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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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ncti
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Adapted from Marek and
Jennings Neurol ‘09
Time
Prediagnostic
Motor Phase
Diagnosis
Initiate TreatmentD
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on
Treatment
Adapted from Marek and
Jennings Neurol ‘09
Time
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
op
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Fu
ncti
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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
op
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eu
ron
Fu
ncti
on Prephysiologic PD
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
op
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Fu
ncti
on Prephysiologic PD
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
__________
Movement Disorders 34:1464-1470, 2019. DOI: 10.1002/mds.27802
__________
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