Annual Scientific Meeting 2023

The Next Frontier in Multimodal Technologies for

Understanding Brain Diseases

The Role Nuclear Medicine

Diagnostics in Brain Diseases

March 18th 2023

 Outlines
• Nuclear Medicine Perspective in Brain Imaging
• Modalities and Radiopharmaceuticals
• Clinical Applications
• Research and Development
• Take Home Message
 Nuclear Medicine
• Nuclear medicine is defined as a medical :
specialty which uses the nuclear properties of
matter to investigate physiology and
anatomy,diagnosis diseases, and to treat with
unsealed sources of radionuclide.
• Nuclear medicine is a specialized area of
medicine that uses very small amounts of
radioactive materials, or
radiopharmaceuticals, to examine organ
function and structure.
 Molecular
Neuroimaging
• Diagnostic nuclear medicine investigations have evolved from being a
research modality in the evaluation of function and disease of the
central nervous system to an established clinical tool in neurology.

• From metabolism to perfusion, brain function has been studied in a

variety of conditions, including dementia, epilepsy, movement
disorders and brain tumours.
 Molecular
Neuroimaging
Key Points:
- Nuclear medicine imaging is the only tool for direct
measurements of neurotransmitter levels and the
distribution, density, and activity of receptors or
transporters.
- PET and SPECT have made a significant contribution
to evaluate the physiological function and
biochemical changes of molecular targets. Both
techniques are based on the measurement of the
radionuclide’s decay, during which a positron or a γ-
ray will be emitted and thus generate photos.
Advantages : Nuclear medicine risks are small, and the benefits are invaluable

• These tests provide functional and anatomic information that is

unattainable in other procedures.
• Nuclear medicine tests provide doctors with the most useful
diagnostic information and the most helpful information to
determine a course of treatment.
• PET scans can tell whether tumors are malignant or benign and can
prevent a patient from getting a more dangerous or more costly
surgery.
• These tests also have the ability to detect diseases in their earliest
stages, and sometimes before the diseases even cause symptoms.
 Modalities and Radiopharmaceuticals
Principles of Nuclear Medicine Imaging
“The visualization of changes of essential cellular
structures gives testimony about the health status of a cell long
before macroscopically or microscopically visible changes in
cell morphology occur”
“Sensitive phenomena are only accessible to investigations with
tracers/imaging agents and in the most delicate cases extremely small
numbers of receptors are available to trigger the specific accumulation
of the imaging agent.” (Catana et al., 2012)
Radiopharmaceutical
s

Schematic design of a radiopharmaceutical

Koen Vermeulen, et.al

Radiopharmaceuticals for Molecular Neuroimaging
• Molecular imaging is performed using radiopharmaceuticals by
single photon emission computed tomography (SPECT) and
positron emission tomography (PET)
• Characteristics :
- to blood-brain-barrier permeability,
- cerebral perfusion and metabolism receptor-binding, and
- antigen-antibody binding.
 SPECT Radiopharmaceuticals
• The blood-brain-barrier (BBB) :
- 99mTcO4-, [99mTc]DTPA, 201TI and
- [67Ga]citrate are excluded by normal brain cells, but enter into
tumor cells because of altered BBB.
• Perfusion agents :
- [123I]IMP, [99mTc]HMPAO, [99mTc]ECD, xenon-133
🡺 are lipophilic agents and therefore, diffuse into the normal brain
• Receptor-binding :
- [123I]QNE, [123I]IBZM, and [123I]iomazenil.
🡺 specific receptors in the brain, thus displaying their distribution in various
receptor-related cerebral diseases.
 PET radiopharmaceuticals
• Commonly labeled with positron-emitters :
- 11C, 13N, 15O, and 18F, although other radionuclides such as
82Rb, 62Cu and 68Ga also were used.
• Cerebral perfusion agents :
- 15O water, 13N ammonia, and 15O butanol
- Other perfusion agents include [15O]O2, [11C]CO, [11C]CO2,
[18F]fluoromethane, [15O]O2, [11C]butanol, and [62Cu]PTSM.
• Cerebral metabolic agents :
- [18F]fluorodeoxyglucose (FDG)
 NM Modalities

