The Parkinson Spectrum, What’s New in Research and Treatment

The Parkinson  Spectrum, What’s  New in Research  andTreatment Nikolaus McFarland, MD, PhD Associate Professor of Neurology Wright/Falls/Simmons Professor of PSP/Atypical  Parkinson’s and Director, UF HDSA Center of  Excellence

Fixel Institute • Continued growth, leading international center! • Volume significantly up (14,000 encouters last year alone) • Added 7 faculty in last 3 years

(L-R) Drs. Matthew LaVoie, Ph.D., Malú G. Tansey, Ph.D., Stefan Prokop, M.D., and Matthew Farrer, PhD (Farrer photo courtesy of UBC Faculty of Medicine)

• Centers of Excellence (PD, LBD, PSP, HD, Tourettes…) • Multidiscplinary model – staffing • SW support • Palliative care

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UF Neuromedicine Hospital

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Parkinsonism What, where, how?

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2030 (total 8.7 million)

Burden of PD

Brazil 4%

Russia 4%

Other 6%

2005 (total 4.1 million)

Other 7%

Brazil 4%

India 8%

Russia 5%

U.S.A. 7%

India 8%

China 48%

China 57%

U.S.A. 8%

Europe 14%

Europe 20%

Based on PD prevalance (per 100,000 over 50 years‐old) in 15 countries

Dorsey et al, Neurology. 86:384‐6.

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Parkinson syndromes • Parkinsonism  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .   • PD most common, >1M in US alone • Atypical parkinsonism or “Parkinson‐plus” syndromes • Clinico‐pathological diagnosis • Protein inclusions • αSynuclein, tau, TDP43, amyloid, ubiquitin,…

Tremor (resting) Rigidity A/bradykinesia Postural instability Flexed posture Freezing…

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PD Pathology • Hallmark, progressive loss of dopamine  cells in brain stem (substantia nigra) • Lewy bodies and neurites • Multiple system atrophy

• Lewy body dementia • Familial Parkinsonism

http://www.urmc.rochester.edu/neuroslides/slide199.html

Lewy bodies

Lewy neurites

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Other PD risk factors Genetic

Environmental

Toxins,  pesticides, herbicides  (MPTP, paraquat, rotenone) Heavy metals 

AGE Gender  (M>F)

Genes Familial

(Fe, Mn, Pd, Cu) Smoking  (‐) Caffeine intake (‐) Uric acid  (‐) Drugs (anti‐inflammatories,  antihypertensives,  statins, vitamins?)

PD

SNCA Parkin PINK, DJ1 LRRK2 Susceptibility GBA H1/H2

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Locus (Chr)

Gene

Protein/Function

Pathology

Dominant PARK1/4 (4q21) PARK5 (4p14) PARK11 (2q37.1) PARK17 (16q13) PARK18 (3q27.1) PARK8 (12p11.2–13.1)

SNCA

α‐Synuclein, synaptic function? Ubiquitin C‐terminal hydrolase

30‐60s, diffuse LBs

UCH‐L1 LRRK2 GIGYF2  VPS35  EIF4G1

30‐50s

kinase

40‐60s, diffuse LBs

Grb10‐interacting GYF protein‐2

retromer

40‐60s, tremor

HLA‐DR misregulation

Adult onset

FTDP‐17

MAPT

Microtubule binding protein tau Transmembrane secretory/endo‐lys

Adult onset, tau tangles

TMEM230

TMEM230

Recessive PARK2 (6q25.2–27) PARK6 (1p35‐36)

PDGenes

Parkin PINK1

E3 ubiquitin ligase

Young‐onset Parkinsonism, LBs

Mitochondrial protein kinase Chaperone, oxidative stress

30‐50s 20‐40s

PARK7 (1p36) PARK9 (1p36)

DJ‐1

ATP13A2 PLA2G6

P‐type ATPase

Kufor‐Rakeb disease

PARK14 (22p13.1) PARK15 (22q12‐13) PARK19 (1p31.3) PARK20 (21q22.11)

PLA2G6

Dystonia‐Parkinson, young‐onset

FBXO7

F‐box only 7 protein

Pyramidal signs Juvenile‐onset PD

DNAJC6

Auxillin‐1 ( GAK , Auxililin‐2)

SYNJ1

Synaptojanin‐1, PIP, synaptic vesicle 

Early‐onset parkinsonism

Other/Risk Gaucher’s

GBA

Glucocerebrosidase

LBs

PARK13 (2p12) PARK16 (1q32)

