Protocol for Submission of Thesis for the Award of Degree of

Doctor of Medicine (Radio-diagnosis)

Session 2019-2022

SPECTRUM OF CEREBRAL WHITE MATTER TRACT

CHANGES AND PERFUSION ABNORMALITIES
IN DIVERSE TYPES OF DEMENTIA

Guru Gobind Singh Indraprastha University

Dr. Apratim Roy Choudhury

Department of Radio-diagnosis
Vardhman Mahavir Medical College & Safdarjung Hospital
New Delhi–110 029

i
 Protocol for Submission of Thesis for the Award of Degree of
Doctor of Medicine (Radio-diagnosis) Session 2019-2022
Title of thesis
Venue of Study
Signature of the candidate
Name of the candidate
Signature of the Supervisor
Name of the Supervisor
Signature of Co-Supervisor
Name of the Co-Supervisor
Signature of Co-Supervisor
Name of the Co-Supervisor
Signature of Head of Department
Name of Head of Department
Signature of the Principal
Name of the Principal
Signature of Medical Superintendent
Name of Medical Superintendent
Spectrum of Cerebral White Matter Tract Changes and Perfusion
Abnormalities in Diverse Types of Dementia
Department of Radio-diagnosis, Vardhman Mahavir Medical
College and Safdarjung Hospital, New Delhi 110029
Dr. Apratim Roy Choudhury
Dr. Yatish Agarwal MD, DSc
Professor, Department of Radio-diagnosis & Dean, University
School of Medicine and Paramedical Health Sciences, Guru Gobind
Singh Indraprastha University, New Delhi
Dr. Neera Chaudhry MD, DM
Professor and Head,
Department of Neurology, Vardhman Mahavir Medical College
and Safdarjung Hospital, New Delhi 110029
Dr. R.S. Sethi MD
Professor, Consultant and Head,
Department of Nuclear Medicine, Vardhman Mahavir Medical
College and Safdarjung Hospital, New Delhi 110029
Dr. Ritu Nair Mishra MD
Professor,Consultant and Head, Department of Radio-diagnosis,
Vardhman Mahavir Medical College and Safdarjung Hospital,
New Delhi 110029
Dr. N.N Mathur MS, DNB, FAMS
Principal & Director Professor,
Vardhman Mahavir Medical College and Safdarjung Hospital,
New Delhi 110029
Dr. Sunil Gupta MBBS, MD
Medical Superintendent
Vardhman Mahavir Medical College and Safdarjung Hospital,
New Delhi 110029
ii
 DECLARATION

I hereby declare that the thesis protocol titled “Spectrum of cerebral white matter tract changes
and perfusion abnormalities in diverse types of dementia” is being submitted by me to the Guru
Gobind Singh Indraprastha University for the award of degree of Doctor of Medicine (Radio-
diagnosis). Such a study has not been undertaken in the last five years under the Guru Gobind Singh
Indraprastha University.

Dr. Apratim Roy Choudhury

iii
 CERTIFICATE

This is to certify that the work entitled, “Spectrum of cerebral white matter tract changes and
perfusion abnormalities in diverse types of dementia” shall be carried out by Dr. Apratim Roy
Choudhury under our guidance and supervision in the Departments of Radio-diagnosis, Neurology
and Nuclear Medicine, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi.

Signature of the Supervisor

Name of the Supervisor
Dr. Yatish Agarwal MD, DSc
Professor and Consultant, Department of
Radiodiagnosis & Dean, University School of Medicine
and Paramedical Health Sciences, Guru Gobind Singh
Indraprastha University, New Delhi

Signature of the Co-Supervisor

Name of the Co-Supervisor
Dr. Neera Chaudhry MD, DM
Professor and Head,
Department of Neurology,
Vardhman Mahavir Medical College and Safdarjung
Hospital, New Delhi 110029

Signature of Co-Supervisor
Name of the Co-Supervisor
Dr. R.S. Sethi MD
Professor, Consultant and Head,
Department of Nuclear Medicine,
Vardhman Mahavir Medical College and Safdarjung
Hospital, New Delhi 110029

iv
 CERTIFICATE

This is to certify that the work entitled, “Spectrum of Cerebral White Matter Tract Changes and Perfusion
Abnormalities in Diverse Types of Dementia”, shall be carried out in the Department of Radio-diagnosis,
Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi.

It is certified that the study is feasible in the given time frame and that the institution has the machinery and
equipment and other essential prerequisites for conducting the study; and that the study sample size has been
calculated on the basis of relatable statistical formula, and that it satisfies the requirements of study design
and the proposed statistical analysis.

It is certified that the thesis plan is not a repetition of a similar study undertaken in the previous five years in
the university, and that the study is not based on a retrospective collection or analyses of data from old
patient case records, and that it does not employ any “off-label drug trial”.

We undertake that the participants enrolled in the thesis project will not have to bear any financial burden on
account of the investigations, devices, implants or drugs employed as a part of the study, and that the study
does not require us to partake of any obligation or any favour from a pharmaceutical company, device
manufacturer or medical supplier.

Signature of the candidate

Name of the candidate Dr. Apratim Roy Choudhury

Signature of Supervisor
Name of Supervisor Dr. Yatish Agarwal MD, DSc
Professor and Consultant, Department of Radiodiagnosis &
Dean, University School of Medicine and Paramedical Health
Sciences, Guru Gobind Singh Indraprastha University, New Delhi

Signature of Co-Supervisor
Name of Co-Supervisor Dr. Neera Chaudhry MD, DM
Professor and Head,
Department of Neurology,
Vardhman Mahavir Medical College and Safdarjung Hospital

Signature of Co-Supervisor
Name of Co-Supervisor Dr. R.S. Sethi MD
Professor, Consultant and Head,
Department of Nuclear Medicine,
Vardhman Mahavir Medical College and Safdarjung Hospital

Signature of Head of Department

Name of Head of Department Dr. Ritu Nair Mishra MD
Professor, Consultant and Head, Department of Radio-diagnosis,
Vardhman Mahavir Medical College and Safdarjung Hospital

v
 UNDERTAKING

I care to abide by the ethical guidelines for biomedical research on human subject (as per the
ICMR guidelines) while conducting the research project being submitted for ethical committee
consideration.

1. This project is absolutely essential for the advancement of knowledge and for the benefit of all.

2. Only subjects who volunteer for the study will be included. Their informed consent will be
obtained prior to commencement of the study and the subjects will be kept fully appraised of
all the consequences.

3. Privacy and confidentiality of the subjects shall be maintained and without the consent of the
subject, no disclosure shall be made.

