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Home , Reboxetine, Synucleinopathy, Tauopathy

Movement Disorders: a practical update

Nicola Pavese, MD, PhD, FRCP Professor of Clinical Neuroscience and Consultant Neurologist Movement Disorders Classification

Movement Disorders

Too Much Movement Insufficient (Hyperkinesias or Movement )

Jerky Movements: Non-jerky Movements: Akinetic, hypokinetic • or bradykinetic • (incl. syndromes • (incl. ballism) ) • tic disorders • Parkinsonian Syndrome

• Parkinson’s disease / with Lewy bodies • Other degenerative parkinsonian syndromes – (MSA) – Progressive Supranuclear Palsy (PSP) – Corticobasal Degeneration

• Multiple cerebral infarction – “vascular ” • Drug-induced parkinsonism Improvement of Clinical Developments Improvement of Clinical Developments Improvement of Neuroimaging Developments

• Functional

– SPECT

– PET

• Structural

– Transcranial doppler sonography (TCS)

– MRI Nigrostriatal pathway

Loss of DA terminals Imaging terminal function

18F-dopa 11C-RTI 32 11C-DTBZ 123I- DDC DAT VMAT2 DAT

PD

Pavese & Brooks, 2009 Diagnostic value

Reduced presynaptic Preserved presynaptic Dopamine function Dopamine function

Parkinson’s disease Multiple System Atrophy Dystonia Progressive Supranuclear Palsy Drug-induced Dementia with Lewy Bodies Vascular Corticobasal Degeneration Diagnostic value PD versus Equally severe reductions of uptake in the caudate and the anterior and posterior putamen at early stages of disease in MSA and PSP 18F-Dopa

In general, considerable overlap

Parkinson’s disease Multiple System Atrophy When Do I Order a DaTSCAN?

• DaTSCAN is no substitute for clinical acumen

• To establish a degenerative parkinsonian syndrome vs.: – tremor (e.g. dystonic, essential) – drug-induced parkinsonism – Functional

• To differentiate DLB from AD

• Not to differentiate typical from atypical parkinsonism Caudate involvement in early PD

We analysed DaTSCANs of 149 PD patients with less of 2 years of disease (PPMI study) Degree of Caudate involvement at baseline SBR < 2 Standard Deviations from the mean of the controls

There was no statistical difference between group’s demographics and clinical markers of disease severity or cognitive scores at baseline Pasquini et al., submitted Median MoCA Score at 4 years

*p=0.026

significantly lower in the bilaterally affected caudate group compared to others Pasquini et al., submitted Median GDS Score at 4 years

*p=0.011

Significantly higher in the bilaterally affected caudate group compared to others Pasquini et al., submitted Median Gait index Score at 4 years

*p=0.044

Significantly higher in the bilaterally affected caudate group compared to normal caudatePasquini et al., submitted Diagnostic value PD versus parkinsonisms

In idiopathic PD, lentiform nucleus glucose metabolism is preserved or raised, whereas it is reduced in most atypical cases 18F-FDG PET Diagnostic value PD versus MSA - 18F-FDG PET

Disease-related metabolic patterns

PD-RP MSA-RP

Poston et al., 2012 PET targeting brain pathology

• versus

• Several Tau tracers are already available while PET tracers for alpha-synuclein are still under development Movement Disorders The role of Neuroimaging

• Functional

– PET

– SPECT

• Structural

– Transcranial doppler sonography (TCS)

– MRI Transcranial ultrasound Echogenicity of the substantia nigra

hypoechoic butterfly-shaped Transtemporal, through the intact skull using mesencephalon “acoustic bone windows” surrounded by the mesencephalic cisterns. midbrain level Transcranial ultrasound Echogenicity of the substantia nigra

Control • 92% of cases with clinically probable PD show midbrain hyperechogenicity – but also 10% of normals and 15% of ET

Parkinson’s disease • No correlation between disability and midbrain echogenicity in PD

* • 10% have no temporal window

• No change in echogenicity with PD progression Berg et al., 2001 Structural MRI in PD

USUALLY NORMAL in early PD  Exclusion of symptomatic parkinsonism

axial early PD Structural MRI in PD

USUALLY NORMAL in early PD  Exclusion of symptomatic parkinsonism

brainstem lesions (glioma) axial PS due to toxins early PD (methcathinon, manganese)

Vascular PS basal ganglia lesions (inflammatory/ infectious) Structural MRI in PD

USUALLY NORMAL in early PD  “red flags” (features typical for atypical parkinsonian disorders)

• Putaminal atrophy • Putaminal slit sign • Putaminal hypointensity

axial early PD MSA-P Structural MRI in PD

USUALLY NORMAL in early PD  “red flags” (features typical for atypical parkinsonian disorders) MSA PSP

hot cross bun

Mickey mouse sign

Hot cross bun sign Structural MRI in PD

USUALLY NORMAL in early PD  “red flags” (features typical for atypical parkinsonian disorders) midsagittal

early PD MSA-P PSP • atrophy of the pons • atrophy of the midbrain • atrophy of the cerebellum • with dilatation IV ventricle Structural MRI in PD

USUALLY NORMAL in early PD  “red flags” (features typical for atypical parkinsonian disorders) midsagittal „small head“ and „big body“

early PD MSA-P PSP • king-penguin sign

‘penguin’ or ‘hummingbird’ sign with the shapes of midbrain tegmentum (bird’s head, above the white line) and pons (bird’s body, below the white line) looking like the lateral view of a standing penguin/hummingbird Neuromelanin sensitive MRI

