The document discusses the current and future potential applications of PET/MR imaging in neurodegenerative diseases. PET/MR combines the molecular imaging capabilities of PET with the high spatial resolution of MRI. It allows simultaneous acquisition of PET and MRI data. Current applications include detection of amyloid plaques and dopamine deficits. Emerging tracers may image tau and alpha-synuclein. Novel MRI techniques like diffusion tensor imaging and arterial spin labeling also show promise. Combined PET/MR could become a routine first-line tool for diagnosis and may aid basic research into neurodegeneration.

1. The Current And Future Potential
Applications Of PET/MR Imaging
In Neurodegenerative Diseases
By
Dr. Walid Rezk, M.D.
Lecturer of Radiodiagnosis
Ain Shams University

2.  Neurodegenerative disorders such as Alzheimer
disease are among today’s most alarming health
problems in our aging society.
 The clinical assessment of neurodegenerative
disorders benefits from recent innovations in the field
of imaging technology.
 These innovations include emerging tracers for
molecular imaging of neuro-degenerative pathology
and the introduction of novel integrated PET/MR
imaging instruments.
Introduction

3.  Neurodegenerative diseases are characterized by a
progressive and chronic loss of neural tissue in cognitive,
motor, sensory, and other brain systems.
 This entity of diseases includes:
o Dementias
o Parkinsonian syndromes including movement diseases
such as multisystem atrophies (MSA), cortical-basal
degeneration (CBD), and progressive supranuclear
palsy (PSP)
o Huntington disease (HD)
o Amyotrophic lateral sclerosis (ALS)
o Prion diseases like Creutzfeldt-Jakobdisease (CJD)
Neurodegenerative disorders

4.  In daily routine, most neurodegenerative diseases are
diagnosed by a combination of clinical testing
together with biomarkers, like brain imaging or
cerebrospinal fluid analysis.
 In brain imaging of neurodegenerative disease, MRI
represents the standard tool. This is based on the
high spatial resolution and the high soft tissue
contrast this modality offers as well as the rather
specific findings in at least some movement disorders
such as MSA and PSP.

5.  Often MRI is employed in suspected
neurodegenerative diseases to exclude other non-
neurodegenerative causes for the symptoms
observed, like vascular disease, brain tumors, and
traumatic or inflammatory brain changes.
 In addition, certain brain atrophy patterns may
support the clinical diagnosis of distinct
neurodegenerative diseases.

6.  Brain PET has also been used over many years to
diagnose neurodegenerative diseases.
 The main advantage of PET over MRI lies in its higher
sensitivity to detect pathologies on a molecular level,
which at least in principle permits more sensitive or
even earlier diagnoses, because these diseases start
with pathobiochemical processes that only lead to
morphologic changes visible on MRI after a certain
time period.

7. Current PET Tracers to Image
Neurodegenerative Diseases

8.  It is evident that [18F]FDG, which is transported into
intracellular space by glucose 1 transporters followed
by phosphorylation via the hexokinase reaction, is the
most often employed PET tracer in this regard.
 [18F]FDG represents a universal marker of neuronal
and synaptic integrity with relatively disease-specific
uptake reduction patterns as for example:

9. AD: bilateral temporoparietal areas are mainly
affected exhibit [18 F]FDG uptake reductions.

10. o Frontotemporal lobar
degeneration (FTLD) in
which, depending on its
subtype, mainly frontal
region or temporal
region or both exhibit
[18 F]FDG uptake
reductions.

11. o Parkinsonism: [18F]FDG-PET allows discrimination
between primary PD and atypical parkinsonian
syndromes, as major glucose consumption deficits
being only found in the latter.
o HD: mainly showing striatal uptake reduction
o ALS: showing variable uptake reduction patterns
depending on the ALS subtypes.

12.  CJD: showing patchy uptake reductions of different
patterns throughout the cortex and subcortical
structures.

13.  Apart from [18F]FDG, two groups of more disease-
specific PET tracers are currently available in clinical
routine:
1. Amyloid plaque tracers:
 In AD, β-amyloid plaques, one of the
histopathologically hallmarks of the disease,
recently became traceable by PET tracers, like [18F]
florbetapir, [18F] florbetaben, or [18F] flutemetamol.
 These tracers are now approved for clinical use and
are currently employed to show or exclude brain
amyloid load in mild cognitive impairment (MCI), and
early-onset clinical presentation of AD-like dementia.

