dr. renzo manara

Dr. Renzo Manararmanara@unisa.it

Unraveling the brain:

advanced imaging and “old” techniques in

hematologic disorders

➢ What is “Magnetic Resonance” (MR)

➢ What is “conventional MR imaging and angiography”

➢ What are “advanced techniques”

➢ What are “advanced analyses”

➢ Possible applications for hematologic disorders

• Topics

➢ What is “Magnetic Resonance” (MR)

➢ What is “conventional MR imaging and angiography”

➢ What are “advanced techniques”

➢ What are “advanced analyses”

➢ Possible applications for hematologic disorders

• Topics

Magnetic Resonance is based on:

✓ a strong static magnetic field (1.5-11.2T),

✓ rapid magnetic gradients (small additional magnetic fields) activated in

specific sequences

✓ low-energy electromagnetic radiations

a strong static magnetic field (1.5-11.2T),

✓ iron and steel objects are attracted

Ferromagnetic objects are attracted and act as missile objects

The magnetic field is always active and the strength of the attraction

increases exponentially.

In 10 years in Padova I saw

1 monitor

1 polisher

2 oxygen cylinders

1 chair

2 IV poles

2 scissors

Several coins, keys and so on…

These objects might act as missile objects (rare cases of death, several cases

of severe patient injury)

rapid magnetic gradients (small additional magnetic fields)

✓ electric devices (e.g. pacemaker) do not work properly inside the

scanner room

The gradients might inactivate the pacemaker and induce overheating of the

metallic filament (burning lesions of the heart).

About 50% of patients die during the exam.

low-energy electromagnetic radiations

✓ the exam is non-invasive and can be repeated

BUT

✓ the exam lasts 30-60 minutes

✓ good compliance is required (non collaborative patients such as children

or those confused or affected by claustrofobia might require invasive

sedation)

➢ What is “Magnetic Resonance” (MR)

➢ What is “conventional MR imaging and angiography”

➢ What are “advanced techniques”

➢ What are “advanced analyses”

➢ Possible applications for hematologic disorders

• Topics

It includes all the sequences used in the clinical routine for investigating

brain parenchyma and intracranial vessels.

There are more than 50 sequences (each providing different information)

and each sequence lasts about 3-5 min.

Protocols include only some sequences according to the clinical problem.

Typical standard protocol

✓ T1-weighted

✓ FLAIR T2weighted

✓ Diffusion weighted imaging (DWI)

✓ T2 weighted

✓ T2 weighted gradient echo (T2*)

• conventional MR imaging and angiography

• conventional MR imaging and angiography

FSE T2-weighted MPRAGE T1-weighted

HASTE T2-weighted

• conventional MR imaging and angiography

FLAIR is especially used for detecting vascular like changes

DWI is especially used for detecting acute ischemic strokes

T2* is especially used for detecting microbleeds

• conventional MR imaging and angiography

FLAIR

DWI

• conventional MR imaging and angiography

MR-angiography MR-venography

(time of flight, ToF) (phase contrast, PC)

• conventional MR imaging

MR spectroscopy shows metabolite concentrations

in a chosen volume (e.g. NAA, choline, etc.)

Different sequences show different metabolites

(short/long TE, single voxel, 2D, 3D, etc)

The higher the magnetic field strength, the higher

the metabolite discrimination (i.e. 3T better than

1.5T)

MR spectroscopy

➢ What is “Magnetic Resonance” (MR)

➢ What is “conventional MR imaging and angiography”

➢ What are “advanced techniques”

➢ What are “advanced analyses”

➢ Possible applications for hematologic disorders

• Topics

They include sequences that usually require post-processing to show their

findings

Qualified personnel is needed (imaging engineers, highly qualified

technicians, dedicated physicians)

Imaging findings are usually choreographic in a clinical setting on single

subjects (rare cases diagnosed by these techniques), extremely interesting

and powerful in a research setting with group analysis

✓ diffusion tensor imaging (DTI)

✓ functional MRI (fMRI)

✓ metabolite imaging

✓ iron quantification/myelin maps

✓ T1rho maps, T2rho maps…

• advanced techniques

Isotropy and anisotropy

Characterization of diffusion

x

y

z

Measure diffusion along

various directions (> 6)Calculate shape of the

ellipsoid

l1

l2

l3

Characterization of diffusion

x

y

z

Measure diffusion along

various directions (> 6)Calculate shape of the

ellipsoid

l1

l2

l3

1. Measure

diffusion

along various

directions

(>6)

2. Calculate

shape

of the

ellipsoid

Diffusion

Magnitude

Diffusion

Direction

Eigenvector

Direction

field

Cat primary visual cortex – coronal view

• Pixel color reflects the

direction of the prevailing

eigenvectors.

•

• Pixel intensity depends on FA

value= TRASVERSAL

= ANTERO-POST.