Matsuura et al. 2013 Neuromelanin sensitive MRI

Kashihara et al., 2011 Increased iron on MRI images (SWI)

PD

Diagnostic accuracy greater than 90% for Parkinson disease Schwarz et al., 2014 2018; 5(2): 131–140. Progression of Parkinson’s disease Progression of Parkinson’s disease Currently Available Advanced Therapies

Antonini 2018 Deep Brain Stimulation Absolute criteria for considering referral for DBS

• Parkinson’s disease for at least 4 yrs • Presence of bothersome disease- related symptoms and/or side effects • Motor improvement with dopaminergic medications • Absence of medical conditions precluding surgery • Absence of ongoing severe, medically resistant neuropsychiatric diseases DBS in early PD Other indications for DBS

 Classical Indications  Parkinson’s Disease  Dystonia  Essential tremor New indications for DBS

 Depression– nucleus accumbens  Obsessive –compulsive Disorder – multiple targets  – anterior thalamic nucleus  Alzheimer’s disease - fornix/hypothalamus  Anorexia - subcallosal cingulate Parkinson’s disease Research in Newcastle

On going Clinical Trials On going Clinical Trials CD/LD Accordion Pill

• CD/LD being folded in an accordion-like shape into a standard regular oral capsule

• The accordion unfolds and is retained in the stomach for 8-12 hours

• Steady flow of drug towards absorption site CD/LD Accordion Pill NEURODERM ND0612H

• A combination of CD/LD in liquid solution delivered by belt pump

• No surgical procedure required

• Constant drug exposure 24 hours NEURODERM ND0612H

ND0612H has demonstrated bioequivalence to intraduodenal infusion of levodopa/carbidopa (Duodopa) Cynapsus/ Sunovion-APL- 130277

• Oral transmucosal formulation of apomorphine

• Ability to circumvent first-pass hepatic metabolism in the gut

• Rapid onset of action Cynapsus/ Sunovion-APL- 130277 Cynapsus/ Sunovion-APL- 130277 Other Clinical Trials for patients with motor fluctuations/ Dyskinesias

• PXT002331 (foliglurax), metabotropic glutamate receptor 4 positive allosteric modulator

• Effect of on Dyskinesias Disease-modifying drugs

Increased iron on MRI images

Is this build-up of iron causing harm to the brain cells?

Can we improve the motor symptoms of the disease or slow its progression if we remove it? SKY Study Study of Parkinson’s Early Stage

Deferiprone is an iron chelator indicated for the treatment of iron overload in patients with thalassemia

A Dose-Ranging Study of the Efficacy, Safety, and of Deferiprone Delayed Release Tablets in Patients with PD BIIB054 and α-synuclein

BIIB054 is a novel, human- derived mAb that targets primarily aggregated forms of α-synuclein

Phase 2, randomized, double- blind, placebo-controlled, parallel-group study to examine safety, pharmacodynamics, and PK of BIIB054, administered every 4 weeks via IV infusion for 2 years Non-motor symptoms

Dementia

Sleep disorders

Dementia

Hyposmia Depression in PD

Higher prevalence in PD than in Aged-matched population

Prevalence of Depression in 90 consecutive patients with PD

PD patients Age/sex matched controls (90) Major 21.1% 3.3% p<0.01 Depression

Dysthymia 18.8% 4.4% p<0.05

Panic 30% 5.5% p<0.01 Disorder

Nuti et al, 2004 Challenges in the diagnosis of depression and in PD

Different phenomenology

Overlap of PD symptoms and somatic features of mood disorders

Motor and non-motor fluctuations

Coexisting cognitive dysfunction

Side effects of anti-parkinsonian medications Treatment of Depression in PD

Dopaminergic medications

• Piribedil • Pramipexole • Extended Release • Rotigotine

Improved depression scores in PD patients in both open- labelled studies and double blind trials Treatment of Depression in PD Psycotropic parmacotherapy

• (, ) • Selective • Serotonin and noradrenaline reuptake inhibitor () • Selective noradrenaline reuptake inhibitor (Reboxetine) • Presynaptic alpha-2-adernoreceptor antagonists ()

• There is insufficient evidence to support antidepressant efficacy for SSRIs, Pramipexole, Pergolide and SNRIs

• TCAs might be the best choice when starting antidepressant treatment in PD patients, followed by Pramipexole and SNRIs, SSRIs might be the last choice Treatment options in Dementia

• inhibitors – type I evidence to support treatment with rivastigmine & donepezil in DLB & PDD

• – type I evidence for global improvements in LBDs – pattern of cognitive & neuropsychiatric responsiveness uncertain

O’Brien 2017 Bavisant in Excessive Daytime Sleepiness in PD

Preclinically, H3 cause sedation whilst H3 antagonists/inverse agonists increase wakefulness

Bavisant is a potent H3

Dose finding phase IIb study of Bavisant to evaluate its safety and efficacy in treatment of EDS in PD Non-Pharmacological Approaches Non-Pharmacological Approaches

. Greater DA release after stationary cycling in the caudate nuclei of habitual exercisers compared to sedentary subjects

. Habitual exercisers revealed • greater activation of ventral striatum during an fMRI reward task • lower apathy • lower bradykinesia score Conclusions

• Significant improvements and progresses in clinical diagnostic criteria and neuroimaging biomarkers

• Several trials are currently ongoing to improve complications and slow down/halt progression of PD and other parkinsonisms

• Encourage patients to undertake regular physical activity Thank you

Repositioning Approaches : Pimavanserin selective serotonin 5-HT2A inverse

Cummings 2014