4. Proper precautions shall be taken so as to minimize risk and prevent irreversible side effects.

5. The study will be conducted by professionally competent persons.

6. The study will be conducted in a fair, honest, impartial and transparent manner. Researcher
(that is myself) shall be accountable for maintaining proper records.

7. The study will be conducted keeping in view of the public interest at large.

8. Study reports, materials and data will be preserved.

9. Result of the study will be made known through scientific publications.

10. Professional and moral responsibilities will be of the researcher, directly or indirectly
connected with the research.

11. The protocol has been discussed and approved in my department.

Signature of candidate
Name of the candidate Dr. Apratim Roy Choudhury
MD (Radio-diagnosis) Student
Vardhman Mahavir Medical College
and Safdarjung Hospital,
New Delhi 110029

vi
 INSTITUTIONAL REVIEW BOARD CERTIFICATE

The Institutional Review Board/Thesis Protocol Review Committee of VMMC & Safdarjung
Hospital has reviewed and discussed the research proposal entitled “Spectrum of cerebral white
matter tract changes and perfusion abnormalities in diverse types of dementia”.

The Institutional Review Board duly reviewed the thesis protocol in line with the formally ratified
2019 regulations of the USM & PMHS, Guru Gobind Singh Indraprastha University, and found the
Introduction; Review of Literature; Lacunae in existing knowledge; Research question and
Hypothesis; Aims and Objectives; Material and Methods; Statistical methods; References; and
Appendices to be suitably drawn and based on sound scientific and ethical foundation.

The Institutional Review Board confirms that the supervisor and co-supervisors of the study meet
the formally ratified 2019 regulations of the USM & PMHS, Guru Gobind Singh Indraprastha
University, and that neither the supervisor nor co-supervisors are a part of thesis projects more than
that permitted to them.

The Institutional Review Board/Thesis Protocol Review Committee meeting was chaired by
__________________________________and the following members of the committee were
present during the meeting:
1.
2.
3.
4.
5.
6.
The Institutional Review Board/Thesis Protocol Review Committee approved the
study to be conducted in the present form at VMMC & Safdarjung Hospital, New Delhi.

Signed by the Chair,

Institutional Review Board/Thesis
Protocol Review Committee

Signed by the Dean/Head of Institution,

Name of the Dean/Head of Institution

vii
viii
 TABLE OF CONTENTS

S. No. Content Page numbers

1. Introduction 1-2
2. Review of Literature 3-5
3. Research Question and Hypothesis 6
4. Lacunae in Existing Knowledge 7
5. Aims and Objectives 8
6. Materials and Methods 9-12
7. Statistical Methods 12
8. Study Flow Chart 13
8. References 14-15

Appendices
Undertaking vi
Questionnaire 22-23
Study Proforma 24-26
Patient Information Sheet 16-19
Informed Consent Form 20-21
Candidate’s Check List 27-29

ix
 INTRODUCTION

A common geriatric problem, dementia — more recently reclassified as a major neurocognitive

disorder [1] — accounts for considerable morbidity and a significantly reduced quality of life.[2] It
produces a progressive loss of memory and a decline in cognitive faculties such as judgement,
language and planning skills, and impairment in social function and daily activities.

The prevalence of dementia has been on the rise in the Indian population, with variable rates reported
in different regions of the country which range between 0.6 % and 3.5% in the rural areas and 0.9%
to 4.8 % in urban areas. [3,4]

Dementia can be of many types. Of them, Alzheimer’s disease (AD) is the commonest, followed, in
turn, by vascular dementia (VaD), frontotemporal dementia (FTD), diffuse Lewy body disease (LBD)
and mixed dementia. Each type is characterized by a distinct pathological change. For example, while
AD is marked by deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles
in the grey matter areas of medial temporal lobe and anterior and posterior cingulate regions; VaD is
associated with diminished cerebrovascular flow and heterogeneous findings peculiar to the anatomic
location of vascular compromise; FTD is characterized by atrophy of the frontal and anterior temporal
lobes; and DLB features presence of Lewy bodies in the neurons of cerebral cortex. However, these
pathological changes until hitherto, can only be identified on brain tissue autopsy following a patient’s
demise. [5]

Till date, dementia is usually diagnosed clinically based on DSM-5 criteria. There are certain clinical
scores like the Montreal Cognitive Assessment Score (MoCA) and the Addenbrook’s Cognitive
Examination 3 (ACE 3) score [6] which are used to assess the cognitive status of the patient. To
identify the type of dementia, there are also specific criteria like the NINCDS-ADRDA (National
Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and
Related Disorders association) for AD and NINDS-AIREN (National Institute of Neurological
Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en
Neurosciences) for vascular dementia. However, with new therapeutic molecules being discovered
for halting the progression and treatment of dementia, there has been a great interest in early diagnosis
of the disease in vivo and thus comes the role of neuro-imaging.

There are several options of imaging the brain ranging from Non-Contrast CT Scan to newer MRI
sequences like Diffusion Tensor imaging [7], and also perfusion imaging using radionuclides.
Structural scans like NCCT or conventional MRI sequences cannot detect early changes of reduced
perfusion or subtle white matter abnormalities in the patients of dementia. However, MRI sequences
like DTI has the capability of detection of subtle white matter abnormalities and 99m Tc-ECD scan, a
type of radionuclide scan can detect reduced cerebral blood flow in specific areas of the brain at an
incipient stage of the disease [8].

1
Endowed with the ability to determine the orientation and integrity of WM tracts by measuring the
diffusion of water molecules in the neural tissue and being able to demonstrate subtle changes in the
white matter, DTI can quantitatively measure the white matter abnormality by measuring the degree
of anisotropy (fractional anisotropy, FA) of water molecules locally in the region of interest (ROI).[9]

Some recent studies [10-12] have demonstrated specific white matter changes in AD with significant
lower FA in the corpus callosum as well as in the frontal, parietal and temporal lobes in comparison
to healthy controls. They have also found strong correlations between MMSE score and the detectable
white matter change. In the same way, in DLB, the FA change has a pattern of posterior
predominance, with involvement of the parieto-occipital and temporal white matter tracts and with
relative sparing of the frontal lobes. [13] Specific patterns of white matter changes can also possibly
help distinguish between AD and VaD: while para hippocampal tracts stand predominantly affected
in AD, VaD demonstrates more widespread white matter changes. In VaD, genu of the corpus
callosum is predominantly affected, while in AD, splenium takes the brunt. [14-15]

Regional blood flow to regions of the brain are studied by 99m Tc-ECD scan. Studies have shown,
there is evidence of reduced relative Cerebral Blood Flow (rCBF) in the bilateral temporo-parietal
lobes in AD patients. Flow reductions in temporal and frontal regions without posterior extension
indicates Fronto-Temporal Dementia. Similarly, global hypo perfusion indicates vascular dementia,
whereas occipital lobe hypo perfusion is indicative of Dementia with Lewy Body (DLB).[16-19]

The current study will endeavor to determine the type of dementia in clinical setting by unfolding
these potential determinant roles of DTI and SPECT, and also correlate diffusion parameters of white
matter with the perfusion parameters of the brain.

