NEUROIMAGING IN PARKINSONISM edited.pptx

NEUROIMAGING IN
PARKINSONISM
DR PRAKARSH SHARMA
SR NEUROLOGY

INTRODUCTION
• PD is a progressive neurodegenerative disorder.
• 2nd most common neurodegenerative d/o
• characterized by the loss of dopaminergic neurons in the substantia nigra-pars
compacta.
• resulting in a striatal dopaminergic deficit
• Symptoms- motor tremors, rigidity, bradykinesia, postural fall.
• demonstration of intracytoplasmic Lewy bodies is the pathological hallmark of PD
and is necessary for a definitive diagnosis of PD.
Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis
Antonina Kouli, Kelli M. Torsney, and Wei-Li Kuan.

Pathophysiology
1 alpha synuclein : when aggregates in neurons k/as LEWY BODIES,
• Seen in PD & DLBD (DIFFUSE LEWY BODY DEMENTIA)
MSA ( aggregates in glial cell)
2. TAU PROTEINS
PSP AND CBD
Hyperphosphorylated tau protein – Alzheimer
Hyperphosphorylated tau protein- Pick’s disease
Parkinsonism refers to several conditions — including Parkinson’s disease — that have similar
symptoms and features.

The gold-standard diagnostic technique in PD is expert clinical
opinion.
• The sensitivity for establishment of a clinical diagnosis of PD by
a movement disorder specialist has been reported to be as high
as 91.1%
• however, clearly a difference in diagnostic accuracies between
early and advanced disease.
Hughes AJ, Daniel SE, Shlomo YB, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service.
Brain 2002;125:861-70

• Neuroimaging (NI) in these early stages can help to distinguish
PD from PD-mimics.
• It can also aid in the differential diagnosis of parkinsonian
syndromes,
• monitor disease progression,
• and measure the effects and complications of various therapies.

MRI IN PARKINSON
• extensively used for parkinsonian syndromes.
• wide range of imaging findings depending upon the severity of
the disease and the subtype.
• completely normal scan / classical diagnostic features
• Imaging is helpful to confirm the diagnosis of parkinsonian
syndromes,
• classify them into various subtypes, rule out the alternative
differential diagnosis and determine the severity of brain
changes.

• recent advanced techniques including
-diffusion weighted imaging with tensor imaging,
-MR morphometry,
-magnetization transfer imaging
- MR spectroscopy have also been used in the diagnosis
of these group of disorders.

MRI
• Loss of the normal swallow tail appearance of susceptibility signal pattern in
the substantia nigra on axial imaging is perhaps the most promising diagnostic
sign.
• signal intensity in substantia nigra depends on loss of neuromelanin and iron
accumulation.
• identify features which may indicate secondary parkinsonism
Savoiardo M. Differential diagnosis of Parkinson's disease and atypical parkinsonian disorders by magnetic resonance
imaging. Neurol Sci 2003;24(Suppl 1):S35-7.

Features of Parkinsonism on MRI
• T1
• may show mild hyperintensity of compact and reticular parts of
to iron accumulation)
• may show loss of normal slight hyperintensity in substantia nigra due to loss
• T2* (GRE/SWI)
• absent swallow tail sign
• reported diagnostic accuracy of over 90%, with a 100% sensitivity and
95% specificity, and 69% positive predictive value being reported in one
Brammerloh M, Kirilina E, Alkemade A et al. Swallow Tail Sign: Revisited. Radiology. 2022;:212696. doi:10.1148/radiol.212696 - Pubmed

Normal substantia nigra anatomy on axial SWI slice at the level of nigrosome-1 showing the midbrain anatomical structures: 1 red nucleus, 2
midbrain tegmentum, 3 aqueduct, 4 medial leminiscus, 5 nigrosome-1, 6 substantia nigra, 7 cerebral peduncle. High signal intensity at the
level of nigrosome-1 is called the normal swallow tail sign.
References: Research Unit of Radiology, National and Kapodistrian University of Athens, GR
2 /

Axial T2 weighted MR image at the level of midbrain shows hyperintense signal changes
(arrows) involving bilateral substantia nigra in this patient of Parkinson's disease

• FLAIR (A) and T2(B) images of a PD patient, show blurring and thinning of pars compacta (yellow arrows). Eventually, the
red nuclei and substantia nigra are almost touching.
•
l FLAIR (A) and T2(B) images of a PD patient, show blurring and
thinning of pars compacta (yellow arrows). Eventually, the red
nuclei and substantia nigra are almost touching.
References: Research Unit of Radiology, National and
Kapodistrian University of Athens, GR

• abormal substantia nigra on axial SWI images in a patient with Parkinson Disease. The arrow indicates the abnormal
swallow tail sign (hypointensity in nigrosome-1) on SWI sequences, due to iron deposition.
•

• Recent studies with ultra-high-field MRI (7 T) have shown promising results
regarding both sensitivity and specificity .

