Initial Clinical Assessment of a Parkinsonian Patient

Jill Ostrem, MD

Carlin and Ellen Wiegner Endowed Professor of Neurology

Division Chief and Medical Director

UCSF Movement Disorder and Neuromodulation Center

Disclosures• Consultant: Medtronic, Abbott

• Educational grant support: Medtronic, Allergan, Boston Scientific, AbbVie, Merz

• Clinical trial support: Boston Scientific, Cala Health, Medtronic, Biogen, Roche, Neuroderm

Diagnosis of Parkinson’s Disease

• Comprehensive history and physical exam

• No definitive test to confirm PD

• Clinical diagnosis requires review of history, assessment of symptoms, careful examination, rule out alternative diagnosis

• It can take time to work out

26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects53% accuracy in early PD responsive to medication (5 years’ duration)85% diagnostic accuracy of longer duration, medication-responsive PD

Parkinson’s Disease Clinical Features

MDS Diagnostic Clinical Criteria for PD

MDS Diagnostic Clinical Criteria for PD

Common Initial PD Symptoms

• Non-motor – often “Pre-motor”• Loss of sense of smell• Constipation• Sleep disorders – Rapid Eye Movement Behavior Sleep

Disorder (RBD)• Depression

• Motor• Subtle rest tremor in one arm/hand/finger• Sense of stiffness in one limb

• Maybe interpreted as orthopedic problem

• Sense of slowness in one limb• Decreased dexterity, decreased arm swing

• Stooped or slow walking• Decrease blink rate/ softer voice

Case Mild Parkinsonism• 55 yo male• Initial symptoms right shoulder pain• mild intermittent right hand rest

tremor• RBD, poor smell

Case of Early PD

• 50 yo male• Initial symptoms mild intermittent right hand>leg

rest tremor• Insomnia, constipation, anosmia, urinary urgency

Case: Mild Parkinsonism • 61 yo RH male• Initial symptoms mild

intermittent right hand rest tremor followed by toe curling and ankle inversion (foot dystonia)

Parkinson’s Disease-Slower Rest Tremor

Parkinson’s Disease

Parkinson’s Disease

Parkinson’s Disease- Rigidity

Parkinson’s Disease- No Tremor

PD - Postural Instability

PD Subtypes

jamanetwork.com

Advanced PD

OFF medication

ON medication

Scales Used to Access Newly Diagnosed PD(Maybe)

• UPDRS

• MDS-UPDRS

• Hoehn and Yahr – available since 1960’s• Five stages mild to bedridden

• Other scales used• Mood scales ?

• MOCA

• Tremor scales ?

UPDRS New Version• Parts IA (investigator) and B (patient):

non-motor experiences of daily living• Part II: motor experiences of daily living• Part III: motor exam, on and off• Part IV: motor complications

11

Assessment of Cognitive Impairment/Dementia

Montreal Cognitive Assessment (MOCA)(range 0-30)

• Characteristics of PD – MCI/D• Less problem with memory,

language (AD)

• Attention, apathy, executive (FRONTAL)

• Fluctuation level of consciousness

• Hallucinations/delusions, visuospatial (PARIETAL/TEMPORAL)

• Score >26 = cognitive impairment

Assessment of Cognitive Impairment/Dementia

• Parkinson’s Progression Markers Initiative(PPMI)• Multi-site longitudinal study of early, untreated PD patients and HC.

• Baseline, 22% of 423 PD patients met the recommended screening cutoff for cognitive impairment on the MoCA (<26), but only 9% met detailed neuropsychological testing criteria for PD-MCI (level I impairment).

• Estimated rates of MCI might be higher when using a screening instrument versus cognitive test battery, given recommended cut-off scores for screening instruments typically prioritize sensitivity over specificity.

Weintraub D, Simuni T, Caspell-Garcia C, et al. Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson’s disease. Mov Disord 2015;30:919-927.

