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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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)



Dr. Alastair Noyce


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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



Dr. Alastair Noyce


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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



Dr. Alastair Noyce


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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



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



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)



Dr. Alastair Noyce


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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



Dr. Alastair Noyce


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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



Dr. Alastair Noyce


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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



Dr. Alastair Noyce


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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%)




Dr. Alastair Noyce


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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


‘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)


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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




Dr. Alastair Noyce


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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


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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



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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dr. alastair noyceearly clinical features of parkinson’s disease and related disorders dr....

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