14. 2. PET tracers that target different components of
dopaminergic transmission:
Dopamine precursor tracer 3,4-dihydroxy-6-[18F]-
fluorol-phenylalanine ([18F] FDOPA)
The presynaptic dopamine transporter (DAT)-
targeting [18F] fluoropropyl carbomethoxy
iodophenylnortropane (FP-CIT)
Both are used for clinical routine purposes to
diagnose parkinsonian syndromes

15.  In the scan of a disease-free brain, made with [18F]-
FDOPA PET (left image), the red and yellow areas show
the dopamine concentration in a normal putamen.
Compared with that scan, a similar scan of a
Parkinson’s patient (right image) shows a marked
dopamine deficiency in the putamen.

16. Current MRI Techniques to Image
Neurodegenerative Diseases

17. Disease Typical MRI Sequences
Alzheimer disease T2 FLAIR and T1 3D GRE
FTLD FLAIR and T1 3D GRE
Vascular dementia FLAIR, T2*/SWI, and DWI
DLB FLAIR and T1 3D GRE
Parkinson disease T1, T2 multiplanar, and T2*/SWI
Atypical parkinsonian syndromes T1, T2 multiplanar, and T2*/SWI
Huntington disease T1, T2, and T2*/SWI
ALS T1 and T2
CJD DWI, FLAIR, T1, and T2
Current Clinical Routine MRI Sequences to Image
Neurodegenerative Diseases

18. The routine MR imaging may reveal specific pattern of
atrophy as in:
 AD: Temporal atrophy patterns according to
established scores (Scheltens score)

19.  PSP: mesencephalic
atrophy (mickey mouse
sign)

20.  Cerebellar MSA (formerly known as olivopontine
cerebellar atrophy): pontine and cerebellar atrophy
patterns combined with distinctive signs of pontine
neurodegeneration (hot cross bun sign)

21.  Advanced stages of HD: isolated putamen and
caudate head atrophy

22.  Hallervorden-Spatz
disease, and
occasionally PSP and
CBD: iron
accumulation with
gliosis and
spongiosis of the
pallidum (eye-of-
the-tiger sign)

23.  Parkinsonian MSA (formerly known as MSA-
striatonigral degeneration): periputaminal gliosis
 CBD: unilateral atrophy of the primary motor cortex
together with cortico-spinal tract degeneration

24.  Diffusion-weighted MRI may show typical signal
changes of the basal ganglia and cortex in CJD with
greater visibility than on T2-weighted images owing
to restricted diffusion with extracellular edema

25. Combined PET/MRI to Image
Neurodegenerative Diseases

26.  Taking the aforementioned status and advantages of
both PET and MR to image neurodegenerative
diseases, it was a logical early step to clinically test
the potential of combined PET/MRI technology in
improving and simplifying neurodegeneration
imaging.

27.  One of the main technical challenges of integrated
PET/MRI is to find a reliable substitute for the standard
transmission-based (CT or line sources) attenuation
correction (AC) of the PET data, a technique which is not
available within combined PET/MRI systems.
 In the current PET/MRI systems, AC of the PET data is
mainly accomplished by using a 2-point Dixon MR
sequence that segments tissues into four classes (lung, air,
fat, and soft tissue) and is in some systems supplemented
or substituted by an ultrashort echo time (UTE) sequence
that provides additional bone contrast or segmentation.

28.  An MR localizer precedes an approximately 20-
minutes data acquisition interval in which a PET
emission scan is simultaneously obtained with an
array of MR sequences
 Dixon or UTE sequences or both for AC of the PET
data
 T2 Fluid-attenuated inversion recovery sequence to
decide on the extent of vascular lesions and atrophy
Protocol of PET/MR examination

29.  T2 turbo spin-echo sequences to give optimal
contrast to infratentorial structures and to evaluate
atrophy
 Susceptibility-weighted sequence to detect
microbleeds
 T1-magnetization–prepared rapid acquisition gradient
echo sequence for further, also quantitative,
anatomical imaging and potential morphometric
analysis.
Protocol of PET/MR examination

30.  Left two columns, represent amyloid PET/MR overlay together with the z-
score map illustrating pathologic neocortical amyloid plaque burden (AD,
DLB) or normal tracer uptake (VaD)
 Middle column, the corresponding transverse anatomical T1-magnetization–
prepared rapid acquisition gradient echo (MPRAGE) MR slice.
 Right two columns, the corresponding transverse slices of other imaging
modalities demonstrating biparietotemporal glucose consumption deficits
(AD, DLB) or periventricular vascular lesions (VaD).

