2/22/2016

DOPAMINE AND AGING (YEARS)

Onset Diagnosis
Dopaminergic neuron loss in PD
Diagnosis and prognosis of new
Nnnmntnr m i_ni

onset Parkinson disease tA<xoyr

/ Sleep ^ ^ ^ * ^ ^ ^ ^
/ Olfactory* ^ ^ ^ ^ ^
G. Dewanto f Mood ^
A u t o n o m i c system
Department of Neurology
Faculty of Medicine Q Pre symptomatic phase . _. _
Early nonmotor symptoms Specific symptoms
Q
Atma Jaya Catholic University
Time (years) 60-80% of dopaminergic
Jakarta ' O l f a c t o r y dysfunctio nay predate clinical PD by at l e a s t A years. neurons are lost before
the motor signs of PD
Halpenn et al. Neurotherapeutics 2009:6128-140.
emerge.
Lang. Neurology 20Q7;68-9<t3-952.
Ross e l a l Ann Neurol 2008:63:167-173

Parkinson Disease Parkinson Disease

Pre-Motor Symptoms (i) Pre-Motor Symptoms (2)
Braak Hypothesis
Unilateral tremor Falls
Based on 6 different neuropathological stages -Hyposmia Rigidity -Dependency W'"
Sleep cisoider
- Constipation Akinesia -Cognitive decline \ v
Neuronal damage first occurs in Stage 1: the Dorsal IX and X nucleus Bt-ddsr disorder
Depression
Bilateral disease -Chair/bedbound
-Poor o.iance -Dementia1
in the pre-symptomatic phase and moves up to stage 6: the
neocortex Neocortex
:
[secondary & primary] .PrasyTnptomatic;FTi

(scoiio^ S primiiy)
Ftec-cotei association '..::,'. ,:! j wPF
>-, mm
S-Dstanfa nigra %^^ IllrTJT .'

Locus ceruleus

Dorsal IX IK nucleus
Olfactory buio ,~->'"
1 2 3 4 9 S
I Docsallxanucleis
Ollactorrbulb Stage1

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 2/22/2016

a r a a h ' s S t a g e 1-2 B r e a k ' s S t a g e 3-4 Brash's S t a g e S-6

I . ij_j

utor Phase C l i n i c a l l y E v i d o n l (PD) With Complications ( P D - D |

Symptom* s p e c i f i c i _1
gttnjtnc ntrtmtg
Fr-on_ Convex UtR^.'-r:!
HypoimW Memory Impairivvont
Coctlpatton Steep D i s o r d e r HfftSftr'S :I-TT ^
Depression ;:..c r-HflrO- C-V
Acute D e l i r i u m :f-U.lVPi-
Articular p a i n Nocturia M J
F'.llif.lMO
- O ' t n o u t i i n c Hy
Dystagia w i t t i p n g u i n i ^'
w
Trail "in ili

Accurate diagnosis is critical and remains Diagnostic criteria have been developed, with
founded on clinical grounds as nonspesific the most commonly used being the UK PDSBB
diagnostic test is available so far. criteria (1992), it has been suggested that an
( M a s s a n o j . Bfiatia KP: Clinical Approach to Parkinson's Oisesase: features. Diagnosis, and Principles of
M a n a g e m e n t . 2013. Cold Spring H^r_ Perspeci M e d )
accuracy of 75-90% is the best that can
achieved with clinical assessment and clinical
Although PD is common, it can be difficult to diagnostic criteria, and confirmed on autopsy.
diagnose clinically, particularly in early stages,
and approximately 5-10% of patients with PD
are misdiagnosed.

(
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UK Parkinson's Disease S o c i e t y Brain Bank's Clinical C r i t e r i a

for the diagnosis of probable Parkinson's disease
(Hughes et al in J Neurol Neurosurg Psychiatry 1992;55:181-184 and Neurology 1992;42:1142-
11461
Step 2
Exclude other causes of parkinsonism
Stepl History of repeated strokes Cerebellar signs
History of repeated head injury Early severe autonomic involment
- Bradykinesia, and at least one of the History of definite encephalitis Early severe dementia

following: Oculogyric crises Babinskisign

Neuroleptic treatment Presence cf cerebellar t u m o r or
- Muscular Rigidity More than one affected relative communicating hydrocephalus on CT
scan
Sustained remission
- Rest Tremor 4-6 Hz Negative response to large doses of
Strictly unilateral features after
LD
- Postural instability three years
MPTP exposure
Supra nuclear gaze palsy

