PRODROMAL PD:

IMPORTANCE OF EARLY

DIAGNOSIS AND

DIAGNOSTIC ACCURACYCharles H. Adler, M.D., Ph.D.

Professor of Neurology

Mayo Clinic College of Medicine

Co-Principal Investigator

Arizona Study of Aging and Neurodegenerative Disorders (AZSAND)

Learning Objectives/Key Points

• Discuss stages of prodromal PD

• Recognize that PD is a systemic disorder

• Discuss accuracy of a clinical diagnosis of PD

• Discuss incidental Lewy body disease as a possible key to preclinical detection of PD

• Evaluate potential strategies for preclinical detection of Parkinson’s disease

Time

Prediagnostic

Motor Phase

Diagnosis

Natural History of Parkinson’s DiseaseD

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Adapted from Marek and

Jennings Neurol ‘09

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Prediagnostic

Motor Phase

Diagnosis

Initiate TreatmentD

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Treatment

Adapted from Marek and

Jennings Neurol ‘09

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Disease Modifying TreatmentD

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Biomarker found

treatment initiated

Adapted from Marek and

Jennings Neurol ‘09

Stages of Prodromal

Parkinson’s Disease

1. Prephysiologic- genetic predisposition

2. Preclinical- disease specific biomarker(s)

3. Premotor- non-motor signs/symptoms likely

due to extranigral pathology

4. Prediagnostic- motor and non-motor

features due to nigral dopamine neuron loss

and nigral/extranigral Lewy synucleinopathy

Adler and Stern Clin Insights ‘13

Time

Prediagnostic

Motor PD

Diagnosis

Prephysiologic PDD

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Genetic predisposition

SNCA, LRRK2, DJ-1, parkin,

PINK1, GBA, UCHL1

Adapted from Marek and

Jennings Neurol ‘09

Time

Prediagnostic

Motor Phase

Diagnosis

Preclinical PDD

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Preclinical PD

Molecular

Imaging

Adapted from Marek and

Jennings Neurol ‘09

Biological Fluids

• Proteomics- measure protein levels,

structure, and function

• Metabolomics- measure low molecular weight

molecules

• Total RNA and microRNA levels

• Gene expression profiles

Time

Prediagnostic

Motor Phase

Diagnosis

Premotor PDD

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Premotor PD

Hyposmia

RBD

Autonomic

Depression/anxiety

Vision

Preclinical PD

Adapted from Marek and

Jennings Neurol ‘09

PreMotor Findings: Clinical

Findings Support Extranigral

• Hyposmia

• Visual changes

• Sleep disorders

• Autonomic disorders- cardiac, GI, etc

• Depression and anxiety

• Cognitive changes

Hyposmia

• Well documented in PD patients1,2

• Sensitive not specific for PD:

– AD, DLB5, MSA, ALS, pure autonomic

failure6,7, possibly vasc parkinsonism8 and PSP9

– Not RLS2,3, and most studies of ET2,4,10,11

• Hyposmia occurs in RBD12, ILBD13-15, and LRRK2

PD16 cases

1Stern et al. Neurol ’94; 2McKinnon et al. Intl J Neurosci ’10; 3Adler et al. Mov Dis ’98; 4Busenbark et al. Neurol ’92; 5Williams et al. JNNP ‘09; 6Goldstein, Sewell Park Rel Dis ‘09; 7Silveira-Moriyama et al. Neurol’09; 8Navarro-Otano et al. Park Rel Dis ’13; 9Silveira-Moriyama et al. Mov Dis ’10; 10Silveira-Moriyama et al.