Progressive supranuclear palsy
• characteristic imaging findings in PSP include atrophy of the midbrain with signal
changes on T2 weighted images.
• The tegmentum, inferior olives and superior cerebellar peduncles show atrophy
• resulting in prominent cerebrospinal fluid (CSF) spaces around the midbrain
• On a sagittal view, the shape of the midbrain tegmentum and the pons in these
patients is described as a 'hummingbird' sign.
• a useful imaging biomarker in classic and brainstem variants PSP
Oba H, Yagishita A, Terada H, Brkovich AJ, Kutomi K, Yamauchi T, et al. New and reliable MRI diagnosis for progressive
supranuclear palsy. Neurology 2005;64:2050-5.

• midsagittal T1-weighted image of a PSP patient shows midbrain - tegmental atrophy without
pontine atrophy, giving the impression of the head and body of a humming bird or a penguin.

• MR Parkinsonism Index (MRPI)
• midbrain to pons area ratio : reduced area ratio on the midline sagittal
plane to approximately 0.12 (normal ~ 0.24)
• most accurate imaging feature which also helps to distinguish it from multiple
system atrophy parkinsonian type (MSA-P) (which shows both pontine and
midbrain atrophy)
• midbrain to pons width ratio: reduced on the midline sagittal plane to
<0.52
• midbrain width: reduced on the midline sagittal plane to <9.35 mm
Gröschel K, Kastrup A, Litvan I, Schulz J. Penguins and Hummingbirds: Midbrain Atrophy in Progressive Supranuclear
Palsy. Neurology. 2006;66(6):949-50.

MRI imaging surface measurements showing decreased midbrain to pons ratio in a patient with PSP. A:
Corpus callosum, B: midbrain tegmentum , and C: pons surfaces.

• hummingbird sign also known as the penguin sign: the key is a
flattening or concave outline to the superior aspect of the midbrain
which should be upwardly convex
• Mickey Mouse appearance: reduction of anteroposterior midline
midbrain diameter, at the level of the superior colliculi on axial
imaging (from interpeduncular fossa to the intercollicular groove: <12
mm)
• morning glory sign: loss of the lateral convex margin of the
tegmentum of midbrain

• Axial T2-weighted images of the brain on a PSP patient show selective atrophy of the midbrain tegmentum with relative
preservation of tectum and cerebral peduncles resembling the head of Mickey Mouse.

MRPI INDEX
• (P / M) x (MCP / SCP)
• MCP = average width of middle cerebellar peduncles
• SCP = average width of superior cerebellar peduncles
• P = area of pons in midsagittal plane
• M = area of midbrain in midsagittal plane
• A value of more than 13.55 indicates an abnormal result, and strongly suggests that these
patients will go on to develop PSP.
Morelli M, Arabia G, Salsone M et-al. Accuracy of magnetic resonance parkinsonism index for differentiation of progressive supranuclear palsy from probable or
possible Parkinson disease. Mov. Disord. 2011;26 (3): 527-33.

Multisystem atrophy – Parkinson
variant (MSA-P)
• MSA-P show changes in both the supra and infra-tentorial brain tissue.
• The characteristic infra-tentorial findings include atrophy of the pons
with signal changes on T2 weighted images giving rise to the classical
'hot cross bun' sign , cerebellar atrophy and hyperintensity of middle
cerebellar peduncles.
• The supratentorial findings include atrophy of the putamen with
slightly hypointense signal changes on T2 weighted images with a
hyperintense putaminal rim.
• These findings are not very sensitive but are highly specific, and thus,
can be used to differentiate between MSA-P and PD

Axial (a) and sagittal (b) T2 weighted images of a patient of MSA-P shows the
classical 'hot cross bun' sign in the midbrain (arrows in A). Note the marked
atrophy of the pons (arrow in B) and the cerebellum

AXIAL SWI image of a MSA-P patient shows reversal of the expected magnetic susceptibility pattern within the basal
ganglia with more prominent hypointensity of the putamen comparing with the globus pallidus, due to abnormal iron
deposition.

Axial T2 (A) and coronal T2*(B) images of a MSA-P patient, depict bilateral low signal intensity of the posterolateral segment of
putamen with an irregular high signal intensity rim along their lateral borders ("hyperintense putaminal rim" sign)-yellow
arrows.