2
 REVIEW OF LITERATURE
Dementia, a common problem in the geriatric population is clinically diagnosed by criteria set by
Diagnostic and Statistical Manual of Mental Disorders,5th edition (DSM-5).[1] Additionally, there are
several sets clinical criteria for the diagnosis of diverse types of dementia, like the NINCDS-ADRDA
criterion for diagnosis of Alzheimer’s Disease and NINDS-AIREN criterion for diagnosis of Vascular
dementia. Newer and functional neuroimaging techniques like DTI measuring diffusion
abnormalities of white matter tracts and 99mTc-ECD SPECT Scan quantifying cerebral perfusion
abnormalities play a complimentary role in the diagnosis and classification of diverse types of
dementia.

Types of Dementia
Globally the most common dementia is Alzheimer’s Disease (AD) followed by Vascular Dementia
(VaD). The other common types of dementia include Fronto-Temporal dementia (FTD) and Dementia
with Lewy Body (DLB).

Pathological Characteristics
Each type of dementia is characterized by distinct pathological findings, for example presence of
amyloid plaques in AD, subcortical infarct, temporal lobe sclerosis and periventricular
leukoencephalopathy in Vascular dementia. FTD is characterized by frontal and temporal lobe
atrophy whereas DLB shows presence of alpha-synuclein, commonly known as Lewy Body in the
cortical and subcortical areas. These pathological changes are quite specific and thus are considered
to be the gold standard in diagnosis, however pathological diagnosis is achievable only after demise
of the patient and thus it is not much useful in management. [6]

Clinical Diagnosis
Dementia is diagnosed clinically by the DSM-5 criterion. The severity of cognitive dysfunction is
graded by clinical scores like the Montreal Cognitive Assessment Score (MoCA) and the
Addenbrook’s Cognitive Examination 3 (ACE 3) score. To identify the type of dementia specific
clinical criteria are used like NINCDS-ADRDA (National Institute of Neurological and
Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders association)
for AD and NINDS-AIREN (National Institute of Neurological Disorders and Stroke and Association
Internationale pour la Recherché et l'Enseignement en Neurosciences) for vascular dementia.

Role of Imaging
Imaging in patients suspected of having dementia has shifted from an exclusionary to inclusionary
approach and every modality of imaging like CT and MRI has some specific functions to fulfil.
However in the present day scenario, where early diagnosis and proper characterization of the disease
is of utmost importance functional neuroimaging modalities like DTI and 99m Tc-ECD scan are
playing pivotal roles.[7]

3
Computed Tomography
Non Contrast CT Scan has a limited role in neuro-imaging of dementia. It is useful only to exclude
the surgical causes of the disease like subdural hematoma and tumors.

Nuclear imaging
Nuclear imaging modalities like 99mTc ECD (ethyl cysteinate dimer) Single Photon Emission
Computed Tomography (SPECT) can demonstrate decreased metabolism and reduced cerebral
perfusion before the structural changes become apparent. [8]

Conventional MRI Sequences

Conventional MRI can assess extent and areas of brain atrophy, can detect degree of vascular
compromise but it cannot detect early changes of dementia.

Diffusion tensor magnetic resonance imaging (DTI)

Diffusion tensor magnetic resonance imaging (DTI) measures the degree and direction of diffusion
of water molecules and provides information about the size, shape, orientation and geometry of brain
structures. It also demonstrates the white matter abnormalities not detected on conventional MRI.

The preference of diffusion of water molecules in the direction of the fibers is called fractional
anisotropy (FA) and it is used in mapping the functional integrity and specific organization of white
matter tracts. [9-13]

Studies on DTI have shown that in AD the fractional anisotropy (FA) values are statistically
significantly lower in the corpus callosum, the white matter tracts of frontal, parietal and temporal
lobes, and also in the posterior cingulum, superior longitudinal fasciculus and uncinate fasciculus
compared to healthy controls. Strong correlations have been observed between the declining FA score
and the worsening cognitive status of the patients. It was further seen that in AD the splenium of
corpus callosum was affected more compared to genu. [11-13]

In dementia with Lewy Body (DLB), altered measurements of FA have been reported in the parieto-
occipital and temporal white matter tracts with relative sparing of the frontal lobes.

In FTD the white matter tracts of frontal and temporal lobe, along with splenium of corpus callosum
have been found to be more severely affected.[13,20]

Studies on brain perfusion SPECT have demonstrated reduced cerebral perfusion in dementia. It has
also been found that in early AD reduced flow occurs in the inferior medial aspect of temporal lobe
while limbic structures, posterior temporal lobe and parietal lobes show diminished flow as the
disease progresses. Reduced flow to occipital lobe signifies DLB while frontal and temporal hypo-
4
perfusion indicated FTD. Global hypo-perfusion was seen in vascular dementia. [16]

Significance of in vivo determination of type of dementia

As new therapies develop for AD and other forms of dementia, early and specific diagnosis of type
of dementia may help improve the management, outcome and prognosis. [21]

5
 RESEARCH QUESTIONS AND HYPOTHESIS

Research questions:

 Does dementia diminish fractional anisotropy in the cerebral white matter tracts identifiable
on diffusion tensor imaging, and do these abnormalities affect specific anatomic areas of the
brain in different types of dementia?

 Does the degree of cerebral white matter tract diffusion abnormality run congruent with the
cognitive status of the patients and do the affected brain regions also suffer from impaired
perfusion?

Hypothesis:
Dementia diminishes fractional anisotropy in cerebral white matter tracts, and different
types of dementia affect white matter tracts in specific anatomic areas of the brain. The
degree of diffusion abnormality runs congruent with the cognitive dysfunction and the
affected brain regions also suffer from impaired perfusion.

6
 LACUNA IN EXISTING KNOWLEDGE
Literature comparing the role of DTI and 99m Tc-ECD scan in in identifying and establishing the
severity of different types of dementia is scarce.

