Dr. Alastair NoyceEarly Clinical Features of Parkinson’s Disease and Related Disorders Dr....
Transcript of Dr. Alastair NoyceEarly Clinical Features of Parkinson’s Disease and Related Disorders Dr....
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
1The screen versions of these slides have full details of copyright and acknowledgements
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Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
Specialist Registrar in Neurology, London Deanery
Parkinson’s UK Doctoral Research Fellow
Project lead for PREDICT-PD
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Declarations
• Salary: Parkinson's UK, Barts and the London NHS Trust
• Grants: Parkinson's UK (F-1201, K-1006), GE Healthcare,
Elan/Prothena Pharmaceuticals
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Topics for discussion
• General concepts
• Parkinson's disease
� Early non-motor features
� Early motor features
• Parkinson's plus (multiple system atrophy,
progressive supranuclear palsy)
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
2The screen versions of these slides have full details of copyright and acknowledgements
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Objectives
1. To understand the general concepts around early
identification of neurodegenerative disease
2. To be able to list the recognised early non-motor features
and motor features of PD
3. To understand the time course of these, the specificity,
and possible neuropathological correlates
4. To recognise early features that might indicate
an alternative Parkinsonian syndrome
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Relevance
• As the world’s population ages so with it increases
the burden of neurodegenerative disease.
• As caseloads increase, there is rising concern about
the absence of drugs available to treat these diseases.
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General concepts: subclinical decline
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
3The screen versions of these slides have full details of copyright and acknowledgements
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General concepts: heterogeneity
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General concepts: fallibility
• Even in the hands of experts, at post mortem 10-15%
of patients diagnosed in life with PD, turn out to have
an alternative pathological diagnosis.
• What lies beneath can be difficult to say
with absolute certainty during life.
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Parkinson’s disease
• 4 million worldwide in 2005, 9 million by 2030
(Dorsey, Neurology 2007)
• 2nd most common neurodegenerative disorder
• Diagnosis based on motor signs (Gibb, JNNP 1989)
• Motor features arise once there is 50-60% loss of cells
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
4The screen versions of these slides have full details of copyright and acknowledgements
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Fearnley & Lees, Brain 1991
Normal Aging4.7% loss per decade
PD45% loss first decade
Fearnley & Lees, Brain 1991
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Braak, Neurobiol Aging 2003
1. DMV, Olfactory bulb
2. Locus coeruleus
3. Substantia nigra
4. Mesocortex
5. Neocortex
6. Further neocortex
• 41 PD
• 69 ILD
• 58 controls
Braak, Neurobiol Aging 2003
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Parkinson’s disease timeline
Hawkes, Park Relat Disord 2010
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
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Subjective reporting
• de Lau and colleagues found significant associations
with PD and self reporting of: stiffness, tremor,
slowness and falls (de Lau, Arch Neurol 2006)
• O’Sullivan and colleagues found in a pathologically
confirmed series of PD patients that along with typical
motor features; pain, urinary dysfunction and mood change
were also common as presenting features of PD,
and frequently led to misdiagnosis and delayed diagnosis (O’Sullivan, Mov Disord 2008)
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Non-motor features of PD
• Smell disturbance
• Sleep disturbance
• Autonomic dysfunction
• Mood change
• Cognitive change
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Smell
• Olfactory dysfunction - common finding (up to 80%)
• Evidence that hyposmia precedes motor PD:
1. First-degree relatives of patients with PD underwent
smell identification testing and [123I] β-CIT SPECT scans
(Ponsen, Ann Neurol 2004).
