Tóm tắt luận án tiến sĩ research into morphological features and some special pulse sequence on brain magnetic resonance in alzheimer patients

HANOI MEDICAL UNIVERSITY NGOC TRAN VAN RESEARCH INTO MORPHOLOGICAL FEATURES AND SOME SPECIAL PULSE SEQUENCE ON BRAIN MAGNETIC RESONANCE IN ALZHEIMER PATIENTS Specialism : Radiology Dia

HANOI MEDICAL UNIVERSITY

NGOC TRAN VAN

RESEARCH INTO MORPHOLOGICAL FEATURES AND SOME SPECIAL PULSE SEQUENCE ON BRAIN MAGNETIC RESONANCE IN ALZHEIMER PATIENTS

Specialism : Radiology Diagnosis

SUMMARY OF THESIS ON DOCTOR OF MEDICINE

HANOI MEDICAL UNIVERSITY

INTRODUCTION

Alzheimer disease is the degeneration pathology of the central nerve system with features of gradually increasing but unrecoverable progression It causes the memory loss, cognitive disorder, and changes

in behaviors, which affects patients’ occupation and social lives Current criteria for Alzheimer disease is mainly diagnosed based on such three globally accepted current clinical criteria as DSM V1, ICD

X2, NINCDS-ADRDA3

Magnetic resonance images (MRI) can be considered as paraclinical tests relevant to Alzheimer disease diagnosis as they allow to precisely measure the brain weight in 3 directions (3D), especially the size of the hippocampus and related areas5 as well as image changes in AD patients based on their diffusion, spectro, and perfusion

Therefore, the development of image diagnosis methods by MRI for Alzheimer disease in the pre-clinical stage is very vital and pressing, especially for the 3 pulse sequences: diffusion, spectro, and perfusion This has brought about a positive imaging method in AD diagnosis Some researchers in Vietnam have initially studied the MRI morphology However, none of them has utilized such pulse sequences as: diffusion, spectro, and perfusion to quantify changes in brain images

in AD patients We have conducted the theme: “Research into morphological features and some special pulse sequences on brain magnetic resonance in Alzheimer disease patients” in order to:

1 Description of brain’s morphological features in Alzheimer disease patients;

2 Analysis of magentic resonance features like diffusion, perfusion, and spectro in Alzheimer disease patients’ brains

3 Assessment on changes in pulse sequences of brain magnetic resonance in Alzheimer disease patients based on other age, gender, and disease level variables

1 T he thesis’s topicality

Practical questions put forward by clinicians in the past have been researched and settled in the thesis The AD diagnosis is completely based on clinics and the implementation of clinical tests for the diagnosis work depends on assessors’ subjectivity Therefore, the development of

MRI techniques shall help clinicians make diagnosis more quickly and objectively

Besides, parameters of pulse sequences of Diffusion-weighted imaging show the number of AD infected people patients quickly increases in countries worldwide in general and in Vietnam in particular This causes pressure for diagnosis, cares, and treatment The search for

an early and precise diagnosis method is necessary

The thesis orients toward changes in AD patients’ brains compared to those people with normal brains based on MRI filming, especially the application of pulse sequences of diffusion, spectro, and perfusion Although the benefits of using MRI to diagnose AD have been studied and pointed out by many researchers, there have been remained several inconsistent viewpoints and assessment by researchers in the world The benefits need further researching in machines of new generations and higher magnetics whereas there haven't been any researches into these three pulse sequences in Vietnam yet

2 The thesis’s new contributions

The use of clinical diagnostic tests causes many difficulties in diagnosis, especially at those places where there are not specialists Results from brain MRI of our AD patients may help clinicians gain more foundations for AD diagnosis in line with the Vietnamese’s parameters The T13D pulse sequence shows differentiation in AD patients’ brain morphology compared to that in the control group in terms of changes in MTA, IUD, B, E Indicators, and especially the volume of the hippocampus The clinicians may base on these to make diagnosis

This is the first research in Vietnam with diffusion, spectro, and perfusion that utilizes MRI to quantify changes in AD patients’ brains and point out clear differentiation compared to those in the control group By measuring the changes in these pulse sequences, it

is easy to identify brain injuries caused by AD These Indicators may suggest identifying the parameters to diagnose AD as well as those in Vietnamese people with normal brains

The conclusions of this research do not only help radiologists gain foundations for identification of brain injuries in AD patients on MRI image films, especially on diffusion, spectro, and perfusion but help

clinicians and researchers in diagnosing, treating, following up and making other researches into AD patients as well