7
 AIM AND OBJECTIVES
Aim:
• To study the spectrum of white matter tract changes and perfusion abnormalities in
diverse types of dementia.
Objectives:
• To determine the role of in measuring the diffusion abnormality of cerebral white matter
tracts and the role of 99m Tc-ECD (ethyl cysteinate dimer) scan in assessment of reduced
cerebral blood flow in patients with dementia.
• To determine if the degree of diffusion abnormality in cerebral white matter tracts runs
congruent to cognitive status of patients with dementia.
• To determine if the degree of impairment of cerebral perfusion runs congruent to cognitive
status of patients with dementia.

• To determine if the DTI and/or 99m Tc-ECD findings have any correlation with each other.
• To determine if the alterations in measurements of fractional anisotropy and/or relative
cerebral blood flow can identify specific types of dementia.

8
 MATERIALS AND METHODS
1.0 Study design
Case Control Study

2.0 Study setting

The proposed study will be carried out in the Department of Radio-diagnosis in collaboration with
Department of Neurology and Department of Nuclear Medicine, Vardhman Mahavir Medical College
and Safdarjung Hospital, New Delhi.

3.0 Study period

The study will be conducted over a period of 18 months.

4.0 Size of the sample

A previous study has employed DTI to assess the white matter damage in AD. [11] This study found
the mean FA values of white matter areas to be 0.32 ± 0.04 in AD and 0.37 ± 0.02 in controls. By
employing these values as reference, the following formula can be used to provide the minimum
required sample size which would carry 90% power of study and 5% level of significance:

N= (Zα+Zβ)2 x σ2
Ϩ2
Where,
N is the sample size in each group,
Zα is value of Z at two-sided alpha error of 5%,
Zβ is value of Z at 90% confidence interval
σ refers to the pooled standard deviation, and
Ϩ is the difference in the mean values of cases and controls

Since the value of Zα is 1.96 while that of Zβ is 1.282, and σ is 0.03 and Ϩ equals 0.05, when
N is calculated,
N= (1.96+1.282)2 x (0.03)2
(0.05)2
N= 10

Thus the value of N equals to 10, however to reduce the margin of error, the total number of
participants to be included in the study will be 50 (35 cases and 15 controls). In these 50 patients MRI
brain and 99m Tc-ECD brain SPECT scan will be carried out.

9
5.0 Selection of participants
Each patient above 40 years of age presenting to the neurology outpatients with cognitive impairment
and diagnosed as Dementia as per the DSM criteria, willing to participate in the study, will be enrolled
for the study.

Inclusion Criteria:
 All patients age > 40 years; diagnosed as dementia under the DSM criteria.
 Age matched healthy subjects will act as controls.

Exclusion criteria:
The following shall not be included in the study:
 Such patients who cannot be taken for a MRI study due to one or the other contraindication.
 Such patients who are known to have a major territorial infarct.
 Such patients who are known to have an intra axial SOL in the brain.
 Such patients who have a history of seizure disorder.
 Pregnant women.
 Patients with prior history of radiotherapy.

6.0 Methodology
Written informed consent will be taken from each patient (or the patient’s legal guardian) who fulfils
the inclusion criteria and is willing to participate in the study. Detailed clinical history and
neurological examination (including Montreal cognitive assessment and Addenbrook’s Cognitive
Examination Score) will be undertaken in each patient and the findings will be duly recorded using a
pre-designed clinical proforma. Type of dementia will be assigned clinically for each patient based
on appropriate clinical criteria such as NINCDS-ADRDA criteria for probable Alzheimer’s disease;
NINDS-AIREN criteria for probable vascular dementia; clinical criteria for probable Lewy body
dementia by LBD association; clinical criteria for Behavioural variant fronto-temporal dementia by
international by FTD consortium diagnostic criteria. After detailed clinical evaluation the participants
will be subjected to MRI brain and Brain SPECT with 99mTc- ECD (ethyl cysteinate dimer).

6.0.1 Equipment
The MRI examination will be carried out on the 3T MR machine. (GE discovery MR750W 3T)
The SPECT examination will be done in Precedence-16 (SPECT/CT) Gamma Camera.

10
6.0.2 MRI Sequences
Brain imaging would be acquired in a single session on 3 tesla MRI system with the use of 32 channel
head coil. 3D T1, T2- weighted and T2- weighted fluid attenuated inversion recovery sequence
(FLAIR) images shall be obtained. Diffusion weighted Echo planar images would be acquired in the
same system with following parameters: TR/TE= 5016/85.3ms, FoV 256x256 mm2, matrix 128x128,
slice thickness 5mm with no interslice gap, b-value 1=0 s/mm2 and b-value 2= 1000 s/ mm2,
resolution 2x2x2 mm3. Diffusion sensitive gradients will be applied in optimized collinear directions.
Raw data will be corrected for geometric distortion secondary to eddy current. Maps of fractional
anisotropy will be generated from diffusion weighted images.

6.0.3 SPECT Imaging

Brain SPECT imaging with99mTc- ECD (ethyl cysteinate dimer) will be done. 20 mCi dose of
radiotracer will be injected intravenously and scan will be done 2 hours after injection using
Precedance-16 (SPECT/CT) Gamma Camera.

6.0.3 MRI image analysis

After acquisition of scan, all relevant images would be transferred to work station where image
reconstruction and post processing analysis is to be done. Diffusion tensor images will be
reconstructed from raw data in 3D neuro reconstruction application. Region of Interest (ROIs) of
variable size, depending on the anatomical region studied, will be placed bilaterally in the following
areas:
 White matter tracts in all four lobes i.e. frontal lobe, temporal lobe, parietal lobe and occipital
lobe
 Corpus callosum segmented into genu, body and splenium.
 Superior longitudinal fasciculus (SLF)
 Inferior longitudinal fasciculus (ILF)
 Uncinate fasciculus (UF)
 Posterior limb and genu of internal capsule
 Anterior and posterior pericallosal areas
The mean FA of cases and controls in all these areas will be compared using suitable statistical
methods.