1 2 PET MRI
SPECT , SPECT/CT PET CT
 NM MODALITIES
SPECT PET
Single photon emission-computed tomography Positron-emitting tomography

- resolution limited by technology only - high sensitivity

(submillimeter) - 3D acquisition
Advantages - good resolution, but with a physical limit
- can differentiate between isotopes
with different radiation energies - quantification possible

- short-lived isotopes
- 2D (planar images) and
- isotopes produced in cyclotrons
reconstructed 3D
Disadvantages - expensive tracer production & equipment
- semiquantitative data only
- higher tissue doses, but balanced by higher
- low sensitivity
sensitivity

- readily available and in widespread use - [18F]FDG becoming routine in oncology

- wide range of clinically Clinical use - special applications in neurology and
tested tracers cardiology
 Hybrid Imaging
❑Hybrid imaging has been in the medical scene since 1990s
❑Hybrid Imaging modalities have shown great potential in
medical imaging and diagnosis
❑Hybrid imaging in neuroscience is to improve the noise
rejection, attenuation correction and provide image
fusion for anatomical referencing.
❑Hybrid imaging has functional anatomical mapping (FAM),
precisely align the two sets of images and eliminate the
inaccuracies caused by breathing movements and other
artifacts.
🡺 PET-CT and SPECT-CT 🡺used for precise
anatomical localization
🡺 PET-MRI 🡺 used for reduced radiation exposure
and superior soft tissue contrast
 Clinical Applications

Common imaging applications :

🡺Imaging of cerebral blood flow
🡺Imaging of brain metabolism
🡺Imaging of neurotransmitter systems
🡺Imaging of other cerebral functions such
as amyloid and
🡺Brain tumour imaging.
 Imaging of cerebral blood flow
❑ Evaluation of cerebrovascular disease : Acute stroke, Chronic ischaemia,
Preoperative evaluation
❑ Evaluation of suspected dementia :
🡺 Indications include the early detection and differential diagnosis of
various forms of dementia : Alzheimer’s disease , Lewy body dementia
, Parkinson’s disease with dementia , vascular dementia and
frontotemporal dementia
🡺 In the pre-dementia phase of these diseases, known as mild
cognitive impairment, SPECT can detect a functional deficit and thus
guide prognosis
❑Evaluation of traumatic brain injury
❑Evaluation of suspected inflammation
❑Assessment of brain death.
 Brain Death Ischemic Stroke
*) Scintigraphic Confirmation of Brain Death, Partha Sinha MD, Gary R. Conrad MD *) Radionuclide Imaging in Ischemic Stroke, Wolf-Dieter Heiss
 A B C

Epilepsy
*) PET and SPECT in epilepsy: a critical review C la Fougère 1, A Rominger, S
Förster, J Geisler, P Bartenstein

Traumatic Brain Injury

*) FDG-PET imaging in mild traumatic brain injury: a critical review, Kimberly R Byrnes, et.al
 Imaging of brain metabolism
Brain Tumours :
❑ During Initial Evaluation
Determining degree of malignancy
Assessing prognosis

❑ After Therapy
Assessing persistent tumor after surgery
Grading degree of malignancy
Assessing prognosis
Monitoring progression
Differentiating recurrence fromn ecrosis
 PET Scan can provide information regarding tumor grading, delineation of tumor
margins, guidance for stereotactic, biopsy, response to therapy, and prognosis

