Diffusion Tensor Imaging: Is It Ready For The Clinic ? eEdE:14

Tushar Chandra, MD1

Mohit Agarwal, MD1

Ibrahim Tuna, MD1

Laura Kohl, MD1

Andrew Klein, MD1

Leighton Mark, MD1

Mohit Maheshwari, MD1

Suyash Mohan, MD2

Sumei Wang, MD2

John Ulmer, MD1

Medical College of Wisconsin, Milwaukee1

Perelman School of Medicine, University of Pennsylvania2

Disclosures

Nothing to disclose

Educational Objectives

Succinct overview of the fundamental principles and techniques of diffusion imaging, Diffusion tensor imaging (DTI), fiber tractography and Diffusion kurtosis imaging (DKI)

Simplified interpretation of DTI metrics

Discuss clinical application of DTI in neuropathology

Overview technical limitations and pitfalls

Educational Objectives

Introduction

Diffusion Tensor Imaging (DTI) is a novel method which has various applications in clinical neuroimaging and research

Within the central nervous system, water diffusion is more anisotropic in white matter and isotropic in gray matter and CSF

This property can be exploited to highlight white matter changes in various pathological processes

DTI is a powerful tool for assessment of microstructural integrity of the white matter qualitatively as well as quantitatively

Introduction

Water molecules in biological tissues are in constant movement, governed by two major principles:

a. Fick`s Law: Random diffusion due to concentration differences b. Temperature and ion-ion interactions

Diffusion of water molecules can be restricted in various pathological conditions

RandomBrownian Motion

Free Diffusion

Restricted Diffusion

Diffusion imaging - Principle

Free Diffusion Restricted Diffusion

Diffusion imaging

Diffusion imaging - TechniqueDetects the molecular motion of

water and allows for quantitative assessement of the freedom of diffusion

The addition of 2 strong, symmetric gradients to a EPI SE sequence helps in differentiation of stationary from mobile water molecules

If there is net movement of spins (i.e. if diffusion occurs) between the 2 gradients, signal attenuation occurs

Radiographics 2006;26: S205-223

Diffusion imaging

Diffusion Signal

Gradients cause a drop in signal if diffusion is present

Diffusion imaging

No DiffusionBetween Gradients - More signal

More DiffusionBetween Gradients - Less signal

Application of gradients

Signal drop

Represents the strength of ‘diffusion sensitizing gradients’

Expressed in s/mm2

The larger the b value, the smaller magnitudes of water motion detected.

‘b’ value

b 0 image: No diffusion weighting Poor man’s gradient or T2

Measures area of water molecular diffusion in 1 second

Expressed in mm2/sReduced ADC - acute stroke, abscesses,

cellular neoplasms, recurrent tumorsIncreased ADC – benign lesions, necrosis,

post radiation changes

Apparent diffusion coefficient - ADC

Why Apparent?Since MRI cannot distinguish molecular motion arising from differences in concentration gradient from that resulting from temperature gradient or other reasons, the coefficient is apparent and not a true value

Exponential Apparent diffusion coefficient -eADC

Derived from dividing DWI by T2 images to remove effects of T2 shine through

True restricted diffusion – dark on ADC, bright on eADC

ADC or eADC maps can be used depending on whether we want contrast to match, or be opposite to, the diffusion weighted images

An area of increased diffusion signal on DWI image in the left parietal lobe in a 60 y/o male with treated astrocytoma is slightly dark on ADC but not increased in signal on eADC, suggesting that there is no ‘true’ restricted diffusion.

DWI

ADC

eADC

Exponential Apparent diffusion coefficient -eADC

There was no recurrent tumor on pathology

ANISOTROPIC – Diffusion preferentially increased in some directions

ISOTROPIC- Equal diffusion in all directions

Diffusion Tensor imaging

DTI requires obtaining data from diffusion acquisitions with gradients in different directions in each acquisition to provide directional information to the diffusion data

The information is provided by 3 eigen values which represent the direction of 3 major axes of the ellipsoid and 3 eigen vectors that represent the magnitude in these directions

In the white matter, diffusion is anisotropic and is related to cell density and integrity, axonal integrity, and myelination status

Isotropic Diffusion

Anisotropic Diffusion

Diffusion Tensor imaging

H2O

H2O

H2O

H2O

Diffusion Gradients

Whitematter

Physiological Principals of DTI

Diffusion Ellipsoids

H2O

H2O

Voxel

Whitematter

Commentaries: Mark, Ulmer. AJNR 2002, 2004

Physiological Principals of DTI

Diffusion Tensor

Tensor is a mathematical model of directional anisotropy of diffusion

Diffusion tensor describes Gaussian diffusion distribution - a 3D ellipsoid with lengths and orientations of the 3 axes corresponding to the eigen vectors - λ1, λ2 and λ3