Step 3
3 or more required for diagnosis definite PD: Practice Parameter:
- Onset is typically asymmetric Diagnosis and prognosis of new onset Parkinson
- Rest tremor present
- Progressive disorder disease (an evidence-based review)
- Persistent asymmetry affecting side of onset most Report of the Quality Standards Subcommittee of the American
- Excellent response (70-100%) to levodopa Academy of Neurology
- Severe levodopa-induced chorea (dyskinesia) O. Sucowersky, S.Reich. J. Perlmutter, T. Zesiewiecz, G. Gronseth,
WJ Weiner
- Levodopa response for 5 years or more
Continuum Vol 13, N u m b e r 1, Februari 2007, page 158-165
- Clinical course of 10 years or more

ACCURACY OF PD DIAGNOSIS: 65-95%

(

1. Which clinical features and diagnostic
modalities distinguish PDfrom other
parkinsonian syndromes?
2. Which clinical features predict rate of
disease progression?
Diagnostic modalities
LD and apomorphine challenge should be considered for
confirmation when diagnosis of PD is in doubt (Level B)
Olfaction testing should be considered to diffrentiate PD from
PSP and CBD but not PD from MSA (Level B)
GH stimulation with clcnidine, electro-oculography and SPECT
scanning, may not be useful in diffrentiating PD from other
parkinsonian syndromes (Level C)
Insufficient evidence to distinguihing PD from other
parkinsonian syndromes: urodynamics, autonomic testing,
urethral or anal EMG, MRI, brain parenchyma sonography and
FDG PET (Level U)
2/22/2016
Recommendations
Question: Number 1: Distinguished PDand other parkinsonian
Clinical Features
The following clinical features in early stages of disease should
be considered to distinguish PD from other parkinsonian
syndrome: (Level B)
1. falls at presentation and early in the disease
course.
2. poor response to LD
3. symmetry at onset
4. rapid progression (to Hoehn and Vahr stage 3 in 3 years)
5. lack of tremor
G. dysautonomia {urinary urge incontinence, fecal incontinence, urinary
retention requiring catheterization, persistent erectile failure,
symptomaticorthostatic hypotension)
Recommendations
Question: Number 2: Clin features predict disease progression
In pts with newly diagnosed PD, older age at onset and
rigidity/hypokinesiaas an initial symptom should be used to predict more
rapid rate of motor progression (Level B}
The presence of associated comorbidities (stroke, auditory deficits and
visual impairments), PIGD (Postural Instability/Gait Difficulty), and male
sex may be used to predict faster rate of motor progression Level C)
Tremor as a presenting symptom may be used to predict s more benign
course and longer therapeutic benefit to tD (Level C)
Older age at onset and initial hypokinesia/rigidity should be used to
predict earlier development of cognitive decline and dementia (Level C)
Older age at onset, dementia and decreased dopamine responsiveness
may be used to predict earlier nursing home placement as well as
decrease survival (Level C)
C
 2/22/2016

MDS-PD Clinical Diagnostic Criteria

The criteria were finalized and ratified in San Diego, California, USA,
in June 2015
(Movement Disorders, Vol 30. No 12. 2015)
Full diagnostic certainity is impossible during life, between 75- Diagnostic error can be attributable to:
95% of patients diagnosed with PD by experts have their - failure to recognise other pathologies causing
diagnosis confirmed on autopsy.
neurodegenrative or secondary parkinsonism (MSA, PSP,
Diagnosis accuracy varies considerably according to:
subcortical arteriosclerotic encephalopathy, and so forth)
- disease duration (lower on 1st visit than after longer follow-
- absence of a true progressive parkinsonian disorder
up)
(essential tremor, dystonic tremor, and so forth)
-age
- the expertise of the clinician
MDS-PD criteria are designed to minimize both of these
- evolution in our understanding of PD diagnostic errors

MDS-PD Criteria include two distinct levels of

diagnostic certainity.
Of note, studies have suggested that experienced clinicians 1. Clinically Established PD:
can diagnose PD with greater accuracy than formal diagnostic
Maximizing specificity, at 90% will have PD (expense of
criteria.
reduced sensitivity)
Therefore, until definitive validated diagnostic markers are
available, clinical expert opinion will be the gold standard
diagnostic tehnique in life. 2. Clinically Probable PD:
MDS-PD Criteria are intended for use in clinical research but Balancing sensitivity and specificity, at least 80% of pts
also may be used to guide clinical diagnosis
diagnosed as probable PD truly have PD, but also that 80%
of true PD cases are identified
 2/22/2016

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 2/22/2016

Estimated life expectancy of Parkinson's pts compared

with t h e UK population
Ishihara LS, Cheesbrough A, Brayne C, Schrsg A
1 Neurol Neurosurg Psychiatry 2O07;78:B0U-1309