6.0.4 SPECT Image analysis

After acquisition of the scan, all relevant images would be transferred to work station where image
reconstruction and post processing analysis is to be done. The relative Cerebral Blood Flow (rCBF)
of the following regions will be studied:
 All 4 lobes of the bilateral cerebral hemispheres.
 Posterior cingulate gyrus and pre-cuneus
 Medial temporal lobe

11
The mean rCBF values of cases and controls in all these areas will be compared using suitable
statistical tests.

7.0 Statistical analysis

The data will be entered in MS EXCEL spreadsheet and analysis will be done using Statistical
Package for Social Sciences (SPSS) version 21.0. Categorical variables, like the Montreal Score will
be presented in number and continuous variables, like FA and rCBF will be presented as mean ± SD.
Normality of data will be tested by appropriate statistical tests like Kolmogorov- Smirnov Test or
Shapiro-Wilk Test. If the data is not normally distributed then nonparametric test will be used. The
following comparisons will be made:

 FA values of white matter tracts of dementia patients (cases) will be compared with
corresponding FA values of controls by the 2group t test.
 Correlation between average FA values of all the white matter tracts with the Montreal Score
will be done by Spearman’s rank correlation co-efficient.
 rCBF values of all the mentioned areas of the brain of cases will be compared with the
corresponding rCBF values of controls using 2group t test.
 Correlation between average rCBF values of all the mentioned areas of the brain with the
Montreal Score will be done by Spearman’s rank correlation co-efficient.
 Correlation between average rCBF values of all the mentioned areas of the brain with the
average FA values of all the white matter tracts will be done by Spearman/ Pearson correlation
coefficient.

A p value of <0.05 will be considered statistically significant.

12
 STUDY FLOW CHART

Patients diagnosed of having dementia clinically will be considered as cases and age matched
participants with no signs of cognitive impairment will be taken as controls.

Informed Consent and detailed clinical

history will be taken to plan further
course of action.

Participants fitting into

exclusion criteria will
not be included

Participants will undergo MRI Brain Participants will also undergo Brain
examination. The sequences will include Perfusion Imaging using 99mTc ECD
T1, T2, FLAIR and DTI

Fractional Anisotropy values of relative Cerebral Blood Flow (rCBF) of

specified white matter tracts will be specific areas of brain will be calculated.
calculated

Statistical Analysis

13
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Arlington:American Psychiatric Pub; 2013 May 22.592.
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diencephalic network and methodological considerations. Frontiers in aging neuroscience. 2014;6:266
10. Sexton CE, Kalu UG, Filippini N, Mackay CE, Ebmeier KP. A meta-analysis of diffusion tensor imaging
in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2011;32:2322.5-18.
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Alzheimer’s disease assessed in vivo using diffusion tensor magnetic resonance imaging. J Neurol
Neurosurg Psychiatry. 2002;72:742–6.
12. Duan JH, Wang HQ, Xu J, Lin X, Chen SQ, Kang Z, et al. White matter damage of patients with
Alzheimer’s disease correlated with the decreased cognitive function. Surg Radiol Anat. 2006;28:150–6.
13. Watson R, Blamire AM, Colloby SJ, Wood JS, Barber R, He J, et al. Characterizing dementia with Lewy
bodies by means of diffusion tensor imaging. Neurol. 2012;79:906-14.
14. Palesi F, De Rinaldis A, Vitali P, Castellazzi G, Casiraghi L, Germani G, et al. Specific patterns of white
matter alterations help distinguishing Alzheimer’s and Vascular Dementia. Front Neurosc. 2018;12:274.
15. Bonte F, Harris T, Hynan L, Bigio E, White C. Tc-99m HMPAO SPECT in the Differential Diagnosis of
the Dementias with Histopathologic Confirmation. Clin Nucl Med. 2006;31(7):376-8.
16. McNeill R, Sare G, Manoharan M, Testa H, Mann D, Neary D et al. Accuracy of single-photon emission
computed tomography in differentiating frontotemporal dementia from Alzheimer's disease. J Neurol
Neurosurg Psychiatry. 2006;78(4):350-5.
17. Matsuda H. Role of Neuroimaging in Alzheimer's Disease, with Emphasis on Brain Perfusion SPECT. J
Nucl Med. 2007;48(8):1289-300.

14
18. Cavallin L, Axelsson R, Wahlund L, Öksengard A, Svensson L, Juhlin P et al. Voxel-based correlation
between coregistered single-photon emission computed tomography and dynamic susceptibility contrast
magnetic resonance imaging in subjects with suspected alzheimer disease. Acta Radiol.
2008;49(10):1154-61.
19. Beach T, Monsell S, Phillips L, Kukull W. Accuracy of the Clinical Diagnosis of Alzheimer Disease at
National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropath Exp Neur.
2012;71(4):266-273.
20. Lu PH, Lee GJ, Shapira J, Jimenez E, Mather MJ, Thompson PM, et al. Regional differences in white
matter breakdown between frontotemporal dementia and early-onset Alzheimer's disease. J Alzheimers
Dis. 2014;39:261-9.
21. Lambracht-Washington D, Rosenberg RN. Advances in the development of vaccines for Alzheimer's
disease. Discov Med. 2013 May;15:319.

15
 Annexure 1A
PARTICIPANT INFORMATION SHEET

You are invited to participate in the study, “Spectrum of Cerebral White Matter Tract Changes
and Perfusion Abnormalities in Diverse Types of Dementia”. Before you take part in the study,
we wish to explain about the details of the study, and give you the chance to ask questions. Please
read carefully the information provided here. If you agree to participate, please sign the informed
consent form.
Introduction: Dementia is a common health problem which occurs in middle and late years of life.
It leads to a reduced quality of life. The doctor makes the diagnosis on the basis of symptoms and
clinical examination. However, MRI and SPECT can play a useful role in identifying the extent of
brain changes caused by the illness. The identification of these changes can validate the doctor’s
diagnosis and help in the management.
Purpose: This study aims to identify the brain changes in different forms of illness which presents
with forgetfulness and or other symptoms of brain dysfunction.
Method: If you are willing to participate in the study, you will be asked to report on specified dates.
A complete clinical history and examination will be conducted. You will undergo MRI of the brain
and brain SPECT imaging.
Risks: The MRI scanning is a safe diagnostic modality with no risk of ionizing radiation. However, if
you have a metallic implant or pacemaker device you should not undergo MRI scanning. Brain
SPECT has minimum exposure to radiation, however it carries little or no risk.
Benefits: By participating in the study, the scans will guide your diagnosis and the doctor will
understand the disease condition better.
Costs: You shall be exempted from the cost of the study.
Study rights: It is your right to decide whether to take part or not to take part in this study. You are
free to ask us if you have any queries or concern.
Confidentiality: All your information and personal details shall be kept strictly confidential and shall
be accessible only to the study investigators. In future, the results of the study may be published in a
scientific journal but your identity will not be disclosed.