Acquisition in at least 6 directions is required, but clinically up to 30 directions are used From the tensor, we can calculate: a. Direction of greatest diffusion

b. Degree of anisotropy

c. Diffusion constant in any direction

λ1

λ2

λ3

Diffusion Tensor imaging

Diffusion Kurtosis imaging

Mean Diffusivity (MD) = (λ1+λ2+λ3)/3

Axial Diffusivity (Da) = λ1

Radial Diffusivity (Dr) = (λ2+λ3)/2

λ1λ2

λ3

λ1

λ2

λ3

ISOTROPIC ANISOTROPIC

Diffusion Kurtosis imaging Diffusion Kurtosis imaging DTI Metrics and Tensor

Measures the degree of anisotropic (unequal) diffusion in a voxel

Ranges from 0 to 1 (no units) 0 – isotropic (sphere-like) 1 – Purely anisotropic (straight line)

Can characterize demyelinating lesions, e.g., breakdown of myelin and axonal loss can reduce FA and remyelination can increase FA

FA value of CSF is 0.

Fractional anisotropy - FA

Color coded FA map (Red –Higher FA, Blue – Lower FA) Note thatWM tracts showing red color have a higher FA

Measure of directionally averaged

magnitude of diffusion (λ1+λ2+λ3)/3

Higher MD values mean that the tissue is more isotropic

MD is an inverse measure of membrane density and tumor cellularity

Sensitive to cellularity, edema and necrosis

Mean Diffusivity - MD

Color coded MD map (Red –lower MD Purple – higher MD)

Da is the apparent diffusion parallel to white matter tracts

Da = Prinicipal Eigen value = λ1

Da is variable in white matter pathologies

Da decreases in axonal degeneration

Axial Diffusivity - Da

Color coded Da map (Red –Higher Da Blue – Lower Da)

Apparent diffusion perpendicular to the white matter tracts

Dr = (λ2+λ3)/2

Dr generally increases in white matter demyelination and dysmyelination

Change in axonal diameter and density also affect Dr

Radial Diffusivity - Dr

Color coded Dr map (Red –Higher Dr Green – Lower FA)

DTI - Tractography

Technique to assess direction of white matter tracts within the brain

Directional information from neighboring voxels is combined to estimate 3D structure of major white-matter pathways

Voxels are connected together taking into consideration both the direction of principle Eigen vector and FA value

Fiber Tractography

DTI - HARDI

DTI ellipsoid not accurate for detecting white matter tracts as it assumes one direction of axons in each voxel (in truth, there are crossing fibers in each voxel)

HARDI – can assess crossing tracts in the same voxel

DKI is an extension of conventional DTI.

DTI assumes Gaussian distribution (bell shaped curve) of diffusion (not accurate), as water diffusion in biological tissues is non-Gaussian.

Due to the effects of cellular microstructure e.g., cell membranes, organelles & myelin in brain

Diffusion kurtosis – studies non-Gaussian diffusion behavior.

Kurtosis measures the "peakedness" of the probability distribution.

Qualitatively, a large diffusional kurtosis suggests a high degree of diffusional heterogeneity and microstructural complexity.

Diffusion Kurtosis imaging

Leptokurtic- K>0Mesokurtic –K=0Platykurtic –K<0

From the diffusion and diffusional kurtosis tensors several rotationally invariant metrics such as the mean, axial, and radial kurtoses can be computed

The extra information provided by DKI can also resolve intra-voxel fiber crossings and thus be used to improve fiber tractography of white matter

DKI protocols require at least 3 b-values (as compared to 2 b-values for DTI) and at least 15 independent diffusion gradient directions (as compared to 6 for DTI)

Typical protocols for brain have b-values of 0, 1000, 2000 s/mm2 with 30 diffusion directions

Diffusion Kurtosis imaging

Functional MRI

As neural activity increases, blood flow increases

Deoxyhemoglobin (paramagnetic) concentration decreases

Magnetic field homogeneity increases And therefore gradient echo EPI signal

increases, rather than loss of signal BOLD technique is used with DTI fiber

tractography in pre-surgical mapping.

BOLD – Blood Oxygen Level Dependent

Rest: Normal flow

Activity: High flow

- Deoxyhemoglobin- Oxyhemoglobin

Fiber tracking provides critical information about white matter anatomy and connections

Regions with similar tractographic features tend to be functionally co-activated - “neurons that fire together, wire together”

IQ has been positively correlated with anisotropy in white matter association areas

Reading ability has been correlated with anisotropy of left temporoparietal areas

In the visual pathway, DTI has shown the retinotopic organization of fibers

Clinical Applications – Normal Brain

MD decreases as tumor cellularity increases, due to decreased ECF volume

Atypical and malignant meningiomas - lower MD than typical meningiomas

Primary CNS lymphoma and Medulloblastoma also have low MD

MD increases with tumor response with treatment and can be used as a biomarker

Relationship of FA with tumor cellularity and treatment response is unclear

In the peritumoral zone, DTI metrics do not reliably differentiate edema from tumor infiltration

Clinical Applications - Tumors

Flair hyperintense mass in Right frontotemporal region

Increased MD suggesting low cellularity

Gr II glioma at biopsy

Clinical Applications - Tumors

Edematous or tumor-infiltrated tracts lose some anisotropy but remain identifiable

