Application of Diffusion Tensor Imaging in Alzheimer's Disease:Quantification of White Matter Micro-structural Changes
Conditions: Alzheimer Dementia
Sponsor: Assiut University

 
 
 
 
Diffusion Tensor Imaging of white matter degeneration 
in Alzheimer disease  
Protocol of thesis submitted in partial fulfillment of the requirements 
for the Master degree in Diagnostic Radiology 
BY 
Shereen Magdy Abd ElMalak  
(M.B.B.CH)  
Supervised by  
Prof. Ahmed Mostafa Hamed 
Professor of Radiodiagnosis 
Faculty of medicine-Assuit University  
Dr. Radwa Kamel 
Lecturer of Radiodiagnosis  
Faculty of medicine- Assuit University 
2017 
 
Faculty of medicine  
Diagnostic radiology  departement 

 
 
Introduction 
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, accountings for 60-70% 
of all demented cases. (Fratiglioni  et al. 2007). It is a neuro-pathological diagnosis determined by 
presence of neurofibrillary tangles and senile plaques in the brain of patients with dementia. The 
disease frequently starts with memory impairment, but is invariably followed by a progressive global 
cognitive impairment. (Harvey et al. 1999). 
Alzheimer's disease including a review of factors that increase or reduce its risk.(Mayeux & 
Stern,2012).The major risk factor for Alzheimer disease is age, with prevalence doubling every 5 years 
after the age of 65 (Brookmeyer et al. 1998). Vascular risk factors such as hypertension, elevated 
cholesterol levels, Diabetes, obesity and Apo-E4 gene. 
The prevalence of Alzheimer disease in 2002 was estimated to be 2.3 million individuals over age of 
70, based on a national population- based sample. (Plassman  et al. 2007).By Looking to the future, the 
number of Americans surviving to 80s,90s and beyond is expected to grow dramatically due to medical 
advances as well as social and environmental conditions.(Ortman et al.2014). So number of new cases 
and existing cases of Alzheimer's disease grows rapidly. In 2010, there were estimated 454,000 new 
cases of Alzheimer' disease. By 2025, the number of people age 65 and older with Alzheimer's disease 
is estimated to reach 7.1 million (almost 40% increase from the 5.2 million age 65 and older affected in 
2016). By 2050, the number of people age 65 and older with Alzheimer's disease may nearly triple from 
5.2 million to a projected 13.8 million. (Hebert et al.2013). Alzheimer's disease is becoming a more 
common cause of death. As severe dementia causes complications such as immobility, swallowing 
disorders and malnutrition that significantly increase the risk of other seriouse conditions that can 
cause death. One such condition is pneumonia, which is the most commonly identified cause of death 
among elderly people with Alzheimer's disease. (Brunnstorm HR, England EM.2009).Between 2000 
and 2013,deaths attributed to Alzheimer's disease increased 71% while those attributed to other 
causes of death such as heart disease decreased 14% ,stroke decreased by 23%. Many researchers 
believe that early detection of Alzheimer’s disease will be key to preventing, slowing, stopping the 
progression of the disease and preserve brain function. Future treatments (called “disease-modifying” 
treatments) will be most effective when administered early in the disease; either at the mild cognitive 
impairment (MCI) stage or during the proposed preclinical stage especially in cases with a lower 
burden of Amyloid and Hyperphosphorylated tau and can attenuate the negative effects of secondary 
events caused by deposit of those toxic products in tissues. Biomarker tests will be essential to identify 
which individuals are in these early stages and should receive disease-modifying treatment when it 
becomes available. They also will be critical for monitoring the effects of treatment.( Albert et al. 2011). 
Brain changes associated with Alzheimer's disease are variable; a healthy adult brain has about 100 
billion neurons, each with long, branching extensions. These extensions enable individual neurons to 
form connections with other neurons. At such connections, called synapses. The brain contains about 
100 trillion synapses. They allow signals to travel rapidly through the brain’s neuronal circuits, creating 