• advanced techniques

• advanced techniques

• Reconstruction of 3D trajectory through the propagation of a line that follows local eigenvector orientation

Tractographic representation

• advanced techniques

Hemoglobin

Oxyhemoglobin

(Hb)

Diamagnetic (χ< 0)

Deoxyhemoglobin

(dHb)

Paramagnetic (χ> 0)

• advanced techniques

Task or Stimulus↓

change in neuronal activity↓

change in oxygen levels↓

change in magnetic properties of haemoglobin↓

endogenous contrast

fMRI

• advanced techniques

Brain activity

Oxygen consumptionn

Signal ↓:

hypointensity

deoxyHb

• advanced techniques

Brain activity

Oxygen consumptionn

Signal ↑: hyperintensity

In reality....

Hb↑ dHb ↓

Blood Flow ↑↑

T2* ↑

Magnetic susceptibility ↓

• advanced techniques

time0.5 - 2 sec 5 sec 10 sec

Signal Intensity

+1-5%

0

- <0.5%

stimulus

Hemodynamic response in time and space

BOLD Effect: Blood Oxygenation Level Dependent contrast

• advanced techniques

BOLD technique(Blood Oxygen Level dependent)

Short Stimulus

Long Stimulus

▪ initial dip (500 ms-1s)

▪ positive BOLD response (~6 s)

▪ post stimulus undershoot

P. Tofts, Quantitative MRI of

the Brain, Wiley

P. Tofts, Quantitative MRI

of the Brain, Wiley

• advanced techniques

EPI (Echo Planar Imaging)

- Very fast planar acquisition and good SNR

- Susceptibility artefacts

- Signal change due to the stimulus at 1.5T: 3-5%

• advanced techniques

Example time-courses

MRI signal from voxel that correlates well with task: Active

Task

TIME

Time-course of task versus rest periods

Rest

Task

Rest Rest

Signal from voxel that does NOT correlate with task: Inactive

• advanced techniques

fMRI samples huge 4D data-sets of brain images

• 100.000 points sampled in the brain

• signal changes due to noise and neural activity

• statistical methods discriminate between the twos

How does fMRI work

Scan 1°

Scan 2°

Signal changes due to

neural activity

a-priori reference

function

How does fMRI work

Statistical methods - Inferential processing

Language (repetition)

Colour represents statistical significance of how well the voxel’s activation correlates with the task.

The hi-res grayscale anatomical picture underneath the coloured blobs is a completely different type of image, from a different type of scan. Shows the anatomy at the spot where the significant voxel’s time-course was recorded.

Magnetic resonance imaging of glutamate

Kejia Cai1 Nature Medicine 2012

• advanced techniques

➢ Myelin maps

➢ R2* maps

➢ Thalassemia young patient

• advanced techniques

• advanced techniques

T1rho and T2rho are images based on novel contrast (rotating magnetic

vectors). Brain imaging changes in diseases is unexplored.

➢ What is “Magnetic Resonance” (MR)

➢ What is “conventional MR imaging and angiography”

➢ What are “advanced techniques”

➢ What are “advanced analyses”

➢ Possible applications for hematologic disorders

• Topics

MR-Morphometry

• Advanced analyses

They include post-processing based group analyses that allow parameter

quantification on conventional or advanced sequences.

They require normalization of the brain and allows a voxel-based

comparison between groups (e.g. patients and controls, treated and

untreated, etc.)

Qualified personnel is highly needed (imaging engineers, dedicated

physicians or physicists)

Imaging findings are extremely interesting and powerful but adapt only in a

research setting with group analysis

✓ Voxel based morphometry

✓ Cortical thickness

✓ Fractional anisotropy, mean, radial, axial diffusivity with DTI

✓ functional MRI (fMRI) task or event-related, resting state

✓ iron quantification/myelin maps

✓ T1rho maps, T2rho maps…

• Advanced analyses

• MRI post-processing quantitative techniques:

- detect parenchymal abnormalities even in patients with normal brain at conventional MRI

- allow for longitudinal evaluation of lesion burden

Sun et al. AJNR 2012

• Advanced analyses

➢ Quantifies gray and white matter density

➢Allows a voxel-wise comparison of the local concentration

of gray and white matter between two groups of subjects

Voxel-Based Morphometry (VBM)

• Advanced analyses

Voxel based Morphometry

(basis functions)

Time (months)

Hip

pocam

pal

volu

me

Navigation-related structural change

in the hippocampi of taxi drivers

VBM

E. A. Maguire, PNAS 2000

Freesurfer Subject 2 aligned with Subject 1

(Subject 1’s Surface)

Registration to a template (e.g. MNI/Talairach) doesn’t account for individual anatomy.