Coronal T1(A) and T2(B) MR images show gross atrophy of pons and cerebellum in a patient with MSA-C.

Axial FLAIR image of a MSA-C patient shows bilateral hyperintensity of the middle cerebellar peduncles (arrows).

Axial T2 weighted images at the level of pons show cruciform hyperintensity-the "hot cross bun" sign (yellow arrow) in a MSA-C
patient.

Cortico-basal degeneration
• The imaging findings are non-specific in CBD and
include cortical atrophy with signal changes in the
cortex and subcortical white matter. The putamen may
also show hypointensity on T2 weighted images, as
seen in MSA-P.

Axial T2(A) and T1(B) images show asymmetric parietal cortical atrophy and widening of the postcental sulci in a CBD
patient.

DLBD
• generalized decrease in cerebral
volume most marked in
• frontal lobes
• parietotemporal regions
• enlargement of the lateral ventricles
• relatively focal atrophy of :
• midbrain
• hypothalamus
• substantia innominata
• absent swallow-tail sign

VASCULAR PARKINSONISM
• Periventricular white matter
lesion, lacunar infarcts in the
basal ganglion, dilatation of
lateral and third ventricles
• Presence of microbleed,
subcortical or cortical atrophy

NORMAL PRESSURE HYDROCEPHALUS
BRADLEY TEXTBOOK EIGTH EDITION CHAPTER 95

Diffusion weighted and diffusion
tensor imaging
• DTI – random motion of water molecules in brain tissue
• Mean diffusivity- diffusion of water molecules in organic tissues.
• Fractional anisotropy – orientation distribution of random movement of water
molecules
• Patients of PD have shown decreased fractional anisotropy (FA) values in the
region of substantia nigra as compared to healthy
• This can help to diagnose PD even when no changes are seen on conventional MR
images.
• Similarly, measurement of increased diffusivity values in the putamen, middle
cerebellar peduncles and superior cerebellar peduncles
Diffusion Tensor Imaging in Parkinson's Disease and Parkinsonian Syndrome: A Systematic
Review

Volumetry and morphometry
• Advanced MR software allows quantitative measurement of
volumes of various regions of the brain.
• Quantitative assessment of volume of the regions involved in the
Parkinson's disorders like the putamen, cerebellar peduncles,
midbrain, pons and cerebral cortex is helpful to objectively
determine the volume loss which is an integral feature of the
disorders.
• Selective volume loss of one region compared to the other is
helpful in differentiating the various disorders.

• In Parkinson's disease (PD), the most frequent form of parkinsonism, atrophy
of the frontal cortex and hippocampus usually occur at the late stages,
consistent with the timing of deposition of α-synuclein-positive Lewy bodies.
• MRPI measurement on a patient with Parkinson Disease (PD). b: MRPI
measurement on a patient with PSP. MRPI was calculated with the formula
[(P/M) × (MCP/SCP)] where P/M is the pons area–midbrain area ratio and
MCP/SCP is the middle cerebellar peduncle width–superior cerebellar
peduncle width ratio

• Volumes of striatum, cerebellum, and brainstem are low in patients with
multiple system atrophy,
• whereas volume reduction of brain, striatum, midbrain, and cortical regions of
frontal lobe is usually found in patients with PSP.
• In corticobasal degeneration, frontal lobe atrophy predominates

MR spectroscopy
• MR spectroscopy helps to determine the levels of
various metabolites in the brain parenchyma.
• Spectroscopy done in the affected region shows a
decreased N-acetylaspartate to creatine (NAA/Cr) ratio.
• Evaluation of the pons, midbrain and putamen can be
done for differentiating the various subtypes.

• In particular, the reduction of NAA levels in cortical-basal ganglia
networks reflects neuronal loss and mitochondrial metabolic
dysfunction in PD.
• On the same time, changes of Glu and GABA concentrations
detected in vivo in basal ganglia of PD patients could be suggestive
of dysfunction of neuronal excitatory and inhibitory activities
which are involved in the control of movements.

Ultrasound
• B-mode transcranial sonography of the substantia
nigra can show increased size of the region of
echogenicity.
• This is thought to be a sensitive sign,
• exact sensitivity depends on the exact cut-off value of
substantia nigra area used
• and on the type of ultrasound machine employed .