31.  Severe bilateral
hippocampal atrophy
evident by severely
reduced hippocampal
volume (white arrows)
(Left more than right) on
Axial MRI images (A)
With prominent bilateral
frontal and temporal
hypometabolism on axial
fused PET MRI images
(white arrowhead) (B
and C). Note preserved
parietal metabolism on
axial and sagittal fused
PET MRI images (white
thick arrows) (D)

32.  By obtaining all required imaging and biomarker
information within one session, not just an improved
convenience to the patients and their caregivers but
also to the referring doctors is anticipated.
 Furthermore, combined PET/MRI is expected to
improve the diagnostic quality of both modalities by
allowing simultaneous image data acquisition as well
as a simplified and more accurate (owing to the
perfect match between the PET and MRI data) image
data analysis.
Advantages of PET/MRI

33.  Head movements during data acquisition can be
online monitored by MRI, allowing for improved
motion correction of the PET data.
 Further, the MR information can be used to correct
PET data for atrophy and partial volume effects.
 Also, PET tracer uptake quantification can be
improved by considering MRI-derived information on
lean body mass, by creating an image-derived arterial
input function, as well as by considering factors
influencing brain tracer supply, like cerebral blood
flow.
Advantages of PET/MRI

34.  Vice versa, the testing and evaluation of new MR
techniques can be improved by validating them
against simultaneously acquired PET gold standard
techniques. Examples of that are ASL, which is tested
in patients with dementia as a substitute for [18F]
FDG, or quantitative susceptibility mapping as a
potential substitute for amyloid PET tracers.
Advantages of PET/MRI

36. Future Potential of PET/MRI in
Neuro-degenerative Diseases

37.  For dementia imaging, there are promising new PET
tracers as well as MR sequence developments.
 For the PET component, the new emergence of tau
tracers and α-synuclein tracers is attractive, as they
will increase the possibilities to visualize different
histopathologic hallmarks of different underlying
dementias.
Future Potential of PET/MRI in
Dementia Diseases

38.  Regarding newer potential MR techniques, especially
diffusion-tensor imaging (DTI), resting-state
functional MRI (rs-fMRI), and perfusion imaging are
considered promising candidates to improve
dementia diagnosis.
 DTI maps showing white matter fiber integrity are
able to provide models of structural brain
connectivity, features that are often disturbed in
neuro-degenerative diseases.
 Rs-fMRI may provide complementary information
about functional connectivity and allow functional
cerebral network analysis.

39.  Perfusion MRI, either traditionally using contrast-
enhancement or arterial spin labeling (ASL), is
another attractive approach.
 In combination with amyloid PET tracers, at least in
principle, the collection of information on both
biomarker categories (amyloid load and neuronal
injury) in AD within one session is possible

40.  Novel PET tracers especially targeting DATs and α-
synuclein are in development, potentially opening the
way for a wider use of PET and PET/MRI as first-line
imaging in these neurodegenerative diseases.
Future Potential of PET/MRI in
Parkinsonian Syndromes

41.  For MRI, standard anatomical imaging as currently
employed in most situations to detect specific
atrophy patterns for different atypical parkinsonian
syndromes might be enriched in the future by routine
voxel-based morphometry and new techniques to
detect and quantify white matter fiber degeneration
and structural connectivity deficiency (DTI), and iron
accumulation, for instance in midbrain or striatal
areas (iron mapping)

42. Future Potential of PET/MRI in Other
Neurodegenerative Diseases
 There are promising new developments regarding
new PET tracers and novel MR sequences to improve
imaging of these diseases.
 Some of the new emerging PET tracers target
neuroinflammatory processes known to occur in HD
or ALS,
 whereas others include more disease-specific
processes like prion amyloid plaques in CJD.

43. Take home message

44.  The recently established combined PET/MRI
technology has a great but yet mostly unexplored
potential to improve early and differential diagnosis
of many neuro-degenerative diseases.
 New emerging PET tracers, like tracers that bind to β-
amyloid, tau, or α-synuclein aggregates, as well as
new MR techniques, like DTI, rs-fMRI, or ASL, will
broaden the diagnostic capabilities of combined
PET/MRI.

45.  From the current knowledge on applying combined
PET/MRI in neurodegenerative diseases, it is
concluded that there is a chance of establishing this
technique as routine first-line one-stop-shop clinical
imaging tool.
 Basic research into neurodegenerative diseases and
antineurodegeneration drug testing are considered
other promising applications of combined PET/MRI

46. Thank you