Lab Tests to Consider

• Vit B12, Vit D

• Methomalonic acid

• TSH (thyroid)

• Toxin screening if patient’s history of suggestive of possible exposure

• Measurement of copper or ceruloplasmin may be warranted – role out Wilson’s disease

• Genetic testing

PD GeneticsGene Mutations Protein/Enzyme Function Age at

onsetPhenotype Pathology

Dominantly inherited last-onset PD

SNCA Missense Alpha synuclein- structural brain protein

60 yr

(30-80)

Levodopa responsive Diffuse lewy bodies

SNCA Locus duplication (and triplication)

31-71 yr Levodopa responsive, younger age, rapid progression, autonomic dysfunction, dementia, wide spread Lewy Bodies

Diffuse lewy bodies, prominent nigral and hippocampal loss

LRRK2 Missense: Arg1441Cys/Gyl/His; Try1688Cys, Gly2019Ser, IIe2020Thr

Polymorphisms, protective haplotypes

Leucine-rich repeat kinase 2- enzyme when mutated causes Lewy-body phenotype –increased kinase activity

60 yrs(32-79)

Levodopa responsive, Like sporadic PD, slow progression, abduction-addition lower limb tremor, little dementia

Brain Stem LB, neurofibrillary tangle or TDP-43 pathology and/or nigral neuronal loss

VPS35 Missense: ASP620Asn 53 yrs(40-68)

Levodopa responsive tremor-dominant, dyskinesia and dystonia, occasionally dementia

Inconclusive- ? No LB

GBA1 Gcase protein activity decreases

51 yrs Levodopa responsive, more dementia Lewy bodies

Juvenile and early-onset recessively inherited PD

PARK2 Numerous missence, exon deletion and duplication mutations

Parkin- a ubiquitin-protein ligase involved in protein degradation

<45yr (12-58)

Levodopa responsive, early dystonia, slow progression, hyperreflexia, dyskinesia, early gait and balance issues, less non-motor

Predominantly nigralneuronal loss

Occasionally with synucleinor tau pathology

PINK1 Misssence: many

Rare: locus and exon deletion

PTEN-induces putative kinase

<45yr (18-56)

Levodopa responsive, akinetic/ridged postural instability, gait, slow progression, sleep benefit

One case with lewy bodies

DJ-1 Misense: Glu163lys, Leu166Pro Exon 1-5 deletion, g.168-185 dup

Positive regulator of androgen- receptor dependent transcription

<40 yr(24-39)

Like PINK-1, rare Unknown

Parkinsonism Genetic Panels

Anti alpha syn

• ASO –

• B2- adrenoreceptor against and antagonist drugs and risk of PD 0 Neurology (paper)

• Tyrosine kinase C-abl inhibitors – Nilotinib (poor CNS penetation

• Propagation of alpha synuclen-

• LRRK2

• Gain of function in LRRK2 to increase the kinase activity and more phosphoralation – RAB10 –failure of autophagy (lysosome)

• Trials : Denali

• ASO coming for this too

• Kinase inhibitors – many- but lots of potential peripheral side effects – lung, kidney, spleen – also increase in some types of cancer

• LRRk2 and Gcase convergence in PD

GBA

• Do J et al 2019 – good slide

• JR mazzulli J cell 2011 – good slide

• AAV- GBA1 gene

• Venglustat –GCS inhibitor

• Small brain penetrant chaperons - ie ambroxol

LRRK2 Mutation Parkinsonism

Phenotype

• Like sporadic PD (later

onset)

• Variable clinical and

pathological phenotype

• Levodopa responsive

• Slow progression

• Abduction-addition

lower limb tremor

• Little dementiaVideo Courtesy of Dr. San Luciano and Darel Ogbonna

• Mutation in the leucine rich repeat kinase 2 (LRRK2) gene (G2019S) is the greatest known genetic cause of PD

• Most common monogenic cause of PD in Europe and North America

• Higher in Ashkenazi Jewish families

• 30% penetrance

• Mutations seem to heighten the activity of LRRK2 kinase

GBA Mutation Parkinsonism

• GBA1 mutations cause dysfunction in the glucocerebrosidase (Gcase) protein-leading to build-up of alpha-synuclein

• More common in Ashkenazi Jewish descent /Gaucher or relative with Gaucher(lipids build up and enlarge organs)

• 5-10 % of PD patients carry this mutation• GBA mutation - 20X increased risk of PD• GBA mutations are common but overall chance of PD is still low

Phenotype• Slightly earlier age of onset• Initial symptom often

bradykinesia• More rapid motor disease

progression, more dyskinesia• More cognitive dysfunction• Less tremor• More depression

Video Courtesy of Dr. San Luciano and Darel Ogbonna

Parkin Mutation Parkinsonism

Parkin- a ubiquitin-protein ligase involved in protein degradation

Numerous missense, exon deletion and duplication mutations, No LB?