 
 
the cellular basis of memories, thoughts, sensations, emotions, movements and skills. The 
accumulation of the protein beta-amyloid (called beta-amyloid plaques) outside neurons and the 
accumulation of an abnormal form of the protein tau (called tau tangles) inside neurons are two of 
several brain changes believed to contribute to the damage and destruction of neurons that result in 
memory loss and other symptoms of Alzheimer’s. As brain changes advance, information transfer at 
synapses begins to fail, the number of synapses declines, and neurons eventually die. The 
accumulation of beta-amyloid is believed to interfere with the neuron-to-neuron communication at 
synapses and to contribute to cell death. Tau tangles block the transport of nutrients and other 
essential molecules inside neurons and are also believed to contribute to cell death. The brains of 
people with advanced Alzheimer’s disease show inflammation, dramatic shrinkage from cell loss, and 
widespread debris from dead and dying neurons. The brain changes associated with Alzheimer’s may 
begin 20 or more years before symptoms appear. When the initial changes occur, the brain 
compensates for them, enabling individuals to continue to function normally. As neuronal damage 
increases, the brain can no longer compensate for the changes and individuals show subtle cognitive 
decline. Later, neuronal damage is so significant that individuals show obvious cognitive decline, 
including symptoms such as memory loss or confusion to time or place. Later still, basic bodily 
functions such as swallowing are impaired. (Bateman et al. 2012). 
Diagnosis of Alzheimer’s typically involves physical and neurological exams, as medical history and 
mental status evaluation, laboratory investigations and it involves brain imaging (such as MRI) which 
could identify other causes of problems such as stroke, tumor or head trauma. By physical and 
neurological examination, Alzheimer's disease characterized by gradual onset and progressive decline 
in cognition with sparring of motor and sensory function until later stages; the average course of 
Alzheimer's disease is approximately a decade, with a range of 3 to 20 years duration from diagnosis to 
death .Memory impairment is present in the earliest stages of the disease; patients have difficulty 
learning new information and retaining it for more than few minutes. As the disease advances, the 
ability to learn increasingly compromised, more distant memories are lost. Other cognitive loses include 
aphasia, apraxia, disorientation and impaired judgment. Cognitive impairment affects daily life; patients 
have difficulty planning meals, managing finances or medication, using telephone, driving. Many 
capacities may remain intact until later stages including performance of self-care activities of daily living 
as eating, bathing. Patients evidence personality alteration, irritability, anxiety, depression. Delusion, 
hallucination and aggression. (Stern et al.1994).Laboratory Evaluation includes Biochemical markers 
as measurement of CSF including Tau protein, amyloid beta peptides or neural thread protein and 
measurement of urinary biomarkers including neural thread protein. Also geneting testing including Apo 
lipoprotein E epsilon 4 allele presenilin genes, amyloid precursor gene or TREM2.APOE gene provides 
a blueprint for a protein that transports cholesterol in the blood stream. Everyone inherits one of three 
forms of APOE gene – e2, e3, e4. The e3 form is the most common; the e2 form is the least common 
.The e4 form is more common than e2 form. People with one or two copies of e4 are at higher risk of 
develop Alzheimer's disease than individuals who don't have copy of e4. (Raber et al.2004). 

 
 
Most of the past imaging studies concentrated on the damage of grey matter based on voxel-based 
morphometry (VBM), some studies point to regional grey matter atrophy mainly medial  and lateral 
areas as the sites of highest atrophy while parieto-temporal areas ,preceneus , post and ant cingulate 
gyri, thalamus, caudate nucleus and putamen show significant but lower grey matter loss . ( Karas et 
al.,2004). Positron emission tomography (PET) studies have highlighted early glucose hypometabolism 
in posterior associative cortical areas, especially in the posterior cingulate cortex and subsequently in 
dorsolateral and medial frontal areas and preisylvian and insular cortex. (Morbelli et al., 2012).Studies 
of cadaver brain revealed that white matter changes are strongly associated with Alzheimer's disease. 
It's found that the White matter had significant pathological changes including demyelinate and loss of 
Axons, DNA breakage and lack of plasmalogen patients with in Alzheimer's disease at early stage. 
(Villain et al. 2008). Previouse studies use Functional MRI to detect alteration in several white matter 
tracts in Alzheimer's disease particularly the corpus callosum, cingulum bundle, fornix and uncinate 
fasciculus.(Hampel et al .1998). They found that AD associated microstructural white matter pathology 
is not homogenously distributed, but it rather involves selectively brain white matter regions which are 
connected with the association cortices (corpus callosum and white matter of the temporal, frontal and 
parietal lobe)with a relative sparing of other white matter areas subserving motor (internal capsule)or 
visual (optic radiations).(Vermersch et al,1996.) 
As Diffusion tensor imaging (DTI) is an imaging technology based on magnetic resonance diffusion 
weighted imaging, which can make quantitative analysis of anisotropy of water molecules in different 
directions, so as to observe the microstructure of tissues non-invasively. So DTI can provide 
information of fiber orientation, the injury of fiber, and membrane permeability which cannot be obtained 
from conventional MRI. DTI enables mapping of WM microstructure changes in development, aging 
and neurological disorders, From the tensor, it's possible to derive the mean diffusivity (DM) and the 
fractional anisotropy (FA) which is the most robust measures of anisotropy which measure the degree 
of deviation from isotropic diffusion. (   Pierpaoli et al. 1996).  More recently, an additional DT-MRI 
derived index has been proposed ( Pfefferbaum  et al.  2000).This index measures the degree of 
similarity of orientation of neighboring voxels and its named inter-voxel co-herence (C). So DTI has 
therefore become a powerful technique in the study of neurodegenerative diseases in recent years. 
So the aim of the present study to point to the alteration of several white matter tracts in Alzheimer's 
disease. In the present study, by DT-MRI (we will calculate D, FA) to investigate the extent of tissue 
damage of several brain white matter regions in patients with Alzheimer’s disease. The ultimate goal of 
the study is to provide a complete picture of the distribution of microstructural white matter damage in 
Alzheimer’s disease and to improve our understanding of their nature. 
Aim of the work: 
To study role of diffusion tensor imaging (DTI) to detect changes in white matter microstructure in patients 
with Alzheimer's disease. 