FUNCTIONAL IMAGING- SPECT AND PET
the dopaminergic pathway is the key neurotransmitter system implicated in PD and APS
• radiotracers that bind to various targets on the presynaptic and postsynaptic
dopaminergic nerve terminal assess the integrity of this pathway.
• Presynaptic
• three major targets on the presynaptic dopaminergic nerve terminal:
• A) aromatic acid decarboxylase (AADC)
• B) Dopamine transporter (DAT)
• C) Vesicular monoamine transmitter (VMAT)

Dopaminergic imaging targets and SPECT and PET
radioligands targeting these sites

• The imaging pattern of striatal involvement for all tracers is similar in PD
• asymmetric striatal decrease, which is more marked contralateral to the
clinically affected side
• rostro-caudal gradient of uptake in which the posterior putamen is maximally
affected
• because neuronal loss in early PD takes place in the ventrolateral part of the
substantia nigra which projects to the posterior putamen.
• The uptake of the dopaminergic tracers declines with disease progression.
The metabolic anatomy of Parkinsons disease: Complementary F-18 fluorodeoxyglucose and F-18
fluorodopa positron emission tomography studies. Mov Disord 1990;5:203-13.

Top row-Tc-99m TRODAT SPECT images of a (a) normal control, (b) early PD-showing decreased tracer binding
in the left putamen, and (c) advanced PD showing decreased binding in both putamina. Bottom row-FDOPA PET
images of a (d) normal control, (e) early PD-showing decreased tracer uptake in the left putamen, and (f)
advanced PD showing decreased tracer uptake in both putamina

• dopaminergic imaging can help to distinguish PD from PD-mimics (like essential
tremor, vascular parkinsonism, drug-induced parkinsonism and psychogenic
parkinsonism. )
• its utility in differentiating PD from the atypical parkinsonian syndromes is limited.
• DAT imaging can distinguish DLB from AD with 78-80% sensitivity and 90-92%
specificity.
• Overall, PET imaging has a superior sensitivity and spatial resolution to the SPECT
imaging; however, this is achieved at a higher cost.
• it has been shown that VMAT2, DAT and FDOPA binding declines in approximately 17
years, 13 years and 6 years, respectively, before the onset of the disease.[
• useful for following the status of transplanted embryonic dopaminergic tissue for an in
vivo assessment of the graft viability.
Thobois S, Jahanshahi M, Pinto S, Frackowiak R, Limousin-Dowsey P. PET and SPECT functional imaging studies in
Parkinsonian syndromes. From the lesion to consequences. Neuroimage 2004;23:1-6.

Tc-99 m TRODAT SPECT images of a 54- year old diagnosed case of PD who underwent cell replacement
therapy, upper row-plain SPECT and bottom row-fused SPECT/CT images at three time points (a) before
intervention showing presynaptic dopaminergic dysfunction (B/L), (b) one month and (c) three months
after therapy showing definite improvement of tracer binding in both basal ganglia

Post synaptic
• D2 receptor imaging has been used to differentiate PD from the atypical parkinsonian
syndromes with a good diagnostic accuracy of about 90%
• But cannot classify different APS
• D2 binding is normal in patients with PD and is decreased in those having the
Parkinson plus syndromes.

Perfusion and metabolism
imaging
• 'Resting-state' measures of regional glucose utilization in the brain.
• can be evaluated using F-18 Fluorodeoxyglucose (FDG) PET.
• PD and the APS have characteristic metabolic patterns that have been
validated as ‘metabolic signatures’ of the disease process
• differentiating idiopathic PD from APS, and also for differentiating amongst
the subtypes of APS
• The sensitivity and specificity for a classification based on F-18 FDG-PET for
detecting PD, MSA and PSP is 75% and 100%, 100% and 87% and 86% and
94%, respectively.
Utility of intrastriatal ratios of FDOPA to differentiate idiopathic Parkinsonian disorders. Nuclear medicine Communications 2013;34:426-
31.

Pattern of dopaminergic binding and metabolic
patterns in PD and APS

(a) Tc-99m TRODAT SPECT images of a case of early PD showing presynaptic
dopamnergic dysfunction, (b) plain F-18 FDG PET images of the same patient
showing the right putaminal hypermetabolism

Top row (a) Tc-99m TRODAT SPECT images of a case of MSA-P showing bilateral presynaptic dopamnergic dysfunction,
(b) F-18 FDG PET/CT showing bilateral putaminal hypometabolism. Bottom row: F-18 FDG fused PET/CT images of a case
of MSA (mixed) showing (c) bilateral putaminal hypometbolism and (d) cerebellar hypometabolism