*) Courtesy of Society of Nuclear Medicine And Molecular Imaging

Anaplastic oligoastrocytoma Grade III in the frontal lobe (A) Contrast-
enhanced, T1-weighted MRI. (B) MRI FLAIR (fluidattenuated inversion
recovery)-sequence. (C) 18F-FDG PET. (D) 18F-FET PET. Delineation of
the tumor is difficult on MRI and 18F-FDG images while 18F-FET
depicts the solid tumor mass and indicates an optimal biopsy site in
this large lesion
*)D. Pauleit, G. Stoffels, et.al , Comparison of (18)F-FET and (18)F-FDG PET in brain tumors.
Diffuse astrocytoma WHOGrade II in the left frontal lobe (A) Contrast
enhanced, T1-weighted MRI. (B) MRI FLAIR-sequence.(C) 18FFDG PET.
(D) 18F-FET PET. There is decreased 18F-FDG uptake within the tumor
while 18F-FET exhibits increased uptake and identifies a local maximum
for biopsy guidance
 Another PET Radiopharmateucals

68Ga-DOTATATE PET/CT scan of neuroblastoma. There 18F-FET PET/CT scan representing tumor recurrence in
is focal uptake in the skull representing bony invasion the posterior left occipital lobe (arrow).
(arrow).

*) An update on PET-based molecular imaging in neuro-oncology: challenges and implementation for a precision medicine approach in cancer care, Hossein Shooli, et.al
 Imaging of neurotransmitter systems

🡺 Dopaminergic neurotransmission plays an important

role in regulating several aspects of basic brain
function, including motor, behavior, motivation, and
working memory :
Clinical applications :
Parkinson’s disease(PD) and related Parkinsonism
 SPECT Radiotracers

Dopamine transporter imaging by administration of 123I-fluopane (FP)-CIT in a

patient with Parkinson’s disease (a), an essential tremor (b), and a healthy control (c)
SPECT imaging using 99mTc-TRODAT-1 in normal control (a) and
patient with early PD (b). In the case of patient with early PD in *) Courtesy of Tolosa E, Borght TV, Moreno E
comparison to control, images show reduced TRODAT-1 uptake
in the striatum
*) Courtesy of Chou K, Hurtig H, Stern M, Colcher A, Ravina B, Newberg A et al
 Imaging of other cerebral functions : AD

1. Amyloid
🡺 Amyloid beta monomers (single peptides) aggregate into soluble
oligomers (small aggregates of peptides), which then combine to form
insoluble fibrils (long aggregates of peptides) and plaques.
Mechansm :
Two pathological hallmarks of the AD: (1) senile plaques, composed of
amyloid-β (Aβ) peptides, and (2) neurofibrillary tangles (NFTs),

Clinical Applications :
Alzheimer's disease is characterized by the abnormal accumulation of
amyloid beta and hyper-phosphorylated tau proteins, which are two
hallmarks of AD.

Radiotracers: 18F-florbetapir (Amyvid), 11C-labeled Pittsburg Compound B

(11C-PiB),
 Examples of
negative and
positive Ab PET
findings using
different tracers

*) Courtesy of Victor Villemagne and Christopher C. Rowe

Amyloid PET Scan : AD
 2. Tau PET Imaging
Mechansim :
The pathological hallmarks of the AD: neurofibrillary tangles (NFTs)/ TAU
Radiotracers : 18F-flortaucipir, 18F-MK6240, 18F-RO948, and 18F-PI2620)

*) Images were acquired at Saint-Luc University Hospital (UCLouvain, Belgium)

18F-THK-5117 (TAU) PET Scan

*) Courtesy of Okamura et al. 2014; reproduced, with permission, from Springer Science and Business Media
 Research and Development

Central nervous system (CNS) radiotracer development from bench to bedside

Different pharmacological and pharmacodynamic behavior of 2-, 5- and 6-[18F]FDOPA

Antony D. Gee, et.al, Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions
 Take Home
Message
Important Clinical Imaging Tools for Suffering from Brain Diseases :
✔ How it Works
✔ Increasing Clinical Applications
✔ Glucose metabolic FDG or other RP, PET Scan : Dementia,
Epilepsy, Brain Tumours
✔ Dopamine Transporter SPECT : Parkinson’s disease
✔ Amyloid – TAU PET : Alzheimer’s disease
✔ Many Radiotracers have developed