3 The thesis’s lay-out

The thesis is 150 page thick In addition to the questioning (3 pages), the conclusion part (2 pages), the part that tells about restrictions (1 page), and the part with proposals (1 page); there are 4 chapters, including: Chapter 1: The overview part which is 42 page long, Chapter 2: The part of research subjects and methods with 23 pages, Chapter 3: The part of research results with 41 pages; Chapter 4: Discussion part with 37 pages The thesis consists of 63 charts, 01 column chart, 30 visuals, and 148 references

CHAPTER 1: OVERVIEW

1.1 Brain anatomy and functions

Anatomy, brain’s functions and components;

The brain lobes: frontal lobe, temporal lobes – hippocampal lobes, occipital lobe, and parietal lobe

1.2 Pathogenesis, risk factors, epidemiology of Alzheimer disease

 Pathogenesis;

 Risk factors of Alzheimer disease: Risk factors of vascular pathology, social psychology, lifestyle factors, and other ones

 Alzheimer disease’s epidemiology

1.3 Injuries in Alzheimer disease patients’ brains

Massive changes arising in the whole brain;

Injuries caused by pathological

Molecular imaging lesions

1.4 Alzheimer disease diagnosis

Since the 1970s of the 20th Century, many SSTT and Alzheimer disease diagnostic criteria have been used: those diagnostic criteria upon DSM - IV - TR1, diagnostic criteria upon the 10th International Classification of Diseases (ICD X)2, and those on NINCDS-ADRDA3which are the 3 criteria sets used to diagnose Alzheimer disease

1.5 Magnetic resonance pulse sequences in Alzheimer disease diagnosis

1.5.1 T1W - 3D pulse

 Brain injury images on magnetic resonance in Alzheimer disease patients: White matter abnormalities, cerebrovascular

disease, ventricular dilatation phenomenon, and brain atrophy phenomenon;

 Assessment on brain atrophy in Alzheimer disease patients;

 Volume of the hippocampus;

 IUD interuncal distance and Bicaudate proportion:

 Evan Indicator

1.5.2 Diffusion-weighted imaging (DWI)

Pathological lesion images are detected thanks to the weighted imaging in diagnosis of white matter disease, fibrous plaques, changes in diffusion in brain regions Diffusion-weighted imaging is the valuable imaging technique, especially in further provision of crucial information on many pathological processes in the cranium which it is impossible or very difficult to assess in tumor disease, inflammation, and white matter disorder, etc., in Alzheimer disease if applying the routine magnetic resonance

Diffusion-1.5.3 Magnetic resonance cisternography (MRC)

Such peak concentration of substances as N-acetylaspartate (NAA), Myoinositol (Myo), Choline (Cho), Creatine (Cr), Glutamate và

Glutamine (Glx), Lactate, Alanine (Ala), and Lipids in the magnetic

resonance cisternography is measured to assess changes in the brain when clinical injuries have not been caused

Upon observation researches, N-acetyl aspartate in Alzheimer disease patients remarkably decreases in brain regions and bilateral hippocampus The NAA/Cr proportion greatly decreases in the posterior brain region Simultaneously, the Myo/Cr proportion remarkably decreases, not only in the posterior brain region but in the gray matter area as well

The data point out that NAA, Myo, and NAA/Cr proportion may be potential biomarkers of brain dysfunctions in AD patients Choline (Cho)/Cr and Myo/NAA may make contributions to the diagnosis process The magnetic resonance cisternography imaging is cheaper, contamination-free, and may be applied in the big community

1.5.4 Magnetic resonance perfusion weighted imaging/MRP

Researches into magnetic resonance perfusion weighted imaging:

Alzheimer disease may reduce target neuron’s activities in the cortical area and cerebral blood flows (CBF) in such areas The correlation

between CBF in the injured areas shows the reduction in magnetic resonance perfusion weighted imaging and changes in the white matter

in AD while micro-weakness may make greater impacts in the

progression stages

Measurement of cebreral blood flow (CBF) is similar to a biomarker that may arise the most early and reliably for Alzheimer disease diagnosis Magnetic resonance imaging (MRA/Magnetic Resonance Angiography) by arterial pulse (MR) measures CBF by marking arteries and utilizing it as an endogenous probe

1.6 Local and foreign research situation

1.6.1 Local research situation

MRI had been applied to diagnose cardiovascular pathology and later, to diagnose such brain pathologies as tumor, injuries, and strokes

in Vietnam from the 1990s of the 20th century The researchers have recently started to study AD pathology, which will help clinicians to manage to early make diagnosis and differientiate other brain pathologies

Despite some initial researches into images of AD patients’ brain injuries on MRI films, they have only focused on the use of basic pulse sequences to assess the morphology and volume of some brain areas None of the researchers has ever deeply analyzed brain injuries in AD patients based on pulse sequences, especially in MRI to early diagnose

AD patients

1.6.2 Foreign research situation

Many recent researches into Alzheimer disease have focused on different approaches to search for images of brain injuries through MRI pulse sequences

