी अग्रवाल, प्रोफेसर
रेडियोडायग्नोसिस विभाग, पं। बी डी। शर्मा पीजीआईएमएस, रोहतक
उद्देश्य: पार्किंसंस रोग और पार्किंसंस प्लस सिंड्रोम के निदान में डिफ्यूजन टेन्सर इमेजिंग की भूमिका- मामला नियंत्रण अध्ययन के
माध्यम से मूल्यांकन करना।
जानकारी:यह अध्ययन केवल शोध कार्य के लिए है। आपको पार्किंसंस रोग और पार्किंसंस प्लस सिंड्रोम के बारे में विस्तार और प्रासंगिक
इतिहास के बारे में पूछा जाएगा। इस अध्ययन के दौरान, नैदानिक रूप से स्थिर रोगियों को लिया जाएगा और पार्किंसंस रोग और
पार्किंसंस प्लस सिंड्रोम से संबंधित प्रासंगिक इतिहास पूछा जाएगा। इसके बाद 3 टी एम आर इमेजिंग परीक्षा होगी। इस अध्ययन में
चर्चा और डेटा संग्रह के लिए प्रत्येक विषय के साथ एक या एक से अधिक बैठक की आवश्यकता हो सकती है। इस अध्ययन में रोगी को कोई
जोखिम नहीं है।
गोपनीयता: अध्ययन के रिकॉर्ड में जानकारी को गोपनीय रखा जाएगा। डेटा को सुरक्षित रूप से संग्रहीत किया जाएगा और केवल
अध्ययन करने वाले व्यक्तियों और नियामक अधिकारियों को उपलब्ध कराया जाएगा। जब तक आप विशेष रूप से लिखित में अनुमति नहीं देंगे,
तब तक डेटा किसी अन्य व्यक्ति को उपलब्ध नहीं कराया जाएगा। मौखिक या लिखित रिपोर्टों में कोई संदर्भ नहीं दिया जाएगा जो
आपको अध्ययन से जोड़ सकता है। जब तक आवश्यक न समझा जाए, तब तक अध्ययन के परिणाम को विषय पर सूचित नहीं किया जाएगा।
भागीदारी: अध्ययन में आपकी भागीदारी स्वैच्छिक है। आप किसी भी समय दंड के बिना और लाभ के नुकसान के बिना भाग लेने के लिए
अस्वीकार कर सकते हैं, जिसके आप अन्यथा हकदार हैं। यदि आप ऐसा नहीं करना चाहते हैं तो आपको इस अध्ययन में भाग लेने की आवश्यकता
नहीं है। भाग लेने से इनकार करने से आपके उपचार पर कोई असर नहीं पड़ेगा। आपके पास अभी भी सभी लाभ होंगे जो आपको अन्यथा इस
अस्पताल में मिलेंगे।
किससे संपर्क करें: यदि आपके कोई प्रश्न हैं, तो कृपया उन्हें अभी पूछें। आप बाद में भी सवाल पूछ सकते हैं। यदि आप बाद में प्रश्न पूछना
चाहते हैं, तो संपर्क करें:
डॉ।कीर्तन, पीजी छात्र, रेडियो-निदान विभाग, पीजीआईएमएस, रोहतक (9164679295)।
डॉ। शालिनी अग्रवाल, प्रोफेसर, रेडियो-निदान विभाग, पीजीआईएमएस, रोहतक (पर्यवेक्षक)।

27. 23
REFERENCES
1. Simon DK, Tanner CM, Brundin P. Parkinson disease epidemiology,
pathology, genetics, and pathophysiology. Clinics in geriatric medicine. 2020
Feb 1;36(1):1-2.
2. Zhang Y, Burock MA. Diffusion tensor imaging in Parkinson's disease and
Parkinsonian syndrome: a systematic review. Frontiers in neurology. 2020 Sep
25;11:531993.
3. Tsai CC, Chen YL, Lu CS, Cheng JS, Weng YH, Lin SH, Wu YM, Wang JJ.
Diffusion Tensor Imaging for the differential diagnosis of Parkinsonism by
machine learning. Biomedical Journal. 2022 Jun 4.
4. Worker A, Blain C, Jarosz J, Chaudhuri KR, Barker GJ, Williams SCR, et al.
Diffusion tensor imaging of Parkinson's disease, multiple system atrophy and
progressive supranuclear palsy: a tract-based spatial statistics study. PLoS One.
2014 Nov 18;9(11):e112638.
5. Parkinson disease: a public health approach. Technical brief. Geneva: World
Health Organization; 2022.
6. Guimarães RP, Campos BM, de Rezende TJ, Piovesana L, Azevedo PC, Amato
-Filho AC, et al. Is diffusion tensor imaging a good biomarker for early
Parkinson's disease?. Frontiers in neurology. 2018 Aug 21;9:626.
7. Menke RA, Scholz J, Miller KL, Deoni S, Jbabdi S, Matthews PM, et al. MRI
characteristics of the substantia nigra in Parkinson's disease: a combined
quantitative T1 and DTI study. NeuroImage. 2009;47(2):435-41.
8. Atkinson-Clement C, Pinto S, Eusebio A, Coulon O. Diffusion tensor imaging
in Parkinson's disease: review and meta-analysis. Neuroimage: Clinical. 2017
Jan 1;16:98-110.
9. Chan LL, Rumpel H, Yap K, Lee E, Loo HV, Ho GL, et al. Case control study
of diffusion tensor imaging in Parkinson's disease. J Neurol Neurosurg
Psychiatry. 2007 Dec;78(12):1383-6.
10. Prodoehl J, Li H, Planetta PJ, Goetz CG, Shannon KM, Tangonan R, et al.
Diffusion tensor imaging of Parkinson's disease, atypical Parkinsonism, and
essential tremor. Mov Disord. 2013 Nov;28(13):1816-22.
11. Zhang Y, Wu IW, Buckley S, Coffey CS, Foster E, Mendick S, et al. Diffusion
tensor imaging of the nigrostriatal fibers in Parkinson's disease. Mov Disord.
2015 Aug;30(9):1229-36.
12. Zhang Y, Wu IW, Tosun D, Foster E, Schuff N, Parkinson’s Progression
Markers Initiative. Progression of regional microstructural degeneration in
Parkinson’s disease: a multicenter diffusion tensor imaging study. PloS one.
2016 Oct 31;11(10):e0165540.

28. 24
PATIENT PROFORMA
PATIENT DETAILS
Name:
Age:
Sex:
Ward/Unit:
CR/OPD No:
Address:
Contact number:
Thesis case No.:
HISTORY
Presenting complaints:
Past History:
Personal History:
Family History:
CLINICAL FINDINGS
(Disease severity using H&Y scale)
MEDICATION STATUS
MRI
A. T1WI, T2WI
B. T2 FLAIR
C. DWI
D. DTI

29. 25
Signature of Candidate