Phenotype:

Younger age onset, levodopa responsive, dystonia, akinetic/ridged, postural

instability, gait, slow progression, sleep benefit Video Courtesy of Dr. Nick Galifianakis

Other Diagnostic Procedures

• Dopaminergic challenge test

• MRI

• DatScan/18 F-FDG PET

• Neuropsychiatric testing

• Sleep studies- Polysomnogram

Acute Levodopa Challenge

• Not performed often

• Very likely to cause nausea- would need to pre-medicate (carbidopa/domperidone)

• Serial exams before and after

• 30% improvement in UPDRS III considered positive

• Many false positive and negative results!

• Can help predict long-term chronic response to levodopa

Structural MRI in Parkinsonism

• Routine brain MRI usually normal in PD• Identify presence of lesions• NPH like picture- MRI r/o hydrocephalus• Lower body PD- r/o vascular PS• Quantify brain atrophy• Red flags on exam - MSA/ PSP• 7T MRI or other scans maybe helpful in the

future

Clinical Medicine 2016 Vol 16, No 4: 371–5

Pagano, Niccolini, and Politis

DatScan Mechanism & Indications

INDICATIONS AND USAGEDaTscan is a radiopharmaceutical indicated for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brainimaging to assist in the evaluation of adult patients with suspected Parkinsoniansyndromes (PS).

DaTscan may be used to help differentiate essential tremor from tremor due to parkinsonian syndrome

Bajal, 2013; FDA Product Label

DatScan

Helpful:

• Essential tremor (nl) from parkinsonian tremor (abnl) (presynaptic dopaminergic deficit)

• Drug induced parkinsonism (nl) from PD (abnl)

• Alzheimer's disease (nl) from Lewy body dementia (abnl)

• Normal from Premotor phase PD (abnl) (clinical trials)

Not helpful:

• PD (abnl) from MSA or PSP (abnl)

Who Makes Diagnosis and Team Involved

• Primary Care Physician

• Family Practice Physician

• Neurologist

• Movement Disorders Specialist

• Team: Nurse, Social worker, Psychologist, Physical Therapist, Neuropsychologist, Neurosurgeon, Genetic Counselor

UCSF Movement Disorders

NeurosurgeryPhilip Starr, MD, PhDPaul S. Larson, MDDoris Wang, MD, PhDDaniel Lim, MD, PhDCoralie De Hemptinne, PhDRo’ee Gilron, PhDWhitney Chen, PhDRobert Wilt

NeuropsychologyCaroline Racine Belkoura, PhD

NursingMonica Volz, FNP, MSSusan Heath, MS, RNGina Bringas-Cinco, RNAnnie Li Wong, NPRigzin Lama, RN

NeurologyJill Ostrem, MDCaroline Tanner, MD, PhDMarta San Luciano, MDNicholas Galifianakis, MDMaya Katz, MDIan Bledsoe, MD,MSJames Maas, MD, PHDChadwick Christine, MDMichael Aminoff, MDRobert Edwards, MD, PhDKen Nakamura, MD, PhDAlexandra Nelson, MD, PhDMichael Geschwind, MD, PhDCameron Dietiker, MDNijee Luthra, MD, PhDEthan Brown, MDSamuel Goldman, MDSimon Little, MD, PhDRafael Zuzuarregui, MD

PsychiatryAndrea Seritan, MD

Physical TherapyHeather Bhide, PT

FellowsFay Gao, MDLauren Spiegel, MDAmir Badiei, MDPrarthana Prakash, MDMia Vuong, MDFaiza Butt, MD

Research /Support StaffSarah Wang, PhDJanet AllenYasmeen GonzalezChristine JiuntiJeverly CalaunanKathleen Comyns, MPHCheryl Meng, MPH Farah Kauser, PhDDanilo RomeroVy NguyenEnrique EsteinouRaisa SyedDarel ObonnaMellssa GittingsMaria Loudette BautistaAaron Daley

Social WorkMonica Eisenhardt, LCSWSamuel Yee

ChaplinJudith Long