(a) Tc-99m TRODAT SPECT/CT images of a case of PSP showing presynaptic dopaminergic dysfunction, (b)
F-18 FDG fused PET/CT images showing bilateral basal ganglia, and (c) midbrain hypometabolism. Bottom
row: F-18 FDG PET images of a case of CBS showing hypometabolism in the right basal ganglia and right
fronto-parietal cortex. Clinical symptoms were more marked on the left side

Cardiac sympathetic denervation
• is an associated autonomic co-morbidity in PD
• alpha-synuclein deposition in the autonomic cardiac plexus and distal axons.
• (MIBG) is a guanethidine analogue and is taken up by the post-ganglionic sympathetic
neurons by the uptake -1 mechanism.
• There is reduction of the myocardial uptake of I-123 MIBG in early PD
• Relative preservation of myocardial I-123 MIBG uptake is seen in APS, which is
associated with central and preganglionic sympathetic dysfunction
• A combination of DAT SPECT and MIBG scintigraphy has been suggested to improve
the specificity of diagnosis of PD
• MIBG scintigraphy documenting cardiac sympathetic denervation has been included in
the supportive criteria of the MDS-PD clinical diagnostic criteria for PD
I-123 IBZM binding compared with long-term clinical follow up in patients with de novo Parkinsonism. Mov Disord 1998;13:16-19.

Parkinson's disease dementia (PDD)
• PD dementia shares a number of characteristics with dementia with Lewy bodies (DLB)
• Over 80% of patients with PD develop dementia over 20 years into the disease
process.
• patients who develop parkinsonism a year or more before the onset of dementia are
likely to be having PDD;
• and, those who develop dementia and parkinsonism concurrently are more likely to be
belonging to the DLB category.
• F-18 FDG PET can be used to distinguish between PDD or DLB and Alzheimer's disease
related dementia (AD)..
Automated differential diagnosis of Early Parkinsonism using metabolic brain networks: A validation Study. J Nucl
Med 2016;57:60-6

• DLB is characterized by metabolic reductions in the primary visual and medial occipital
cortex with preserved uptake in the posterior cingulate cortex (the 'cingulate island
sign’).
• In AD, the visual cortices show a relatively preserved uptake with a decrease in the
uptake in the posterior cingulate cortex.
• Hypometabolism in the visual cortices has been included in the list of supportive
features for the diagnosis of probable-DLB.

Imaging pathological in-vivo targets
• Alpha-synuclein is the pathological hallmark of PD
• efforts are directed to find ligands which could be used to label alpha-synuclein in-vivo.

• Amyloid-β (Aβ), which is the pathological hallmark of AD, can contribute to cognitive
impairment in PD.
• While cortical Aβ is infrequent in PDD, patients with DLB show increased cortical
retention of Aβ

Take home message
• Clinical diagnosis
• Functional and structural neuroimaging provide useful tools for the evaluation of
parkinsonian syndromes.
• Dopaminergic imaging is useful for the diagnosis of neurodegenerative parkinsonism in
its early stages.
• metabolic and perfusion imaging and structural MRI can be used for the classification
of parkinsonian syndromes.
• dopaminergic and metabolism imaging is useful for the differential diagnosis of
dementia with Lewy bodies (DLB) from Alzheimer disease (AD).
• Molecular tools for imaging pathology, like in vivo amyloid and tau, have also provided
useful insights especially in the evaluation of cognitive impairment associated.

References
• Neuroimaging in Parkinsonian Disorders Madhavi Tripathi1, Atin Kumar2, Chandrasekhar Bal1DOI: 10.4103/0028-3886.226460
• Niethammer M, Feigin A, Eidelberg D. Functional neuroimaging in Parkinson's disease. Cold Spring Harb Perspect Med. 2012
May;2(5):a009274. doi: 10.1101/cshperspect.a009274.
• Saeed, U., Compagnone, J., Aviv, R.I. et al. Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging
concepts. Transl Neurodegener 6, 8 (2017). https://doi.org/10.1186/s40035-017-0076-6
• Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis Antonina Kouli, Kelli M. Torsney, and Wei-Li Kuan.
• Hughes AJ, Daniel SE, Shlomo YB, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service.
Brain 2002;125:861-70
•
Savoiardo M. Differential diagnosis of Parkinson's disease and atypical parkinsonian disorders by magnetic resonance imaging. Neurol Sci
2003;24(Suppl 1):S35-7.
• Research Unit of Radiology, National and Kapodistrian University of Athens, GR
• Diffusion Tensor Imaging in Parkinson's Disease and Parkinsonian Syndrome: A Systematic Review
• Automated differential diagnosis of Early Parkinsonism using metabolic brain networks: A validation Study. J Nucl Med 2016;57:60-6

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