16
Contact for further information: Should you have any question or queries, you may contact

Dr. Apratim Roy Choudhury,

Department of Radiodiagnosis,
VMMC and Safdarjung Hospital,
New-Delhi –110029
Contact number: 9874456495
Email: apratim2710@gmail.com

Dr. Yatish Agarwal,

Professor and Consultant, Department of Radiodiagnosis &
Dean, University School of Medicine and Paramedical Health Sciences,
Guru Gobind Singh Indraprastha University, New Delhi
Contact number: 011-2617943

17
 Annexure 1B

पपपपपपपपप पपपपप पपपप

आआआआ " मममममममम मम ममममम मममममममम ममम मममममममम मममममम मममम
ममममममम मममममममम मम ममममममम मममममममममम मम पपपपपप " आआआआआआ आआआ
आआआ आआआआ आआ आआआ आआआआआआआआ आआआआ आआआ आआआ आआआआआआ आआआ आआआ
आआआआ आआ आआआआ, आआ आआआआ आआआआआआ आआ आआआआ आआआ आआआआआआआ आआ
आआआआआ आआआआआ आआआ, आआ आआआआआआ आआआआआ आआ आआआआ आआआआआआ आआआआ
आआआआआ आआआआ आआआआआ आआआआ आआ आआ आआआआआआआ आआ आआआआआ आआ
आआआआआआ आआआ आआ आआआ आआआआ आआ आआआ आआआआ आआआ, आआ आआआआआ आआआआआ
आआआआआ आआआआआ आआ आआआआआआआआआ आआआआआ
पपपपप: आआआआआआआआआ आआ आआ आआआआआआआआआ आआआआआआ आआ आआ आआआआ आआ
आआआआ आआ आआआ आआ आआआआआआ आआआ आआआआ आआआ आआआआ आआआआ आआआआ आआ
आआआआआआआआ आआ आआ आआआआ आआआ आआआआआआआआ, आआआआआआआ आआ आआआआआआआ
आआआआआआआआआ आआ आआआआ आआ आआआ आआ आआआआआआआआआ आआआआ आआआ
आआआआआआआ, आआआआआआ आआ आआआआआआआआआ आआआआआआ आआ आआआआ आआआआआआआआ
आआआ आआआआ आआआआ आआआआआआआआआआ आआ आआआआ आआ आआआआआ आआआआ आआआ आआ
आआआआआआ आआआआआआ आआआआ आआआआ आआआआ आआ आआआआआआआआआआ आआ आआआआआ
आआआआआआ आआ आआआ-आआआआआ आआ आआआआआआ आआ आआआआ आआआ आआ आआआआआआआ
आआआ आआआआआआ आआ आआआआ आआआआ
पपपपपपपप: आआ आआआआआआ आआ आआआआआआआआ आआआआआआ आआ आआआआआआआ
आआआआआ आआआ आआआआआआआआ आआ आआआआआआआआआआ आआ आआआआआ आआआआ आआ आआ
आआआआआ आआ आआआआआआ आआ आआआआआआआआ आआ आआआआआआआआआआ आआ आआआआ
आआआआआआआ आआ आआआ आआआ आआआआआ आआआआ आआआआ
पपपप: आआआ आआ आआआआआआ आआआ आआआ आआआआ आआ आआआआआआ आआआ, आआ आआआआ
आआआआआआआआआ आआआआआआआ आआ आआआआआआआ आआआआ आआ आआआ आआआ आआआआआआ
आआ आआआआआ आआआआआआआआ आआआआआआ आआ आआआआआआआ आआआआ आआआआआआ आआआआ
आआआआआआआआ आआ आआआआआआ आआ आआआआआ आआआआआआआ आआआआआआआ आआआआ
आआआआआआआ
पपपपप: आआआआआआ आआआआआआआआ आआ आआआआआआआआ आआआआआआआ आआआआआआ आआ
आआआआआआ आआआआआआ आआआआआआ आआ आआआ आआआआआ आआआआ आआआ आआआआआआआ,
आआआ आआआआ आआआआ आआआआआआआआआआआ आआआ आआ आा आआआआआआआ आआआआआआ
आआआ आआआ आआ, आआ आआआआ आआआआआआ आआआआआआआआ आआआआ आआआआआआ आआआआआआ
आआआआआ आआआआआआआ आआ आआआआआआ आआ आआआआआआआ आआआआआआ आआआआ आआ,
आआआआआआआ आआआआआ आआआआ आआ आआ आआआ आआआआआ आआआआ आआआआ आआआ
पपप: आआआआआआ आआआ आआआ आआआआ आआ, आआआआआ आआआआ आआआ आआ आआआआआ
आआआआ आआआ आआआआआ आआआआआ आआआआआ आआ आआआआआआ आआआआआआ आआ आआआआआआ
आआ आआआआआ आआआ आआ आआआ आआआआआआआ
पपपप: आआआआ आआआआआआ आआ आआआआ आआ आआआ आआ आआआआआआ
आआआआआआ आआ आआआआआआ: आआ आआ आआआआ आआ आआआआआआ आआआआ आआ आआ आआ
आआ आआआआआआ आआआ आआआ आआआआ आआआआआ आआआ आआ आआआआआ आआआ आआआआ आआआ
आआआआआआ आआ आआआआआ आआ आआ आआआआ आआआआआ आआआ आआआआआ आ आआआआआ
पपपपपपपप: आआआआ आआआ आआआआआआआ आआ आआआआआआआआआ आआआआआआआ आआ
आआआआआ आआ आआआआआआ आआआ आआआआआ आआ आआ आआआआ आआआआआआ
आआआआआआआआआआआ आआ आआआ आआ आआआआ आआआआआ आआआआआआ आआआ, आआआआआआ आआ
आआआआआआ आआआआ आआआआआआआआआ आआआआआआआ आआआ आआआआआआआआ आआ आआआआ
18
आआआ आआआआआ आआआआ आआआआआ आआआआआ आआआ आआआआआआ

मममम ममममममम मम ममम मममममम मममम:

मम ममममममम ममम ममममम
आआआआआआ आआआआआ
आआआआआआआआ आआ आआआआआआआ आआआआआआआ,
आआ आआआआआआ -110029
आआआआआआ आआआआआआ 9874456495
आआआआ apratim2710@gmail.com

पप पपपप पपपपपपप
आआआआआआआआ आआआ आआआआआआआआआआ
आआआआआआ आआआआआ
आआआआआआआआ आआ आआआआआआआ आआआआआआआ,
आआ आआआआआआ -110029
आआआ, आआआआआआआआआआआ आआआआआ आआ आआआआआआआ आआआ आआआआआआआआआआ आआआआआ
आआआआआआआ
आआआआ आआआआआआ आआआआ आआआआआआआआआआआ आआआआआआआआआआआ ,आआ आआआआआआ
आआआआआआ आआआआआआ 011 26179434

19
 Annexure 2A
FORM OF INFORMED CONSENT

Study Title: Spectrum of Cerebral White Matter Tract Changes and Perfusion Abnormalities in
Diverse Types of Dementia

Subject’s name: Subject number/id:

I confirm that I have read and understood the information sheet for the above study and had the
opportunity to ask the questions. I understand that the participation in the study is voluntary and I
reserve my rights to withdraw from study whenever I wish.

