Early Clinical Features of Parkinson s Disease and Related Disorders. Dr. Alastair Noyce

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1 1 Specialist Registrar in Neurology, London Deanery Parkinson s UK Doctoral Research Fellow Project lead for PREDICT-PD Declarations Salary: Parkinson's UK, Barts and the London NHS Trust Grants: Parkinson's UK (F-1201, K-1006), GE Healthcare, Elan/Prothena Pharmaceuticals 2 Topics for discussion General concepts Parkinson's disease Early non-motor features Early motor features Parkinson's plus (multiple system atrophy, progressive supranuclear palsy) 3 1

2 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 4 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. 5 General concepts: subclinical decline 6 2

3 General concepts: heterogeneity 7 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. 8 Parkinson s disease 4 million worldwide in 2005, 9 million by 2030 (Dorsey, Neurology 2007) 2 nd most common neurodegenerative disorder Diagnosis based on motor signs (Gibb, JNNP 1989) 9 Motor features arise once there is 50-60% loss of cells 3

4 Fearnley & Lees, Brain Normal Aging 4.7% loss per decade Fearnley & Lees, Brain 1991 PD 45% loss first decade Braak, Neurobiol Aging DMV, Olfactory bulb 2. Locus coeruleus 3. Substantia nigra 4. Mesocortex 5. Neocortex 6. Further neocortex PD 69 ILD 58 controls Braak, Neurobiol Aging 2003 Parkinson s disease timeline 12 Hawkes, Park Relat Disord

5 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) 13 Non-motor features of PD Smell disturbance Sleep disturbance Autonomic dysfunction Mood change Cognitive change 14 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 [ 123 I] 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 15 c. Other hyposmic subjects had accelerated decline in SPECT 5

6 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 [ 123 I] FP-CIT SPECT, which showed pathological appearances in 5 subjects 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) 16 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 17 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) 18 6

7 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 19 Other early non-motor features Erectile dysfunction Urinary symptoms Pain Voice 20 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 21 7

8 Motor 22 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 Postuma, Brain with idiopathic RBD were included 20 developed Parkinsonism Matched with controls (1:2) Multiple motor assessments Postuma, Brain 2012 UPDRS becomes abnormal 4.5 years before diagnosis 23 Order of involvement: voice>face>bradykinesia>rigidity>gait>tremor 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 24 8

9 Imaging markers 25 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 26 Berg et al., Defining At Risk Populations for Parkinson s disease: Lessons from Ongoing Studies, Mov Disord 2012 PREDICT-PD 27 9

10 PREDICT-PD (2) JNNP 2013 Outcome Top 100 UPSIT score (median, IQR) RBDSQ score (median, IQR) Bottom 100 p-value (group comparison) All subjects (n = 1326) p-value (regression) 30 (28-33) 33 (31-36) < (29-34) < (1-4) 2 (0-3) (1-3) < Finger taps in 30 secs (mean, 95% CI) 54.7 ( ) 58.1 ( ) ( ) Early features of atypical Parkinsonism 29 Multiple system atrophy Wenning, Brain Analysis of 100 cases. Initial clinical feature: Autonomic (46%) Parkinsonism (41%) Cerebellar signs (5%) Mixed (7%) Parasomnia (1%) 30 10

11 Multiple system atrophy (2) 31 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) Multiple system atrophy (3) 32 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 33 11

12 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 34 Progressive supranuclear palsy (3) 35 Kuniyoshi and Leigh et al., Ann.N.Y.Acad.Sci., 2002 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 36 Massey, Mov Disord

13 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