JNNP ’09; 11Shah et al. Park Rel Dis ’08; 12Fantini et al. Brain Res Bull ’06; 13Ross et al. Mov Disorders ’06; 14Adler et al. Mov Disorders ’10; 15Driver-Dunckley et al. Mov Disorders ’12; 16Silveira-Moriyama Neurol ‘08

Parkinson At-Risk Study

• 4,999 subjects without PD did UPSIT

• 669 (13.4%) were hyposmic

• Hyposmia was associated with constipation,

anxiety, depression, and RBD1

• DAT deficit in 11% of hyposmics vs 1%

normosmics. Adding male sex + constipation

DAT deficit in >40% hyposmics2

• Relative risk of conversion to PD in 4 years

was 17.47 if hyposmic with DAT deficit3

1Siderowf et al. Mov Disorders ’12; 2Jennings et al. Neurol ’14; 3Jennings et al. JAMA Neurol ‘17

Parkinson At-Risk Study:

Conversion of Hyposmics

• 185 hyposmic subjects, 19/152 (12.5%)

converted to be by 4 yr f/u

• 95 normosmic subjects, 0/26 with mean of

2.9 yrs f/u

• 14/21 (67%) hyposmic/DAT deficit converted

• 2/22 (9%) hyposmic/indeterminant DAT

deficit converted

• 3/109 (3%) hyposmic/normal DAT converted

Jennings et al. JAMA Neurol ‘17

REM Sleep Behavior

Disorder

REM Sleep Behavior Disorder (RBD)

• Up to 60% of PD patients have RBD

• ~65% of idiopathic RBD cases develop PD or

DLB with RBD predating this by decades, so it is

pre-motor PD or pre-dementia DLB

• RBD patients have hyposmia, orthostasis, heart

rate variability, and visual changes

• Pathology data now c/w synucleinopathy

Schenk et al. Neurol ’96; Gagnon et al. Neurol ’02; Eisensehr et al. J Neurol Sci ’01; Boeve et

al. Mov Dis ’01; Boeve et al. Neurol ’03; Uchiyama et al. Neurol ’95; Postuma et al. Neurol ’06;

Fantini et al. Brain Res Bull ’06; Postuma et al. Brain ’09; Adler et al. Park Rel Dis ‘12

Risk of synucleinopathy in iRBD

• 89 iRBD followed prospectively

• 30% at 3 yrs, 66% at 7.5 yrs

• Key risk factors

– Advanced age HR=1.07

– Hyposmia HR=2.8

– Abnl color vision 3.1

• Estimated subject numbers for

disease-modifying treatment study

Postuma et al. Neurol ‘15

Autonomic Symptoms

Honolulu Aging Study:

Constipation in PD

• Men with 4x risk of PD

than those with >2

BM/d1

• Lewy bodies have

been found in the

myenteric plexus of

the colon2 and

esophagus3

0

2

4

6

8

10

12

14

16

18

20

PD

incidence

per

10,000

person-

yrs

2

Bowel Movements/day

1Abbott et al. Neurol ’01; 2Kupsky et al. Neurol

’87; 3Qualman et al. Gastroenterol ‘84

Movement Disorders 30:1600-1609, 2015. DOI: 10.1002/mds.26431

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Movement Disorders 34:1464-1470, 2019. DOI: 10.1002/mds.27802

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Prodromal PD:

Liklihood Ratios of Risk Markers

Heinzel et al. Mov Dis ‘19

Prodromal PD: Liklihood Ratios of

Prodromal Markers

Heinzel et al. Mov Dis ‘19

LR+ LR-

Importance of Clinical

Diagnostic Accuracy

• Patients want to know what they have

• Enrollment in clinical trials

• Appropriate power for therapeutic trials

• Choosing patients for invasive treatments

• Validating biomarker studies

• Validating genetic and epidemiological studies

Rajput et al.

• 43 patients clinically diagnosed with PD and

followed to autopsy

• 28/43 (65%) had neuropath confirmed PD

• After a mean follow-up period of 12 yrs, 41 still

had clinical diagnosis of PD at final visit before

death yet only 31/41 (76%) had PD pathologically

Rajput et al. Can J Neurol Sci ’91

Hughes et al.

• 76/100 (76%) clinical PD had path confirmed PD1

• Retrospective diagnostic criteria (bradykinesia,

asymmetry, rest tremor, progression, > 5 yr

response to levodopa + dyskinesia, > 10 yr dis

duration) increased accuracy to 73/89 (82%)2

• Tremor predominant had 91% PPV but only 11 of

76 cases had this, so may be chance2

• All 3 cardinal features 88-92% PPV2,3

1Hughes et al. JNNP ’92; 2Hughes et al. Neurol ’92; 3Hughes et al. Neurol ‘01

Adler et al.