I son/daughter of resident of

do hereby give my consent for participation in the study. I also agree to the use of data
originating from this study for scientific purpose(s) without disclosing my identity.

Date: Signature of Participant/Thumb impression

Place:

Signature of witness:

Signature of investigator:

Annexure 2B
20
 ममममम ममममम मम ममममम

ाााााा ाा ाााााा: मममममममम मम ममममम मममममममम ममम मममममममम मममममम

मममम ममममममम मममममममम मम ममममममम मममममममममम मम पपपपपप ा

ााााााााा ाा ााा : ााााााााा ाााााा /ाााा:

ााा ाााााा ाााा ााा ाा ााााा ााााााा ाााााा ाा ााा ााााा ाााा ाााा
ाा ाााा ाा ाा ाााा ाााााा ााााा ाा ाााााााा ाााा ाााा ााा ााा
ााााा ााा ाा ाााााा ााा ााा ाााा ााााााााा ाा ाा ााा ाा ाा ााााा
ाााााा ाा ाााा ाा ाााााा ाााा ााा ाााााााा ााा

ााा ____________ ााााा/ाााााा _______________ाााााा ________________ाााााा

ााा ााा ाााा ाा ााा ाााा ााााा ाााा/ाााा ाााा ााा ाााा ााााा ाा
ाााााा ा ाााा ाााा ाा ाााा ाा ाा ाााााा ाा ााााााा ाााााा ाा
ााााााााा ाााााा ाा ााा ााााा ाा ााा ाा ााााा ाााा /ाााा ाााा

ाााााा:

ााााााााा ाा ााााााााा / ाााााा ाा ााााा

ााा:

ाााा ाा ााााााााा:

ााााााााा ाा ााााााााा:

MRI QUESTIONNAIRE

Name of the patient: Age/Sex:

Reference number: Clinical diagnosis:
The following items may be potentially hazardous or contraindicated and may interfere with the
MRI examination by producing an artefact. Please indicate if you any of the following:
21
 Cardiac Pacemaker Yes ___ No ___
 Aneurysm clip Yes ___ No ___
 Implanted insulin pump Yes ___ No ___
 Implanted drug infusion pump Yes ___ No ___
 Bone growth stimulator Yes ___ No ___
 Neurostimulator (TENS unit) Yes___ No___
 Any type of biostimulator
 Any type of internal electrode(s), including
-Pacing wires Yes___ No___
-Internal hearing and Yes___ No___
-Cochlear implant Yes___ No___
 Any type of intravascular coil, filter or stent
(e.g. Gainturco coil, Gunther IVC filter, Palmaz stent?) Yes___ No___
 Any type of electronic, mechanical or magnetic implant Yes___ No___
 Any metallic foreign body, shrapnel or bullet Yes___ No___
 Swan-Ganz catheter Yes___ No___
 Halo vest or metallic fixation device Yes___ No___

The following items may interfere with the MRI examination by producing an artefact. Please
indicate if you have any of the following:
 Vascular clip(s) Yes___ No___
 Hemostatic clip(s) Yes___ No___
 Orbital/eye prosthesis Yes___ No___
 Wire suture(s) Yes___ No___
 Any type of implant held by magnet Yes___ No___
 Any other implanted material Yes___ No___
 Type Yes___ No___
 Heart valve prosthesis Yes___ No___
 Any type of ear implant Yes___ No___
 Penile prosthesis Yes___ No___
 Tattooed eyeliner Yes___ No___
 Lens implant held in by metallic suture Yes___ No___
 Diaphragm Yes___ No___
 Renal shunt Yes___ No___
 Intraventricular shunt Yes___ No___
 Wire mesh Yes___ No___
 Artificial limb or joint Yes___ No___
 Any implanted orthopaedic item(i.e. pins,rods,
screws, nails, clips, plates, wires) Yes___ No___
 Dentures Yes___ No___
 Dental braces Yes___ No___
 Any type of removable dental item Yes___ No___

22
Name and signature of the patient: Date:

Name and signature of the doctor: Date:

23
 Annexure 3

STUDY PROFORMA

I/D No: Name: Age: Sex: M/F

Contact Numbers:
Address:
Education:
Occupation:
Brief Clinical History:

Duration since diagnosis:

Neuropsychiatric examination findings:

 Montreal Cognitive Assessment:

 Addenbrook’s Cognitive Examination 3 Score:

 Type of dementia, clinically:

Clinical diagnosis:

Conventional MRI Brain Findings:

 Axial T1
 Sagittal T1
 Coronal T1
 Axial T2
 Sagittal T2
 Coronal T2
 Axial FLAIR

24
DTI Findings:

Tracts Fractional anisotropy

values
Right Left
White matter of frontal lobe (three contiguous slices starting
from the most cranial slice which included a fully volumed
lateral ventricle in at least one hemisphere.)
White matter of parietal lobe (in the white matter posterior to
the central sulcus on the most caudal slice where it was visible
and on the subsequent more cranial slice)
White matter of temporal lobe (on three contiguous slices and
the ROIs were placed postero-laterally to the lateral fissure,
starting from the most caudal slice on which it was present)
White matter of occipital lobe (in the optic radiations on two
contiguous slices, starting from the most caudal slice on which
the occipital horn of the lateral ventricle was imaged)
Internal capsule
 Genu (regions bounded by the corner
between the head of the caudate nucleus and the pallidum)
 Posterior limb (regions bounded by the pallidum and the
thalamus)
Peri-callosal areas (The genu and the splenium of the corpus
callosum were sampled on the three consecutive slices on which
they are fully volumed)
 Anterior pericallosal areas
 Posterior Pericallosal areas
Superior longitudinal fasciculus (ROI on 5 axial slices lateral
to the corona radiata)
Inferior longitudinal fasciculus (Occipital ROI on 12 axial
slices (E) and temporal ROI on 5 axial slices in the anterior
portion of the temporal lobe)
Uncinate fasciculus (2 ROIs will be used- One temporal ROI
will be placed over the left temporal lobe9 white matter stem,
and a second sub-caudate ROI will be placed over the sub-
caudate white matter)
Corpus callosum (on the three consecutive slices on which
they are fully volumed)
 Genu
 Splenium