Main findings:
a. Only those with smell loss and abnormal SPECT
got PD within 2 years – 4 subjects
b. 1 additional hyposmic subject had very abnormal SPECT
after 2 years
c. Other hyposmic subjects had accelerated decline in SPECT
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
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Smell (2)
2. Transcranial sonography (TCS) on 26 patients
with idiopathic anosmia (Sommer, Mov Disord 2004)
• Of these, 10/11 that had abnormal TCS went on
to have a [123I] FP-CIT SPECT, which showed
pathological appearances in 5 subjects
3. 2267 subjects in HAAS tested with B-SIT, and followed up
for 8 years (Ross, Ann Neurol 2008)
• 35 incident PD cases. Relative odds of 5.2 (CI 1.5, 25.6)
for developing PD over 4 years if the lowest smell quartile
was compared to the reference group (the highest two quartiles)
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Sleep
• REM-sleep Behaviour Disorder (RBD) is a recognised
sleep disorder characterised by vigorous, and sometimes
injurious, enactment of vivid, action-packed dreams
• A number of observational studies have demonstrated
that RBD can precede the onset of motor PD
• 29 patients with RBD, 11 (38%) had developed PD
at 4 years follow-up (Schenk, Neurology 1996).
With further follow up 65% developed Parkinsonism
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Sleep (2)
• Subjects with RBD tested for the presence of anosmia, and clinical
and imaging evidence of alpha synucleinopathy. Patients had higher
thresholds, lower discrimination, and lower identification. 5 had clinical
features consistent with PD, 3 had early or established abnormalities
in SPECT (Stiasny-Kolster, Brain 2005)
• A follow-up study of 93 patients with a diagnosis of RBD estimated
the 5-year risk of developing a neurodegenerative disorder was 17.7%.
The 10-year and 12-year risks were 40.6% and 52.4%, respectively
(Postuma, Neurology 2009)
• 44 patients assessed in sleep centre. 20 (45%) developed
neurodegenerative disorder after mean time of 11.5 years
from symptom onset (Iranzo, Lancet Neurol 2006)
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
7The screen versions of these slides have full details of copyright and acknowledgements
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Constipation and mood change
• Systematic review & meta-analysis
• MEDLINE search using PUBMED,
April 2011
• Inclusion criteria:
� Observational studies
� Reported risk factors or ENMFs
� Were amenable to screening
in the primary care setting
• Treatment of studies:
� Meta-analysis
� Systematic review
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Other early non-motor features
• Erectile dysfunction
• Urinary symptoms
• Pain
• Voice
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Cognitive
• MDS-Consensus – PD-MCI (Litvan, Mov Disord 2012)
• ParkWest Study (Pedersen, JAMA Neurol 2013) –
MCI puts patients at high risk of developing dementia
• ICICLE study (Yarnall, Neurology 2013)
� Compared 219 incident PD patients with 99 controls
� Patients scored lower on MMSE and MoCA (25 vs. 27)
� 42.5% met level 2 criteria for MCI at 1.5 SDs below normative
� Memory>visuospatial>attention>executive function>language
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
8The screen versions of these slides have full details of copyright and acknowledgements
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Motor
• Signs of Parkinson’s disease
� Bradykinesia
� Rigidity
� Tremor
� Reduced arm swing
� Gait disturbance
• The story of Ray Kennedy
(Arsenal and Liverpool footballer in the 1970’s and 80’s)
by Prof. Andrew Lees
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Postuma, Brain 2012
• 78 with idiopathic RBD were included
• 20 developed Parkinsonism
• Matched with controls (1:2)
• Multiple motor assessments
• UPDRS becomes abnormal 4.5 years before diagnosis
• Order of involvement: voice>face>bradykinesia>rigidity>gait>tremor
Postuma, Brain 2012
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Mild Parkinsonian signs
• An emerging concept analogous to mild cognitive impairment
• Suggests a continuum of motor dysfunction
in various domains between normal aging
and the point where PD is established
• Some association with risk factors/protective factors for PD
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
9The screen versions of these slides have full details of copyright and acknowledgements
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Imaging markers
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Studies in the PD prodrome
• HAAS – population-based, longitudinal study,
risk factors for PD
• TREND – limited early features of PD, regular assessments
(movement, laboratory, imaging)
• P-PPMI – LRRK2, abnormal DATSCAN, RBD,
ansomia, followed like those in PPMI
• PARS – smell for screening, then further assessment
including DATSCAN
Berg et al., Defining At Risk Populations for Parkinson’s disease: Lessons from Ongoing Studies, Mov Disord 2012
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PREDICT-PD
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
10The screen versions of these slides have full details of copyright and acknowledgements
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PREDICT-PD (2)
Outcome Top 100Bottom
100
p-value (group
comparison)
All subjects
(n = 1326)
p-value
(regression)
UPSIT score
(median, IQR)30 (28-33) 33 (31-36) <0.001 32 (29-34) <0.001
RBDSQ score
(median, IQR)2 (1-4) 2 (0-3) 0.016 2 (1-3) <0.001
Finger taps
in 30 secs
(mean, 95% CI)
54.7
(52.6-56.7)
58.1
(55.4-60.9)0.045
56.5
(55.9-57.2)0.001
JNNP 2013
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Early features of atypical Parkinsonism
Slide prepared with Dr. Helen Ling
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Multiple system atrophy
• Wenning, Brain 1994. Analysis of 100 cases.