HTRA2  RAB29 RAB39B

Serine protease

Rab7L1, autophagy‐lysosome pathway

Xq28

Rab39b, early endosome

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PDGenes

Glucocerebrosidase

αSynuclein

LRRK2

Tau

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ProgressiveSupranuclearPalsy

PallidopyramidalComplex

PSP

CorticobasalDegeneration

CBD PD ParkinsonDisease

DLB Lewy body dementia Hemachromatosis HereditaryCeruloplasminemia

SpinocerebellarAtaxias

MSA

MultipleSystemAtrophy Parkinsonism‐dementia‐ALS ProgressivePallidalAtrophy

NBIAs

PDDementia

Gerstmann‐Strausler‐Scheinker

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Overlap in parkinsonisms

Synucleinopathy •Parkinson disease •Familial parkinsonisms •LBD and MSA

Parkinson  disease

Secondary  Parkinsonisms •Vascular •Infectious •Toxins •Drug‐induced •NPH

Hereditary  Parkinsonisms • PARKs •SCAs •FTD‐P

Tauopathy •PSP •CBD •FTD •AD

TDP43‐ opathy •ALS‐FTD •FTLD‐U/MND

•HD •etc

Atypical Parkinsonisms •Progressive supranuclear palsy, PSP •Corticobasal degeneration, CBD •Multiple SystemAtrophy, MSA •Dementia Lewy bodies, DLB

Amyloidopathy •AD

•LBD •CBD

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Is it other than PD?

• Early gait difficulty, freezing, frequent falls • Early prominent speech or swallow impairment • Symmetric presentation • Pyramidal tract signs • Poor response to levodopa (~75% resp) • Oculomotor problems (PSP, CBD) • Dysautonomia, laryngeal stridor, or ataxia (MSA) • Apraxia, myoclonus, or “alien‐hand” (CBD) • Dementia (DLB, PD w/dementia)

Red  Flags

“Plus”  Features

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Secondary causes

Vascular • Multi‐infarct • Binswanger’s

Toxic • Carbon monoxide • Manganese • MPTP, rotenone,  paraquat

Drug‐induced • Neuroleptics • Phenothiazines • Lithium, valproate • Tetrabenazine • CCBs

Trauma • Pugilistic • Chronic traumatic  encephalopathy  (CTE)?

Infectious • AIDS

Structural • Tumor • Hydrocephalus  (NPH) • Hematoma

Metabolic • Hepatocerebral  degeneration • Hypoxia • Hypocalcemia

• SSPE (measles) • Postencephalitic • Prion disease

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Atypical  parkinsonisms When it’s not PD…

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Progressive supranuclear palsy • Most common form atypical parkinsonism • Prevalence & incidence, about /100,000 • Onset in 60’s (ave 63‐66) • Hallmarks: early postural instability, falls,  supranuclear gaze palsy, bulbar symptoms

Average Onset Falls in Parkinsonism

PSP

16.8

Vascular

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MSA

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Other  symptoms

Stare, surprised look Slowed movement/activity Sloppy eating habits Nonspecific visual complaints Apathy, anxiety, irritability Pseudobulbar affect Dementia

LBD

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PD

108

0 24 48 72 96 120

Months

(Williams et al, 2006)

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4RTau pathology •Tufted astrocyte •Dentate, GP, medulla,  striatum, SN, STN,  pontine, oculomotor n. •Spares cortex

Hess, McFarland. Seminars Neurol 2017

Gliosis/degeneration •Marked midbrain atrophy  •Loss pigmented cells SN •Atrophy STN, SCP, MCP, dentate •Mild frontal atrophy

PSP  Pathology

From Dickson et al, Curr Op Neurol 2010

PD

PSP

MSA

Diagnostics •No tissue, CSF markers •Imaging biomarkers

Oba, H. et al. Neurology 2005;64:2050‐2055

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Corticobasal syndrome • Typical features of CBS • Asymmetry, clumsy limb, course tremor • Dystonia, myoclonus, or “alien limb” • Speech, language, apraxia • Later gait/imbalance  • CBD pathology • 4R hyperphosphorylated tau • Astrocytic plaques & corticobasal inclusions • Neuroimaging • CT/MRI – asymmetric frontoparietal atrophy • PET – asymmetric uptake

