Imaging for Movement DisordersMDS-ES Summer School 2021

Irena Rektorová, MD, PhD, FEANFirst Department of Neurology, Faculty of Medicine, St. Anne’s University Hospital

CEITEC, Masaryk University

Brno, Czech Republic

Overview of my talk

• Neuroimaging markers for early diagnosis ofParkinson’s disease

• Neuroimaging for differential diagnosis ofparkinsonism (PD vs. MSA, PSP, CBS)

• Neuroimaging for hyperkinetic MD

Termograms

MIBG cardial scintigraphy

Colonic transit times

11C-donepezil PET/CT

Functional Imaging: prodromal/ indicative biomarkers

• DAT SCAN (FP-CIT SPECT), dopaminergic PET

• Prodromal marker for PD = clearly abnormal (<65% normal, 2 SDs below mean), LR+ = 43

• Indicative biomarker for DLB

• Biomarker for prodromal MCI-LB?

• 75 MCI-LB subjects, 54% had positive results!sensitivity only 54%, specificity 89%, (Thomas, 2018)

• Postmortem studies - up to 50% of cases with synuclein pathology do not have substantial mid-brain involvement (Zaccai, 2008)

Berg et al., 2015, Heinzel et al., 2019

DAT scan and mood (non-motor symptoms)

MADRS: dependent variable

Rektorova et al., Mov Disord 2009

Vriend et al., JNNP 2013

• 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan

• The cohort was followed for 5.5 (0.8) years

• Subjects in the bottom quartile for striatal binding,compared to the top quartile, had an odds ratio of 3.3 for cognitive impairment and 12.9 for psychosis

Cortical dopaminergic deficits: PD-MCI

• [11C]FLB 457 PET: cortical D2 receptor ligand

Christopher et al., 2015

FDG PET: PD-related pattern• Spatial covariance analysis of 18F-FDG PET

data has consistently revealed a characteristic PD-related pattern (PDRP)

• Characterized by hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex. These changes co-vary with hypometabolism in posterior parietal, occipital, and frontal cortices

Ma et al., 2007; Huang et al., 2007;Meles et al., 2020

Evaluation of GM atrophy in early PD

• Voxel-based morphometry (VBM)

• Source-based morphometry (SBM)

• Deformation-based morphometry (DBM)

• Cortical thickness, …..

Uribe et al., 2016

Kunst,…..Rektorová, 2019

More changes in sMRI in PD-MCI

Rektorova et al., 2014Kunst,……Rektorova, 2019

in PD-dementia

Reviewed in: Krajcovicova, Klobusiakova and Rektorova, Current Neurology and Neuroscience Reports 2019

Clinical-anatomical signature of PD identified with PLS and MRI (DBM)

Zeighami et al., 2019

T1w/T2w ratio• PD patients (≤ 2 years of the disease duration)

have a significantly higher T1w/T2w ratio in the midbrain (SN) - AUC=0.901, sensitivity=0.857, specificity=0.857

• PD-related changes in neurons, dendrites, microglia, and iron content

Du et la., Ann Neurol 2019

Neuromelanin-sensitive MRI

Sasaki 2008; Wang 2018; Rizzo, 2019; Pavese and Tai 2018; Gaurav 2020

T1-weighted fast spin echo sequence; by-product of dopamine and noradrenaline oxidative

metabolism responsible for the pigmentation of the SN and the locus coeruleus

Clinico-pathological correlation exists (Kitao et al., 2013)

The width, contrast-to-noise ratio of the substantia nigra pars compacta (SNc) and the

CNR of the locus coeruleus (LC), volume loss in neuromelanin containing structures

in early PD (H-Y stage I, II), changes with the disease progression

Susceptibility weighted (SWI)nigrosome imaging

• Evaluates nigrosome-1, qualitative measure!!