Initial clinical feature:
� Autonomic (46%)
� Parkinsonism (41%)
� Cerebellar signs (5%)
� Mixed (7%)
� Parasomnia (1%)
Slide prepared with Dr. Helen Ling
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
11The screen versions of these slides have full details of copyright and acknowledgements
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Multiple system atrophy (2)
Current diagnostic criteria
(Gilman Neurology 2008)
• Sporadic, progressive,
adult disorder
• Autonomic failure
(incontinence or objective
orthostatic hypotension)
And
• Parkinsonism
(poor L-dopa response)
Or
• Cerebellar signs
Slide prepared with Dr. Helen Ling
‘Red flag’ features supportive of MSA:
• Rapid progression (wheelchair)
• Antecollis
• L-dopa induced fixed orofacial dystonia
• Severe dysarthria or dysphonia
• Jerky action tremor
• Polyminimyoclonus
Others:
• Cold hands, Raynaud’s phenomenon
• REM sleep behaviour disorder (early sign)
• New snoring, sleep apnoea
• Inspiratory stridor/sighs
• Pisa syndrome
• Emotional incontinence (MSA & PSP)
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Multiple system atrophy (3)
Slide prepared with Dr. Helen Ling
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Progressive supranuclear palsy
Presenting complaints
• ‘Withdrawn’
• ‘Depressed’
• ‘Blurred vision’
• ‘Difficulty judging distance’
• ‘Dizziness’
• ‘Falling backward’
• ‘Unsteady’
Misdiagnosis
• Depression
• Early dementia
• Vestibular balance disorders
• Stroke
• Cervical spondylosis
• Cerebellar lesion
• Parkinson’s disease
Slide prepared with Dr. Helen Ling
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
12The screen versions of these slides have full details of copyright and acknowledgements
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Progressive supranuclear palsy (2)
Diagnostic criteria (all 5 of):
(Litvan, Neurology 1996)
• Gradually progressive disorder
• Onset at age 40 or later
• No evidence for competing
diagnostic possibilities
• Vertical gaze palsy
• Slowing of vertical saccades
and prominent postural instability
with falls in the first year
Suggestive findings:
Gait
• Broad-based and brisk
• Gun-slinger
• Dancing bear
Eyes
• Square wave jerks
• Slowed vertical saccades
• Round the houses
• Vertical gaze palsy
with Doll’s eye correction
Slide prepared with Dr. Helen Ling
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Progressive supranuclear palsy (3)
Kuniyoshi and Leigh et al., Ann.N.Y.Acad.Sci., 2002Slide prepared with Dr. Helen Ling
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Imaging in MSA and PSP
MSA
• Pontine atrophy
• Hot cross bun
• Cerebellar atrophy
• T2 hyperintensity in MCP
PSP
• Midbrain atrophy
• Hummingbird/penguin sign
• Morning glory sign
• SCP atrophy
Massey, Mov Disord 2012
Early Clinical Features of Parkinson’s
Disease and Related Disorders
Dr. Alastair Noyce
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Conclusion
• Neurodegenerative diseases have a prodromal phase
in which pathology is accumulating but the diagnosis
is yet to be made
• For PD in particular the prodromal phase is likely long
and offers ample time for intervention
• Prodromal or pre-diagnostic are preferable terms to premotor
• Understanding the pre-diagnostic phase and characterising
objective markers is likely to be pivotal in advancing
the treatment of PD and related disorders
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