Vertex analysis

• Advanced analyses

Surfaces: White and Pial

• Advanced analyses

Cortical Thickness

white/gray surface

pial surface• Distance between white and pial surfaces

• One value per vertex

• Advanced analyses

PAT>CTRL CTRL>PAT

PAT

CTRL

➢ Contrast based on the directional rate of diffusion of water

molecules

➢Depicts brain structural integrity in terms of microscopic

white matter organization

Diffusion Tensor Imaging (DTI)

• Advanced analyses

➢ Mean Diffusivity (MD): magnitude of diffusion in a voxel

➢ Fractional Anisotropy (FA): extent to which diffusion is

directionally restricted

➢ Radial Diffusivity (RA): water diffusivity perpendicular to

axonal fiber

➢Axial Diffusivity (L1): water diffusivity parallel to axonal

fiber tracts

• Advanced analyses

Diffusion Tensor Imaging (DTI)

Feldman et al, 2010

• Advanced analyses

Diffusion Tensor Imaging (DTI)

fMRI

• Advanced analyses

Frequency

representation

(tonotopic maps)

in the human

auditory cortex

500 Hz

1000 Hz

3000 Hz

➢At rest, spontaneous coherent fluctuations of the blood

oxygen level-dependent signal are detected in brain areas

functionally connected

➢ It features (all) different typical neural networks (motor,

visual, acoustic…) simultaneously!

Raichle et al., 2001; van de Heuvel et al., 2008

• Advanced analyses

Resting State Functional MRI (fMRI)

➢ What is “Magnetic Resonance” (MR)

➢ What is “conventional MR imaging and angiography”

➢ What are “advanced techniques”

➢ What are “advanced analyses”

➢ Possible applications for hematologic disorders

• Topics

All MRI techniques and analyses might be applied in the field of

hematologic disorders for clinical and research purposes

• Possible applications

Ehineboh Itohan

PRES, LERRP

• Neuroimaging in SCD

M, 16 years

Metushi Sefer

• Neuroimaging in SCD

➢ Vertebral infarct

➢ Stroke and intracranial artery stenosis are major issues in SCD children

➢ The neuroimaging approach in the acute phases of a stroke does not differ than in non-SCD-related pediatric acute strokes (brain CT for excluding hemorrhage, brain MRI and intracranial artery MRA as soon as possible)

• Neuroimaging in SCD

M, 14 years

Territorial Strokes

Watershed Strokes

• 42/99 patients (42%) presented with vascular changeswith a global score >1

• weak correlation between vascular and parenchymalchanges in the supplied cerebral tissue

A1 A2 M1 M2 P1 P2 TICA

Dx 23/3 1 8 11/1 4/1 4 15/2

Sn 19/2 1 11 12/1 0 4 13/2

Our Sample(Padova and Modena)

• Do we need MRI and MRA?

• MRI is sensitive to silent cerebral infarcts that are present in about 20-37% of pediatric SCD patients

Miller et al. Pediatr 2001

Kwiatkowski et al. Haematol 2009

Pegelow et al. Blood 2002

Arkuszewski et al. Adv Med Sci 20146 yrs

• Silent cerebral infarcts have a (14-fold) higher risk of overt stroke

• Do we need MRI and MRA?

• MRA is sensitive to intracranial artery stenosis (detected in about 10% of children with normal TCD)

Arkuszewski et al. Adv Med Sci 2014

Ventura (Sung) Jasmeen

2010 2012 2014

• Are we looking at ischemic lesions?

QDEC (FreeSurfer)

Right Hemisphere

SCD children versus healthy controls

• Cortical thickness and age-classes

QDEC (FreeSurfer)

Left Hemisphere

SCD children versus healthy controls

• Cortical thickness and age-classes

Temporal evolution of cortical thickness

• Cortical thickness and age-classes

➢ Increased connectivity in SCD children vs healthy controls in the precuneus of the defaul mode network.

➢ The phenomenon is more evident in SCD children with initial cognitive impairment.

• Resting state fMRI DMN analysis

Vascular-like white matter lesions review

• Beta-thalassemia

High lesion burden

• Beta-thalassemia

• Beta-thalassemia

Studies without a control group

Patients and controls do not differ in terms of vascular like white

matter changes (46.7% vs 50.0%)

TDT and NTDT patients do not differ, as well

No association between lesion burden and splenectomy

No association with cognitive performances

• Beta-thalassemia

• Beta-thalassemia

• Precedenti studi sulla quantificazione del

ferro nell’encefalo di pazienti β-talassemici

hanno dato risultati disomogenei

• Beta-thalassemia

Iron overload is a major problem

The brain has been scarcely studied

• Beta-thalassemia

• Beta-thalassemiaE

• Beta-thalassemia

CONCLUSIONS

• Conventional Magnetic Resonance and advancedquantitative neuroimaging can help to unravel the issueof brain involvement in hematologic disorders

Aknowledgements

• Prof Perrotta Silvio, Dr.ssa Tartaglione Imma; Dr.ssa Caiazza Martina

• Dr.ssa Colombatti Raffaella, Dr.ssa Sainati Laura

• Dr. Ermani Mario, Dr.ssa Dalla Torre Alice,

• Prof. Esposito Fabrizio, Dr.ssa Canna Antonietta, Dr.ssa Ponticorvo Sara, Dr. Russo Gerardo Andrea

• Dr. Meneghetti Giorgio and Dr.ssa Rampazzo Patrizia

• Dr Palazzi Giovanni

Thanks for the attention