Dahlbeck and partners48 introduce one variable named Interuncal Distance (IUD) which is the tool to measure the atrophy level of the hippocampus This tool is presented as a simple diagnosis method for Alzheimer disease patients and a distance of 30mm upward may mean the existence of the disease

Scheltens and partners49 report the sensitivity of 81% by visual assessment on the hippocampal and temporal lobes (MTA: Medical Technology Assessment) This result is reported to be significantly correlated with volume atrophy

The remarkable decrease of the average diffusion when making diffusion MRI in the affected areas: the hippocampus, the one near the hippocampus, and cingulate gyrus is the foundation for Alzheimer disease early diagnosis

On magnetic resonance cisternography, NAA decreases while MyoInositol increases in such areas as occipital, temporal, parietal, and frontal lobes in Alzheimer disease patients Lately, MRS has shown the ability to diagnose mild cognitive impairment (MCI) which is a pathology recorded as the start of dementia MRS is also able to anticipate that MCI in patients will evolve into Alzheimer disease Cerebral blood flow (CBF)’s decrease on brain lobes is a reliable biomarker that may arise early when diagnosing Alzheimer disease in the perfusion magnetic resonance

MRI identifes changes in the brain, which helps diagnose Alzheimer disease from the early stage: Magnetic resonance pulse sequences show the images of brain atrophy, especially those of medial temporal and hippocampal lobes in AD patients, the average diffusion level in different brain areas with increases & decreases of substance concentration in the spectro and decreases in brain regions on perfusion pulse sequence, then, Alzheimer disease can be early diagnosed and detected

CHAPTER 2 RESEARCH SUBJETS AND METHODS

2.1 Research subjects, areas, and timing

* The control group of patients (The control group):

The group consists of patients who go for medical checks-up and treatments at Bach Mai Hospital They are assigned to have cranium MRI at Electro Optical Center at Bach Mai Hospital and injected with magnetic contradictory drug to complete diagnostic billan They are 55 years old plus and do not catch any brain-related diseases

2.1.1.2 Exclusion Criteria

- They are patients who suffer from the dementia due to some other reasons like blood vessels, Lewy, frontal – temporal lobes, and in Pick disease

- Patients who suffer from diseases that may cause impacts in such awareness and cognitive activities as cerebrovascular strokes, encephalitis, brain abscess, meningitis, metabolic disorder, and traumatic brain injury

µ1: NAA/Cr proportion in AD patients, μ1 = 1,27 53

µ2: NAA/Cr proportion in people with normal brains μ2 = 1,5 53δ: Criterion deviation, δ = 0,19

α: Statistical significance level α = 0.05

1 - β: Sample force selected by researchers Take 1 - β = 0,8

Research co-efficient: 3

The sample size for each disease group and control group to analyze the differentiation between AD infected people and AD non-infected one is 40 The total number of research participants is 80

The sample size for the research into assessment on changes in AD patients’ brain images on pulse sequences of T13D, diffusion, spectro, and perfusion with age, gender, and level variables is 40

2.2.3 Sampling method

We randomly select samples of patients who go to Central Geriatric Hospital for medical checks-up, treatments, are diagnosed as catching Alzheimer disease and fully meet criteria to be accepted as patients in the research group until reaching the number of 40 patients Similarly,

we randomly select 40 qualified patients to be included in the control group The numbers of the research and the control groups meet the sample sizes (at least 33 patients in each group) to assure for the research’s statistical significance

During the day with screening tests by specialty, we randomly select one patient diagnosed as catching AD with all criteria for selection, approach, explanation, and encouragement for his/her participation in the research process If the patient agrees, we shall select him/her for the research group and conduct an MRI in line with the research process If the patient refuses, we will move to the next patient who will also be selected in a similar way on the next specialty check-up day

The patients selected for the control group are those who go for the first-time check-up and are clinically diagnoses as they do not catch AD

We approach them, give explanations, and encourage them to participate

in the research process If they agree, we shall select them for the control group Afterward, MRI will be provided to them in line with the research process Finally, we shall compare the results with exclusion criteria If any patients do not meet the criteria, we shall exclude them and continue replacing them with other next patients until reaching the sufficient sample size for the research

2.2.4 Research variables

2.2.4.1 Variables of patient features

+ Ages: AD often arises in people of 65 years old plus However, there remain cases in which the disease arises in younger people In

order to cover the age data and simultaneously to further learn about the proportion of AD infected people less than 65 years old, we choose samples of people over 55 years old for the research as it is the retirement age of female employees in Vietnam

+ Gender is considered as one of the causes of AD Many researchers have pointed out that the disease is more common in women However, there have been researches recently that suppose the proportions in women and men are equal It seems the proportion in women is higher because of such factors as longevity, living conditions, occupation, habits, and customs, ect., these are the data collected from patients’ medical records for treatments