 
 
Patient and method 
Patient: 
The study will be performed at the Radiodiagnosis department of assuit university hospital. 
Selection of 20 patients clinically and laboratory diagnosed as Alzheimer disease and another 20 people 
matched healthy controls who have no complaints of cognitive problems. 
Inclusion criteria: 
The inclusion criteria for the patients: (1) cognitive complaints with interference in complex occupational 
and social activities ,(2) changes in cognition reported by the patient ,informant or clinician ,(3) absence of 
profound subcortical ischemic changes. 
Exclusion criteria:  
To minimize the inclusion of patients with Alzheimer’s disease and associated major ischemic vascular 
disorders. 
The exclusion criteria were: (1) state of delirium; (2) stroke event within 2 weeks; (3)appearance of cortical 
and /cortico-subcortical non –lacunar territorial infarcts and watershed infarcts ,hemorrhage ,signs of 
normal pressure hydrocephalus ,and specific causes of white matter lesions (e.g. multiple sclerosis 
,sarcoidosis , brain irradiation ) ,(4)derangements in serology tests contributing to cognitive impairment (e.g. 
abnormal levels of free T4, cortisol, folic acid, vitamin B12, or rapid plasma reagin, and (5)severe hearing or 
visual impairment,(6)cases of severe dementia. 
Patient preparation 
To acquire an optimal MRI examination, adequate patient preparation is as important as the optimization of 
the technique.1) Psychological preparation of the patient including the scanner environment.2) Confirmation 
of absence of any paramagnetic substance. 
 
Technique 
Compared DTI findings among AD,  MCI or elderly healthy controls. The main DTI measures used were FA, 
ADC and MD. Others measures were occasionally cited such as radial diffusivity and axial diffusivity. The 
most relevant encephalic regions assessed were temporal areas, parietal areas, frontal areas, posterior 
areas, and some integrative intra-cortical fiber tracts. Specific structures such as the corpus callosum, 
cingulate gyrus/ cingulate fiber tracts, uncinate fasciculus, inferior longitudinal fasciculus/superior 

 
 
longitudinal fasciculus fiber pathways and hippocampus were studied. Other structures were cited as 
secondary including thalamus, basal ganglia, and internal capsule. The main DTI measures (FA and ADC) of 
the above mentioned encephalic structures showed compromised tissue integrity and marked changes in 
relevant fiber tracts, from very early AD stages. These findings were found to correlate with cognitive 
assessments, and also differentiated between normal ageing, AD. 
MRI acquisition 
 Brain MR Scans were obtained on a magnet operating at 1.5 T. On a single occasion, images using the 
following pulse sequences were obtained from all subjects without moving them from the scanner:(a) dual 
echo turbo spin echo (TSE) (TR=3300 ms, TE=16/98 ms, echo train length=5); (b) T1 weighted SE (TR=650 ms, 
TE=12 ms); (c) pulsed gradient spin echo (PGSE) echo planar pulse sequence (interecho spacing=0.8 ms, 
TE=123 ms), with diffusion gradients applied in eight non-collinear directions ,chosen to cover three 
dimensional space uniformly.26 The duration and maximum amplitude of the diffusion gradients were 
respectively 25 ms and 21 mTm-1,giving a maximum b factor in each direction of 1044 s mm-2. To optimize 
the measurement of diffusion only two b factors were used27 (b1≈0, b2=1044 s mm-2). Fat saturation was 
performed using a four radio frequency binomial pulse train to avoid chemical shift artifact. A birdcage head 
coil of ∼300 mm diameter was used for signal transmission and reception. For the dual echo and T1 
weighted sequences, 24 contiguous interleaved axial slices were acquired with 5 mm slice thickness, 
256×256 matrix and 250×250 mm ﬁeld of view. The slices were positioned to run parallel to a line that joins 
the most inferoanterior and inferoposterior parts of the corpus callosum. For the PGSE scans, 10 5 mm thick 
slices were acquired, with the same orientation of the dual echo scans, positioning the second last caudal 
slice to match exactly the central slices of the other image sets. This set of slices was chosen as these central 
slices are less affected by the distortions due to B0 ﬁeld inhomogeneity, which can affect image co-
registration .Also, this set of slices allowed us to cover a relatively large portion of the cerebral hemispheres 
where white matter is highly represented. PGSE images had a 128×128 matrix and a 250×250 mm ﬁeld of 
view. 
Ethical consideration 
 