Destroyed WM tracts lose directional organization and diffusion anisotropy is lost completely

Intact WM tracts displaced by tumor retain anisotropy and remain identifiable

Jellinson et al. AJNR 2004

Diffusion tensor imaging: Fractional anisotropy, diffusivity (mean, axial and radial) – tumor biology

Diffusion-weighted imaging: Diffusion Image, Apparent diffusion coefficient (ADC), eADC – tumor cellularity

Tractography: Accurate localization of white matter tracts in relationship to the tumor margins

Functional MR Imaging: Depiction of eloquent cortical areas in relationship to tumor margins

Diffusion andFunctional Imaging For Tumors

Clinical Applications - Presurgical Brain Mapping

Progression free survival is directly related to the extent of resection

However, benefits of cytoreduction must be weighed against risk of damage to eloquent structures and white matter tracts

Pre-surgical mapping with DTI and fMRI results in more informed presurgical planning and decreases the risk of post operative neurological deficits Fused image with functional motor areas and white

matter tracts superimposed on FLAIR depict relationship of tumor to eloquent cortex and white matter tracts

Tumor

MotorArea

White Matter Tracts

Fiber Tractography - Presurgical Brain Mapping

34-year-old, right-handed woman with a posterior parasylvian low-grade glioma. SPGR gadolinium-enhanced underlays with 50% faded Colorcoded fractional anisotropy (CC-FA) diffusion tensor imaging (DTI) map

Track-ball filtering of whole brain fiber tracking DTI data reveals better detail of spatial relationships between tumor and SLF HB, SLF IV, IFOF, ILF, and ORIFOF = Inferior fronto-occipital fasciculus, ILF = Inferior longitudinal fasciculus,SLF HB = Superior longitudinal fasciculus horizontal bundle, SLF IV = Superior longitudinal fasciculus IV, OR = Optic radiation, UF = Uncinate fasciculus Ulmer et al Neuroradiology Clinics of North America 2014

Motor (Corticospinal

Tract)

Vision(ILF, IFOF

Optic Radiations)

Vision(Optic Radiation)

Language(SLF,ILF,IFOF)

Tumors - Which functional systems are at risk ?

MS lesions have higher ADC and lower FA values than Normal Appearing White Matter (NAWM)

Significantly increased ADC and lower FA values are seen in acute (enhancing) MS lesions than chronic (non enhancing) lesions

Non enhancing TI hypointense lesions have higher ADC and lower FA values than T1 isointense lesions

Clinical Applications - Demyelination

FLAIR : MS plaque MD image: High MD

Color FA Map : low FA Tractography:Decreased WM fibers

Increased MD and lower FA values are seen in hippocampi of patients with mesial temporal sclerosis

In patients with malformations of cortical development, increased MD and lower FA values are seen in abnormal areas within MCD and also in the normal appearing areas on MR

Increased MD and low FA can be used to localize lesions in MR negative cases of epilepsy

Clinical Applications - Epilepsy

Gray MatterHeterotopia

DecreasedRadial Diffusivity

Displaced WM Tracts

White matter abnormalities in congenital brain malformations can be assessed with DTI

Pertinent applications include callosal agenesis, cortical dysplasia, holoprosencephaly, schizencephaly, Chiari II malformation etc

Improved understanding of white matter abnormalities in developmental lesions

Clinical Applications – Congenital Anomalies

Schizencephaly

fMRI –MotorCortexAlongthe cleft

DTI Disrupted WM Tracts

DTI is a useful technique to evaluate microstructural injury to the white matter fiber tracts in patients with TBI

Decreased FA and increased MD are seen in areas afflicted by TBI, that are occult on conventional MRI

Studies suggest some correlation between findings on DTI with EEG and neuropsychological testing

In the future, DTI may serve as a surrogate marker for closed head injury

Clinical Applications – Traumatic Brain Injury

Cingulum

Temporal White Matter

Tumor, edema and radiation-induced decrease in anisotropy.

Tumor-induced geometric distortions of fiber tracts.

Anatomic constraints• Distinguishing functionally different pathways in the same white matter

bundle.• Acute angulations and blending of white matter pathways.

Interpretative Challenges of Clinical DTI

DTI data are imperfect!

DTI is a powerful tool to investigate microstructural white matter changes and brain connectivity

DTI is currently being clinically used in conjunction with functional MRI for presurgical brain mapping and is gradually becoming the standard of care

For indications such as demyelination, trauma, epilepsy and congenital anomalies, DTI provides useful information that is clinically helpful and often helps in diagnostic interpretation and clinical decision making

As the technique becomes more robust, it will be increasingly applied in clinical practice for other indications

Conclusion

Thank You

Author:Tushar ChandraClinical Instructor, RadiologyMedical College of Wisconsin9200 W Wisconsin Avenue,Milwaukee WI 53226Email: drtusharchandra@gmail.com