+ MMSE point is assessed based on MMSE test kit (appendix) by groups of neurologists at Central Geriatric Hospital with PhD degree upward

- The assessment MMSE scale is presented as the followings: + Level 1: The cognitive impairment has not arisen: ≥ 24

+ Level 2: Mild cognitive impairment: 20 - 23

+ Level 3: Medium cognitive impairment: 14 - 19

+ Level 4: Severe cognitive impairment: 0 – 13

- Patients who do not catch Alzheimer disease (Level 0) in the control group all gain the maximum MMSE points of 30

2.2.4.2 Morphological survey pulse variables on cranium magnetic resonance imaging

* Temporal lobe atrophy: To assess the temporal lobe atrophy based

on the MTA scale which is the easily conducted visual assessment method This is a crucial tool to diagnose AD The criteria scale (Scheltens) is utilized to assess MTA based on image copies of T1W 3D pulse sequence

* Interuncal distance: Interuncal distance measurement technique (interuncal distance, IUD) is identified as the shortest distance between the two hippocampal heads on the axial cutting layer at the level where the front edge appears for the first time

* Bicaudate proportion: In reality, it is very difficult to assess the interuncal distance because of brain sizes and volumes among different groups and races of people to lessen this restriction and eliminate impacts of the head size and brain volume The researchers standardize

values and divide the interuncal distance to the bitemporal distance to gain Bicaudate proportion

Interuncal distance

Intertemporal lobe distance

* Evan Indicator: Evan Indicator is identified as the proportions of the distances between the two frontal horns of the ventricles and the intracranial width Normally, this Indicator is less than 0.3 If it is over 0.3, this proves the dilation of the ventricles and diffusion cerebral atrophy The distance between the identified two frontal horns of the ventricles is the longest distance between the two frontal horns of the lateral ventricles We also utilize the distance formula between two points on Descartes coordinate system as the one to measure the interuncal distance

Evan Indicator =

* Volume of hippocampus: in order to measure the volume of hippocampus, we have identified the hippocampus in the cranium magnetic resonance imaging from the first cutting layer where the hippocampus appears and a boundary line shall be drawn This means the hippocampus area reaching the cutting layer The volumetric result

of the hippocampus is recorded

2.2.4.3 Variables for diffusion pulse sequence:

Technical parameters: TR: 1524ms, TE: 40ms; Slice: 5mm, Phase (cutting direction) R>L, Matrix: 92X90; FOV: 224x224, Gap (Distance among slices):0

Average (Average number of received times): 1

Parameters that need collecting: Average apparent diffusion coefficient

Location to take measurements: at the hippocampus and 4 brain lobes: temporal, parietal, frontal, and occipital lobes on both 2 brain left

& right lobes

2.2.4.4 Variables for magnetic resonance cisternography (MRS): Technical parameters: TR: 900ms, TE: 144ms; Slice: 3mm, Phase (cutting direction) A>P, Matrix:180X160; FOV: 180x180, Gap

(Distance among slices): 0; Average (Average number of received times): 1

Parameters that need collecting: * NAA concentration Myo – inositol concentration, Cr, Cho, Lip, Lac, Glx, and Ala on magnetic resonance cisternography & the NAA/ Cr proportion

Location to take measurements: Temporal lobes and the hippocampus on

both right & left brains

2.2.4.5 Variables for Magnetic resonance perfusion weighted imaging:

* Technical parameters: TR: 1524ms, TE: 40ms; Slice: 5mm, Phase (cutting direction) R>L, Matrix:92X90; FOV: 224x224, Gap (Distance among slices): 0

Average (Average number of received times): 1

* Parameters

- Cerebral Blood Flow CBF (ml of blood /100gr of organization/min): CBF of the average brain’s white matter is at 22 +/- 5 ml/100g/min

- Cerebral Blood Volume CBV (ml of blood/100gr): CBV of the average brain’s white matter is at 1.7 +/- 0.4 ml/100g

- Time for drug concentration through tissues to reach to the peak (time to peak) TTP (sec)

- Mean Transit Time/MTT (sec) CBF = CBV/MTT: 4.8 sec on the white matter region on average

* Measurement locations: The hippocampus and 4 brain lobes: temporal, parietal, frontal, and occipital lobes on both 2 brain left & right lobes

2.2.5 Means and methods of data collection

Cranial MRI imaging research equipment: MRI imaging machines Philips Ingenia 1.5 Tesla are placed Electro Optical Center of Bach Mai Hospital

Cranial MRI imaging scan process: After choosing qualified patients in terms of sample and research subject selection for the research, the following processes like: prepartion of patients, common drugs & medical supplies, and steps of implementation will be conducted