• Hyperintense ovoid region within the dorsolateral border of the SNc in HC: “swallow-tail-sign”

• Present already in 2/3 of iRBD De Marzi et al, 2016, Bae

et al., 2017

Reiter et al., 2015

Schwarz et al., 2014; Mahlknecht et al., 2017

Transcranial sonography

• Enlarged (> 0.20 cm2) nigral echo

• Quality of the temporal bone window

not in 10% of the Caucasian

• Experience of the investigator

• Sensitivity 85%, specificity 89% (Tao et al., 2015)

• For screening purposes, not for diseaseprogression monitoring (PRIPS: Berg et al., 2011)

• May distinguish PD from parkinson plus syndromes

T2 FSE/ T2*GE and increased transverse relaxation rates R2 and R2* (relaxometry)

A: MR signal measured in

multiple images with increasing

echo times

B: Signal shows exponential decay

as a function of echo time

In PD: iron deposition →

magnetic field inhomogeneities →

faster T2 signal ↓

Lehéricy et al., 2012Affected by myelin loss and changes in water concentration

Quantitative susceptibility mapping

• Solves a complex field-to-source inverse problem: from the knowledge of magnetic field to the information about the susceptibility sources distribution

• 3D Multiecho GRE sequence, calculation of magnetic susceptibility from phase GRE MR images

• Results in a map of local tissue susceptibility characteristics

PD vs. HC: accuracy of 68–89% (posterior part of SN)Review in: Ravanfar et al., 2021, Pyatigorskaya et al. 2020

Diffusion tenson imaging (DTI) in PD

Atkinson-Clement et al., 2017

Free water imaging

• bi-tensor diffusion model - increased free-water in the SN (likely represent increased extra-cellular space resulting from nigral degeneration); reflects neuro-inflammation-related edema

• In posterior SN

in early stages,

correlates with

putaminal

dopaminergic

defficiency

Ofori et al., 2015, Planetta et al., 2016, Burciu et al, 2017, Yang et al., 2019

DKI in SN and basal ganglia circuitry

Sejnoha-Minsterova et al., Park Rel Dis 2020

Functional connectivity and resting state networks (rs-fMRI)

Resting state fMRI limitations

• Impact of genetic factors, cognitive reserve, …. (Krajcovicova et al, 2012, Ng et al, 2017)

• Both rs-functional connectivity (rs-FC) increases anddecreases may co-occur in a cross-sectional study

• The rs-FC may↓ due to brain pathology; it may↑ in an attempt to compensate for the pathological load and brain (dis)function (Klobusiakova et al., 2019)

• The results are on the whole difficult to generalize and to use rs-FMRI as a biomarker in individual subjects

Rektorova, Parkinsonism Rel Dis 2019Rektorova, Parkinsonism Rel Dis 2019

Rs fMRI of the basal ganglia (BGG) in PD

Bell et al., 2014

Sensitivity100%, specificity 89.5%,

accuracy 85%

Szewczyk- Krolikowski, 2014

Functional connectivity of the nucleus basalis of Meynert in DLB

Schumacher et al., 2021

2021

Hemiparkinsonian syndrome caused by contralateral vascular lesions

Video and MRI scan provided by Ivan Rektor

MSA

Brooks, 2012

Also atrophy of putamen, CRBL,

MCP

↑ putaminal difusivity

↑ free water in SN, basal ganglia,

thalamus, CRBL

Prange et al., 2019, Meissner et al. 2019

MRI markers of PSP

Both signs are highly specific (≥ 97.7%) in patients with early clinical diagnosis of PSP versus PD Or MSA, but insufficiently sensitive (35.3%)

Hummingbird sign

MRPI (MR parkinsonism index)

• Formula: [(P/M) x (MCP/SCP)]

• Also ↑ 3rd ventricle, ↑ free waterQuattrone et al., 2018

Nigro et al., 2016

Scherfler et al., 2016

[18F]AV-1451: tau PET

Whitwell et al, 2017

Neuropathological correlation supports automated logistic differential diagnosis

Schindlbeck et al., 2021

Cortico-basal syndrome

Normal Pressure Hydrocephalus

MRI hallmarks

Coronal CT and MRI at the level of posterior commisure:

An angle ˂ 90° typical for iNPH (left CT)(Kiefer and Unterberg, 2012)

Evans ratio: the maximal ventricular width divided by the largest biparietal distance between

the inner tables of the skull. Ventriculomegaly is defined as an Evans ratio ≥ 0.30

(Shprecher et al., 2009)

MRI hallmarks:

Dysproportionally enlarged subarachnoid space hydrocephalus (DESH):

tight high convexity and medial subarachnoid spaces, enlarged Sylvian fissure

with ventroculomegaly

(Mori et al., 2012)