• Used clinical diagnosis (by a movement

disorder specialist) at study entry visit

• Clinically ProbPD: 2/3 cardinal signs +

response to dopaminergic meds

Adler et al. Neurology ’13

ProbPD

N 97

Female 32 (33%)

Age at Visit 76.8 (7.5)

Age at Death 80.6 (7.0)

Duration of PD Symptoms at Visit 11.0 (6.6)

Duration of PD Symptoms at Death 14.8 (6.9)

Neuropathologically Confirmed PD 80 (82%)

95% CI 73% to 89%

PPV for ProbPD seen at First Visit

ProbPD ProbPD

Other Findings

• Factors that improved accuracy

– Clear response to dopaminergic meds

– Motor fluctuations (92% vs. 70%)

– Dyskinesias (96% vs. 76%)

– Hyposmia- loss of the sense of smell

• Did not improve accuracy

– Having all 3 cardinal features

– Asymmetry or Rest tremor

• Overall Sensitivity = 86%, Specificity = 90%

Adler et al. Neurology ’13

ClinicoPathological

Studies Support a

Premotor Stage for PD

Incidental Lewy Body Disease

• The presence of Lewy bodies in the absence of

clinical parkinsonism or dementia

• Prevalence increases with age

• 8-12% over age 60 and 16-30% of autopsied

elderly controls have ILBD using synuclein staining

• These cases may be pre-clinical PD or DLB cases

• So, finding clinical, biochemical, tissue, or imaging

biomarkers in ILBD cases may be critical to early

detection

Gibb WR, Lees AJ. JNNP ’88; Mayeux et al. Am J Epidemiol ’95; Saito et al. J Neuropathol Exp Neurol ’04; Bloch et al. NeuropatholAppl Neurobiol ’06; Minguez-Castellanos et al. Neurol ‘07.; Jellinger KA. J Neural Transm ’04; Adler et al. Mov Dis ‘10

Age, yrs Gender

ILBD

(n=11)*

86.5 + 5.9

(74-96)

6M/5F

Control

(n=27)

86.7 + 7.4

(75-102)

12M/15F

Striatal and Epicardial TH in ILBD

Age, yrs Gender

ILBD

(n=12)

77 + 11 6M/6F

PD

(n=16)

78 + 6 14M/2F

Control

(n=17)

77 + 7 12M/5F

Dickson et al. Acta Neuropathol ‘08

UPSIT in Autopsy Cases

PD ILBD Control

N 10 13 69

Age at

UPSIT

79.7 + 8.0 86.2 + 6.2 84.2 + 5.9

UPSIT 16.3 + 5.3 22.2 + 9.1 27.7 + 5.7

Driver-Dunckley et al. Park Rel Disord ‘14

12-odor Cross-Cultural Smell

Identification Test (CC-SIT) in ILBD

Control ILBD

N 147 17

Age at UPSIT 81.5 (5.1) 83.5 (6.1)

Age at death 84.9 87.2

CC-SIT score 6.3 (3.1) 4.6 (2.5)*

Lowest tertile

(0-5)

45/147 (31%) 10/17 (59%)*

Ross et al. Mov Disord ‘06

Honolulu Aging Study:

Constipation in ILBD

• 245 autopsied men, 12.2% had ILBD

• If

1BM/d

• If 1 BM/d 13.5% had ILBD

• If >1 BM/d 6.5% had ILBD

Abbott et al. Mov Dis ‘07

Lessons from ILBD

• Likely preclinical/premotor stage of PD or DLB

• ILBD remains a pathological diagnosis

• Need continued detailed clinicopathologic

studies of controls that will have ILBD at autopsy

• Collecting data on sleep and autonomic sx’s as

well as Heart Rate Variability

• Preclinical and premotor biomarkers may be

identified and confirmed in this population

Conclusions

• PD is a systemic disorder that starts well before

motor findings

• Genetic testing can identify at-risk cases

• Imaging, fluid, tissue testing, non-motor battery

may identify preclinical or premotor cases

• Needed

a-syn imaging

longitudinal path-confirmed studies

Tissue biopsy