25
Brain Perfusion SPECT findings:

Brain Region rCBF Value

Right frontal lobe
Left frontal lobe
Right parietal lobe
Left parietal lobe
Right temporal lobe
Left temporal lobe
Right occipital lobe
Left occipital lobe
Right posterior cingulate gyrus
Left posterior cingulate gyrus
Right pre-cuneus
Left pre-cuneus
Right medial temporal lobe
Left medial temporal lobe

26
 University School of Medicine and Paramedical Health Sciences
Guru Gobind Singh Indraprastha University, New Delhi
Candidate’s Checklist
{to be filled and attached as a part of the thesis protocol }

Name: Course: Institution:

Title of the Thesis Protocol:

S. No. Checklist for Thesis Protocol Place (√) or (×)

Title Page of the Protocol
1. Does the title reflect the aims and objective(s) of the proposal? √
2. Does the title page include your name, course, batch year, college, university? √
First Preliminary Page of the Protocol
3. Does the page carry your name and signature? √
4. Does the page carry the name, university designation and signature of your thesis supervisor? √
5. Does the page carry the name, university designation and signature of the co-supervisor/s? √
6. Does the page carry the name and signature of your Head of Department? √
7. Does the page carry the name and signature of your Head of Institution? √
Undertaking and Certificates
8. Have you attached the declaration (5.5.1) that the thesis protocol does not violate the copyright act in any way, is free √
of plagiarism, and you’ve not reproduced any “questionnaires”, “scores”, diagrams, figures, tables, flowcharts which
may infringe the copyright act?
9. Have you attached your supervisor’s and co-supervisors certificate (5.5.2) that they would supervise and guide your √
work?
10. Have you attached certificate (5.5.3) bearing your own, your supervisor’s, your co-supervisors’ and Head of
Department’s signatures asserting the feasibility of the study; the study sample size having been calculated on the
basis of relatable statistical formula and satisfying the requirements of study design and the proposed statistical
analysis; the thesis plan not being a repetition of a similar work undertaken in the previous 5 years; the plan not
entailing a retrospective collection or analyses of data from old patient case records; not employing any “off-label drug
trial”; assertion that participants would not bear any financial burden on account of the investigations, devices,
implants or drugs employed; and that the study would not require you to take any obligation from a pharmaceutical
company, device manufacturer or medical supplier?
11. Have you attached the certificates of your Institutional Review Board (IRB)/Thesis Protocol Review Board (5.5.4)
and Institutional Ethics Committee (IEC) (5.5.5) conveying their formal approval of the project in the study protocol?
Table of Content
12. Have you drawn a table of contents and numbered all pages of the protocol in the following sequence:
Introduction; Review of Literature; Lacunae in existing knowledge; Research question and Hypothesis;
Aims and Objectives; Material and Methods; Statistical methods; References; Appendices?
Introduction
13. Have you provided a brief description of the existing knowledge on your research topic under “Introduction”?
Review of Literature (ROL)
14. Have you exhaustively reviewed the current literature on the research topic and presented a comprehensive
summary of the current knowledge in a lucid manner under the Review of Literature?
Research Question and Hypothesis
15. Have you clearly stated the research question that you wish to resolve?
16. Does the hypothesis match the research question and is it based on a sound scientific presumption?
Aims and Objectives
17. Have you clearly stated the Aims and Objectives of the study?
18. Is the Aim in accordance with the research topic?
19. Are the Primary Objectives clearly stated?
20. Are the Secondary Objectives clearly stated?
21. Are the Objectives aligned with the research subject?
22. Are the Objectives achievable in a specified time frame?

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23. Are the Objectives achievable within the existing resources?
Materials and Methods
24. Have you stated the place of study?
25. Have you stated the period of study?
26. Have you stated the type of study you’re undertaking?
27. Does the stated study type match with the research design?
28. Is the study population defined?
29. Is the method of recruitment defined?
30. Are the inclusion criteria defined?
31. Are the exclusion criteria defined?

32. In studies where applicable, are the study groups defined?

33. Do you intend to employ a control group?
34. Is the control group suitably matched to the participants of the study?
35. Is the study sample size calculated on the basis of a sound relatable statistical formula?
36. Does the study sample size match the study design and statistical methods you propose to employ on the data?
37. Have you included a detailed study flow chart in the protocol?
38. Have you included the details of the proposed investigations and how they relate to your study?
39. Do you intend to carry out any interventions?
40. Have you included the details of the proposed interventions?
41. Do you have a gold standard to clinch the diagnosis?
42. How accurate is the gold standard?
43. Have you included the outcome measures?
44. Have you included any “clinical scores”?
45. If yes, are these “clinical scores” copyright free?
46. If copyrighted, have you taken steps to ensure you do not violate the copyright?
Statistical methods
47. Have you stated the statistical methods you would employ to gauze the obtained data?
48. Have you explained how the stated statistical methods would be employed to obtain results?
References
49. Have you numbered each reference beginning with page 1 of the introduction and till the end of the protocol in a
continuous sequence in order of their appearance (as is prescribed in Vancouver style)?
50. Have you cited the references as they appear within the text in Arabic numerals in superscript?
51. Under the reference section, have you listed the details of each reference as is prescribed in Vancouver style?
Appendix
52. Does the protocol carry any questionnaire?
53. Is the questionnaire validated?
54. Is the questionnaire copyright free?
55. Have you included a detailed study pro forma to capture all significant elements of the study?
Patient Information sheet (PIS)
56. Have you included PIS in Hindi?
57. Have you included PIS in English?
58. Does the PIS state the purpose of the study?
59. Does it mention how it is going to benefit the participants?
60. Does it state the procedures and tests to be done?
61. Does it elaborate how the procedures and tests will be done?
62. Does it mention the potential side effects and/or risks?
63. Does it include your and your supervisor’s name and contact number?
64. Have you clearly stated any know ethical issue(s)?
Informed Consent Form
65. Have you included an informed consent form in Hindi?
66. Have you included an informed consent form in English?
67. Does the informed consent form bear the name, address, contact number and signature of the participant?

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68. Does the informed consent form bear the name, address, contact number and signature of a witness?
Binding
69. Is the thesis protocol firmly bound?
Candidate’s Checklist
70. Have you submitted the filled up Candidate’s Checklist in the bound thesis protocol?

Signatures of the candidate with date

Signatures of the supervisor with date

Name of the supervisor

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