F and P convexity tightness,

upward bowing of the

corpus callosum (Lee et al., 2010)

Wilson’s disease AR, ATP7B gene mutation on chr 13, copper-transporting transmembrane protein ATP-ase 7B

K-F ring, Dušek et al., 2015

MRI

WD treatment

Liver transplantation Dušek et al., 2015

Video 3

Aceruloplasminemia

• Rare autosomal recessive disorder

• Mutation in the ceruloplasmin genelinked to the accumulation of iron mainly in the liver, brain, retina and pancreas

• Clinically retinal degeneration, diabetes mellitus, microcytic anaemia and neurological symptomatology

• Increased values of serum ferritin in the absence of Kayser-Fleischer ring, normal values of excretion of copper in urine

• Chelatase treatment with deferasirox, deferoxamine, deferiprone, zinc, frozenplasma

Aceruloplasminemia

NBIA: dystonia, parkinsonism, spasticity, psychiatric, cognit.

• PKAN, MPAN, BPAN, PLAN, neuroferritinopathy, aceruloplasminemia

• Iron deposits: hypointensities in GP on T2-weighted magnetic resonance images (MRIs)

•

PKAN: Pantothenate Kinase-Associated Neurodegeneration(PKAN2 gene)

“Eye of the tiger”typical/ atypical

dystonia, rigidity, bradykinesia, posturalinstability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, andcognitive and visual impairment

1–2 per million peopleglobally Thakur et al., 2021

Krause et al., Mov Disord 2006

deferiprone (an iron chelation)fosmetpantotenate (precursor replacement therapy)

Klopstock et al., 2019,Thakur et al., 2021

NBIA mimmics

Zorzi et al., 2021: DYT6, mutation in gene encoding the thanatos-associated protein (THAP1)Zech et al., 2019: KMT2B-related dystonia (DYT28; Encoding the Lysine-Specific Histone Methyltransferase 2B)

Jech, Bareš, et al., 2011

Primary familiar brain calcification

Wider et al., 2009

Dušek et al., 2015

Secondary to:

Hypoparathyroidism

Pseudohypoparathyroisidm

Cysticercosis

Toxoplasmosis

AIDS

Bisphosphonate treatment (etidronate sodium)??

Manganese transporter deficiency

• AR, SLC30A10 gene mutation, syndrome ofhepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia,↓ ferritin

• treated by iron supplementation combinedwith disodium calcium edetate (chelation)

Stamelou et al., 2012

Early onsetgeneralized dystonia, bradykinesia

(methcatinone)

Chorea on MRI: Huntington’s disease

TD: 60 years old woman

Severe depression

since age of 45

alcohol and drug abuse

sulpiride, promethazine

chlorprothixen, tiapride

Hemichorea in non-ketogenic hyperglycemia

Zhou et al. 2012

Danve et al., 2015

Zheng et al., 2020

FXTAS (fragile mental retardation gene)

Hagerman et al, 2013

Cabal-Herrera et al., 2019

WM changes on T2 or FLAIR

Brain atrophy

Other gene premutation disorders in FH:

FXPOI or FXAND

FMR1 gene alteration, CGG triplet expansion

• Start at 50-60s, more severe in males• Tremor, ataxia• Parkinsonism• Postural instability, autonomic dysfuntions• Gaze abnormalities• Polyneuropathy• Psychiatric problems• Executive deficits - dementia

Take home messagesEarly/ prodromal PD diagnosis:

• DaT SCAN, FDG PET for PDRP expression

• SWI: missing “swallow tail” sign, neuromelanin/ iron sensitive MRI

• Free water imaging, diffusion kurtosis imaging

Differential diagnosis of parkinsonism:

• Specific MRI markers, MRPI,..

• Free water in basal ganglia, CRBL, thalamus

• FDG PET patterns expression

Take home messages 2

• T1w changes on MRI: Manganese transport deficiency, FXTAS

• T2w changes on MRI: NBIA and mimmics

• Treatable: NPH, WD, manganese transporter deficiency, aceruloplasminemia, PKAN?, hemichorea in non-ketogenic hyperglycemia

• Think of DBS of Gpi in genetic dystonia(PKAN, DYT 28, DYT 6,..)

Thank you for your attention