 The study of protocol will be submitted for ethical committee of the Faculty of medicine Assuit 
University for revision and approval. 
 All subjects included in the study will be consented after detailed explanation of the nature of the study 
and its procedures. 
 Privacy and confidentially of the obtained data will be assured. 
 There is no probability of risk or harm for the subjects enrolled in the study.  
 Psychological preparation of the patient including the scanner environment. 

 
 
 Confirmation of absence of paramagnetic substance.                        
 
Reference 
 Fratiglioni L, Winblad B, von Strauss E. Prevention of Alzheimer's disease and dementia. 
Major findings from the Kungsholmen Project. Physiol Behav 2007. 
 Harvey R, Fox N, Rossor M. Dementia Handbook. London: Martin Dunitz; 1999. 
 Mayeux, R. & Stern, Y. (2012). Epidemiology of Alzheimer's disease. Cold Spring Harbor 
Perspectives in Medicine doi : 10.1101 Downloaded July 31, 2012. 
  Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States 
and the public health impact of delaying disease onset. Am J Public Health 1998. 
 Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, et al. Prevalence 
of dementia in the United States: the aging, demographics, and memory study. 
Neuroepidemiology 2007. 
 Ortman JM, Velkoff VA, Hogan H. An aging Nation: The older population in the united states 
,current population report , P25-1140,U.S.Census Bureau .Washington D.C 2014. 
 Hebert LE, Beckett LA, Scherr PA, Evans DA, Annual incidence of AD in US projected to the 
years 2000 through 2050.A Dis Assoc Discard 2001. 
 Brunnstorm HR, England EM, cause of death in patients with dementia disorders, EUR J 
Neuronal 2009. 
  Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox N, et al. The diagnosis of 
mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National 
Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease. Alzheimer's Dement 2011. 
 Bateman RJ, Xiong C, Benzeingen TL, Fagan AM, Goate A, Fox NC, Alzheimer disease, N 
Engl J Med.2012. 
 Stern Y, Gurland B, Tatemichi TK, et al. Influence of education and occupation on the 
incidence of Alzheimer's disease. JAMA 1994. 
 Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and 
AD pathology , Neurobiol aging 2004. 
 Karas GB, Scheltens P, Rombouts SARB, et al. Global and local gray matter loss in mild 
cognitive impairment and Alzheimer’s disease. NeuroImage 2004. 
 Morbelli S, Drzezga A, Perneczky R, Frisoni GB, Caroli A, van Berckel BN, et al. Resting 
metabolic connectivity in prodromal Alzheimer’s disease. A European Alzheimer Disease 
Consortium (EADC) project. Neurobiol Aging 2012. 

 
 
 Villain N, Desgranges B, Viader F, de la Sayette V, Me ´zenge F, Landeau B, et al. 
Relationships between hippocampal atrophy, white matter disruption and gray matter 
hypometabolism in Alzheimer’s disease. J Neurosci 2008. 
 Hampel H, Teipel SJ, Alexander G E,et al . Corpus callosum atrophy is a possible indicator of 
region and cell type specific neuronal degeneration in Alzheimer’s disease.1998. 
 Vermersch P, Roche J, Hamon M,et al . White matter magnetic resonance imaging 
hyperintensity in Alzheimer’s disease: correlations with corpus callosum atrophy1996. 
 Pierpaoli C, Basser PJ. Towards a quantitative assessment of diffusion anisotropy. Magn 
Reson Med 1996).        
 Pfefferbaum A, Sullivan EV, Hedehus M, et al. Age related   in brain white matter anisotropy 
measured by spatially corrected echo-planar diffusion tensor imaging. Magn Reson Med 
2000.