Objective:

Diieria Appi calion: to calculate the best possible estimates for age specific life expectancy (LE)
] Does tie pafe* tee &vtorsonsrt * Wnwi w :r* UDS anar^ B_) Ho and anticipated age at the t i m e of death (AAD) in pts with PD compared
a TO frinef probat* P5 ncr dittany es&BitfsG rfl -;an c* jagncseii -* jS with the general population in the UK. These may be greater value to pts
I Ar- any atactic etdtscfl cfltea seserp <o3 fio than standardised mortality ratios (SMRs), which are usually reported in
it "'pis.' T-jtfBrprc^s PO iicf d u o s . ssoDbsted i>0 can be dagnosed. I w
3 MrjmDff of red Sags preset! studies on mortality in PD
i r-.yroa tf sjpwrtrrt aitete presait __.. Methods:
5 to there at -asf ? sujrj&rtnie CBBM .aw rad Hags' *!J te Literature revieyiew identified articles with data on age stratified life
ft yes qanefit Teets cniafa !cr djrsca-fv estadtshec ?0 / w
6 to ttvre w e ftan ? E_ Rags7 m expectancy or SMRs to calculate estimations of LE using Gompertz
*C
ft" ,es" rrrjfcbsj PG amt se rJaoncsN " T function and data on moratality and LE in the UK from the office national
; Is ire .-x "oer nf raj ftsp equal ;& or IPSS tup. Hv m r aw of Riipo*it crrjenu? IK '"] ft Statistics and Actuarial D e p a r t m e n t for the year 2003.
f ! , pa'#rt! meeds eri&a for {HrtsaW'1. <H

Results: Conclusion:
Two UK studies and four from Western Europe were used to estimate LE
The calculation showed that LE and AAD in PD reduced for all
and AAD for pts with PD from SMRs.
onset ages are but this reduction is greatest in individuals
The mean LEs of pts w i t h PD compared w i t h the general population w e r e :
with a young onset. While the results are average estimates,
38 (SD 5) yrs for onset between 25 39 yrs compared with 49 (SD 5) yrs:
these can provide useful indications of LE and AAD.
21 (SD 5) yrs for onset between 40 64 yrs compared with 31 (SD 7) yrs;
5 (SD 4) yrs for onset age >/= 65 yrs compared with 9 (SD 5] yrs.
The average AAD of pts with PD with onset between 25 and 39 yrs was 71
(SD 3) yrs and considerably lower than that of the general population
82 (SD 2) yrs. The difference between average AAD for older individuals
w i t h PD (onset >/=65 yrs) and the general population was smaller, w i t h on
AAD of approximately 88 (SD 7) yrs compared with 91 (SD 5) yrs.
 2/22/2016

Predictors of Survival in PD
National Institute of Health
Willis AW, Schoolman M, Kung M, Evanoff BA, Perlmutter JS, Racette BA, in Arch
Neurol. 2012 May; 69(5); 601-607
Objective:
To determine PD iife expectancy in the US and identifdy demographic,
geographic and clinical factors that influence survival.
Design:
Restrospective cohort study of 138.000 Medicare beneficiaries w i t h
incident PDwere identified in 2002 and followed through 2008
M a i n Outcome Measures:
Confounder adjusted six year,risk of death as influenced by three g r o u p o f
factors: 1) race, sex, age at diagnosis 2) geography, environmental factors
3) clinical conditions.
We examined hospitalization diagnoses in terminal PD, compared PD
mortality to that of other common diseases.
Results:
35% PD cases lived more t h a n six years.
Sex and race significantly predicted survival:
Female (HR0.74,0.73-0.75), Hispanic (HR 0.72,0.65-0.80) and Asian (HR
0.86,0.82-091] cases had a lower adjusted risk of death than white males.
Dementia/cognitive i m p a i r m were similarent, diagnosed in 69.6% of
cases, most often in Blacks (78.2%) and women (71.5%), was associated
w i t h a greater likelihood of death (HR 1.72,1.69-1.75).
PD cases had grater mortality than many common life threatening
diseases.
Terminal PD pts were hsopitalized frequtnly for cardiovascular disease
(!%.06%) and infection (29.52%), rarely for PD related illness (4,2%0.
Regional survival rates were similar, but urban PD cases living in a high
industrial metal emission area had a slightly higher adjusted risk of death
(HR 1.19,1.10-1.29)

Conclusions

Demographic and clinical factors impact PD

survival.
Dementia is highly prevalent in PD and is
associated with a significant increase in
mortality.
More research is needed to understand if
environmental exposures influence PD course
or survival.