Globular  tau inclusion

Ballooned neurons

Scarmeas et. al. Sci. Aging Knowl. Environ. 2001

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Symptomatic Improvement • Levodopa trial (i.e., PSP‐P), may need higher dose • Dopamine agonists – minimal benefit (rotigotine?) • Dystonia/blepharospasm – botulinum toxin, muscle relaxants (avoid anticholinergics) • Myoclonus – benzodiazepines, levetiracetam Dementia • Cholinesterase inhibitors ‐ little evidence and may worsen symptoms • Memantine – no studies in PSP/CBS Emotional lability • Antidepressants • PBA: dextromethorphan/quinidine SupportiveTherapy • PT, OT, SLP, SW, palliative care evaluation • Avoid falls, aspiration

PSP/CBD  Treatment

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Multiple SystemAtrophy • Second most common atypical syndrome • Prevalence ~3/100,000; incidence 0.6/100,000  • Onset in 50’s (median 58 years) • Many faces,  same disease

Shy‐Drager Othostasis, ED, urinary dysfunction, parkinsonism

MSA‐Parkinsonism

Striatonigral degeneration (SND) rapidly progressive parkinsonism,  dysautonomia, poor levodopa response

Glial cytoplasmic inclusions (GCIs) Synucleinopathy Lewy body pathology

Olivopontocerebellar atrophy (OPCA) parkinsonism + cerebellar ataxia,  or clumsiness

MSA‐Cerebellar 

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Dopaminergic therapy • Levodopa trial (1000 mg/d) warranted • Frequently exacerbates orthostatic hypotension

Orthostatic hypotension • Fluids, salt, stockings, binder • Fludrocortisone, pyridostigmine, midodrine, droxidopa  Urinary/bowel dysfunction • Urological evaluation (urodynamics) • Neurogenic bladder therapies (may exacerbate OH) • Constipation – graded formula, stool softeners, laxatives… Sleep disturbance • Sleep apnea, stridor ‐ CPAP • RBD ‐ clonazepam Supportive care • PT, OT, SLP, SW, palliative

MSA  treatment

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Dementia with Lewy bodies  • Clinical criteria:  Fourth DLB consortium

• Additional features: • Gait instability, falls • Autonomic dysfunction • Syncope, transient loss of  consciousness • Delusions, paranoia, other  hallucinations

(McKeith et al. Neurology. 2017 Jul 4;89(1):88‐100) 1. Rapidly progressive cognitive decline  or early dementia 2. Fluctuating cognition, attention,  alertness

3. Recurrent visual hallucinations 4.Parkinsonism (coincident or  following dementia onset)

• Sensitivity to antipsychotics • REM sleep behavior disorder • Depression  (Almeida et al. MDCP 2017)

Combination dementia & psychosis portends a poor prognosis

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Parkinsonism • Levodopa useful, but can exacerbate hallucinations • Dopamine agonists, non‐DA agents generally avoided Cognitive decline • Cholinesterase inhibitors – modest benefit supported for rivastigmine, donepezil  (Emre et al, 2004; Dubois et al, 2012) • Memantine – modest benefit shown  (Leroi et al, 2009; Aarsland et al, 2009; Emre et al, 2010) Fluctuations, RBD  • Evaluate metabolic, infectious causes; supportive care • RBD: memantine, clonazepam Hallucinations, psychosis

DLB/PDD  therapy

• Atypical antipsychotics, clozapine proven benefit  (Klein et al, 2003) • Pimavanserin – 5‐HT2A inverse agonist  (Cummings et al. 2014)

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Parkinsonism

Side effects

vs.

Balancing Act

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Physical therapy • Mobility • Fall prevention

It takes aVillage!  Multidisciplinary care

Occupational therapy • Maintain independence • Activities of daily living

Supportive care

Speech Pathology • Speech impairment • Swallow: prevent choking, aspiration Nursing • Care coordination, dietary/nutrition, wound care • Medication support Social services

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Palliative care (not just hospice)

• Focus on comfort, quality of life • Treat pain/suffering • Emotional well‐being • Psychosocial, spiritual support (patient & caregiver) • End life on my terms (advanced care planning)

What is it?

• Giving up • Cessation of care • Stopping all medications • Losing your doctor

What it’s not?

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Neurodiagnostics andTreatment Frontiers

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Synuclein pathology

• Disrupted intracellular  trafficking • Synaptic endosome‐lysosome  dysfunction • Oxidative stress,  mitochondrial dysfunction

Synaptic  accumulation

• Macroautophagy • Lysosomal degradation • Proteasomal degradation

Degradation

Wild‐type αSyn fibils

• Oligomerization • Fibrilization • Association with vesicles,  membrane organelles

Wild‐type αSyn

Pathologic  accumulation

Misfolded, dimer

Protofibrils Aggregates

Extracellular release • Inflammation • Prion‐like spread • Microglial phagocytosis

Mutant αSyn

Exocytosis

Mutant αSyn fibils

Lewy bodies,  neurites

Modified fromAblevovich &Gitler, 2016

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Frontiers… • Fetal grafts?  • Stem cells • Gene therapy • AAV, ProSavin • What to target?  • What gene? Goal? • Modeling disease • Targeted therapy  (ie. dyskinesias) • Biomarkers • Spreading pathology

Braak, 2003

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Neurodiagnostics • PD diagnosis clinical • No reliable blood/CSF test  • Neuroimaging can be helpful • MRI usually normal • DaTscan™ (Ioflupane I123) • Goal, biomarkers,  presymptomatic diagnosis

Kupsch A R et al. J Neurol Neurosurg Psychiatry 2012;83:620‐628

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PDTreatment*

•Selegiline/rasagiline, amantadine, anticholinergics •Levodopa (LD) vs DA agonists

Early PD

Wearing‐ off

• Increase dose, decrease interval, combine LD/DA •Add COMT inhibitor, patch (rotigotine)

• 50% experience dyskinesias within 5 yrs levodopa •Peak‐dose vs End‐dose vs diphasic •Rapid unpredictable on‐off; dose failures

Moderate  disease

•Dose adjust, simplify (reduce DA) •Motor fluctuations/dyskinesias – rasagiline, amantadine •DBS evaluation, duodopa?

Advanced  symptoms

*Treat also autonomic symptoms, RBD/RLS, mood, cognitive dysfunction, etc.

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“Advanced therapy” • Rytary/IPX066 – • Approved Jan 2015 • Not 1:1 conversion from levodopa  • Combination with other PD meds? • Duopa – enteral CD/LD

• FDA approved Jan 2015; need GJ‐tube (issues…) • May be option for those not DBS candidates • Inhaled levodopa (Inbrija™) • New rescue therapy

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New PD drugs! (some coming…)

new MAOb inhibitor, like selegiline and rasagiline Xadago (safinamide)

Zelapar® (selegiline  hydrochloride)

oral disintegrating tablet

Inbrija

inhaled levodopa, dose limited (84 mg), for rescue only

adenosine A2 agonsist Nourianz (istradefylline) sq. carbidopa/levodopa infusion, limited dose; phase III (iNDIGO) Neuroderm (ND0612)

Apomorphine sq inf.  (ND0701), 

“Listerine strip” formulation

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Emerging therapies for Parkinson disorders • Symptomatic treatment vs Disease modification • Dopamine‐resistant symptoms • Adaptive DBS – not just stimulate but respond to abnormal brain signals • Rescue, salvage, or restore neurons (ie. stem cells) • Slow disease progression • Targeting aSyn and protein pathways • LRRK2 (Denali), Parkin and GBA • Antibodies (PX001/2) and vaccines (PD01/03) • Repurposed meds

• Nilotinib, inosine, isradipine • Individualized treatment • Heterogeneity of clinical PD subtypes

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Isradipine

FK506

Ca++

MICROGLIAL  CELL

NAB

Ub

calcineurin

calcineurin

PRX002

c‐abl

Nilotinib

Ca++

GBA

LAG3 Antibody

solTNF

autophagosome

solTNF

solTNF XPro ® 1595

GLP-1R

Extenatide Lixisenatide

Ambroxol

rapamycin

z

anle138b

NEURON

B CELL

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DBS Surgery • DBS effective for PD • Reduces tremor, dyskinesias • Increases “On” time • GPI vs SN debate –

multiple studies now that indicate both are effective  (Follett et al, NEJM 2010;Weaver et al, Neurol 2012; Odekerken et al, Lancet Neurol 2013) • Differences in tremor control, dystonia, dyskinesias • Effects on cognition, mood  (Okun et al, COMPARE, Ann Neurol 2009) • Is earlier DBS better? • Mean disease duration 7.5 yrs (Schuepbach et al, NEJM 2013) • Earlier? ~4 yrs for tremor… (Hacker et al, Neurol 2018)

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Summary 1. Not all that looks like PD is PD 2. Atypical Parkinsonisms and “Plus” Syndromes 3. Common pathological hallmarks 4. Treatment differences 5. Multidisciplinary, team approach 6. New guys on the block!

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Thank you! Questions? Nikolaus McFarland, MD, PhD 3009 SWWilliston Rd Gainesville, FL 32608 Email: nick.mcfarland@ufl.edu

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