The pre-diagnostic phase of Parkinson s

Transcription

1 The pre-diagnostic phase of Parkinson s Disease Anthony Schapira London, UK GPSRC CNS RTG 1

2 Early diagnosis is it possible? Clinical i l evaluation Imaging Gene testing Biochemistry GPSRC CNS RTG 2

3 Early diagnosis does it matter? Diagnosis i for diagnosis i sake Testing neuroprotective drugs Prescribing neuroprotective drugs GPSRC CNS RTG 3

4 Pre-symptomatic period of PD? Clinical i l clues range from 3 8 years Pathological clues suggest 7 8 years Imaging g clues suggest 7 8 years Genetic causes can be decades GPSRC CNS RTG 4

5 Symptoms of PD Motor symptoms Rest tremor Rigidity Bradykinesia Non-motor symptoms Sensory phenomena Loss of smell REM behaviour disorder (RBD) Depression Dementia Autonomic dysfunction GPSRC CNS RTG 5

6 Diagnostic markers for PD Unilateral l onset (asymmetry) Bradykinesia Rigidity Resting tremor Good and sustained response to dopaminergic therapy GPSRC CNS RTG 6

7 Non-motor symptoms at presentation of PD 21% had only NMS at first visit it median to PD diagnosis i is 1.6 years vs 1.0 years Pain in 53% Urinary problems 16.5% Depression or anxiety 12% Non-specific cognitive impairment 5.5% No difference in time to hallucinations (10 years), dyskinesias (8 years), duration of PD to death (14 years) or age at death (75 years) O Sullivan et al. Mov Disord 2008;23: GPSRC CNS RTG 7

8 Diagnosis of PD Primary care and general physicans accuracy is about 60% Neurologist s s accuracy about 85% Movement disorder specialists: 99% (accuracy in first 4 years 75%) Hughes et al. Brain 2002;125: GPSRC CNS RTG 8

9 Pre-symptomatic markers of PD Olfactory loss Depression REM sleep disorder Constipation GPSRC CNS RTG 9

10 Hyposmia in PD 361 asymptomatic ti relatives of PD patients t 11% hyposmic (40 relatives) 18% of hyposmics (7 patients) had abnormal SPECT 5 patients had worse single photon emission computed tomography (SPECT) at 2 years 10% (n=4) of hyposmic 1 st degree relatives developed PD within 2 years ( 1% all relatives) Ponsen et al. Ann Neurol 2004;56: GPSRC CNS RTG 10

11 Conclusions Hyposmia in asymptomatic ti relatives of patients t with PD is associated with a 10% risk of developing PD Increased rate of binding decline in another 5 patients may increase the risk to as high as 22% Honolulu study: hyposmia <25% Odds ratio 5.2 (10/549); 25 50% Odds ratio 3.1 within 4 years Intact olfactory function lowers the risk of developing e PD (no higher than general population) Webster Ross et al. Ann Neurol 2007;63; GPSRC CNS RTG 11

12 Depression in PD Depression or panic attacks may precede the onset of motor symptoms in up to 44% Mean period of depression preceding PD was 5 years. Patients were younger, less impaired and had positive family history Santamaria et al. J Neurology 1986;36: GPSRC CNS RTG 12

13 Constipation as a risk factor for PD 24 years prospective follow-up data from 6790 men aged years 96 incident cases of PD Relative risk (RR) for PD (adjusted for age and risk factors) significantly increased in males with < 1 bowel movement per day vs 1 bowel movement per day: RR = 2.7 vs 2 bowel movements per day: RR = 4.1 vs > 2 bowel movements per day: RR = 4.5 Abbott et al. Neurology 2001;57: GPSRC CNS RTG 13

14 RBD and Parkinsonism Approx. 30% of PD may develop RBD Idiopathic RBD strongly associated with neurodegeneration: 19 38% at 5 years and 40 60% at 10 years approx. 50% PD PD patients with RBD: akinetic rigid type, more autonomic problems and cognitive impairment Gagnon et al. Lancet Neurol 2006;5:424 32; Iranzo et al. Lancet Neurol 2006;5:572 7; Schenck et al. Neurology 1996;46:388 93; Postuma et al. Neurology 2006;66: GPSRC CNS RTG 14

15 A UP PDRS Score UPDRS Part III B umber Alternate Tap Test N of Taps Alternate Tap Test RBD Control o RBD Control o C 20 Purdue PegBoard D 14 Timed Up and Go umber of Pegs N Time (S Seconds) RBD Control RBD Control Adapted from Postuma et al. Neurology 2006;66: GPSRC CNS RTG 15

16 Olfactory discrimination The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 16

17 Vision (colour) The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 17

18 Colour hue and other factors The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 18

19 Motor speed correlates with hyposmia The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 19

20 New interpretation of Braak hypothesis: PD is a prion disease The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 20

21 Favourable factors The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 21

22 Early diagnosis is it possible? Clinical i l evaluation Imaging Gene testing Biochemistry GPSRC CNS RTG 22

23 Early diagnosis is it possible? Clinical i l evaluation Imaging Gene testing Biochemistry GPSRC CNS RTG 23

24 Inherited Parkinsonism The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 24

25 LRRK2 mutation worldwide prevalence The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 25

26 Healy line graph The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 26

27 Healey Kaplan Meier Healy et al. Lancet Neurol 2008;7: GPSRC CNS RTG 27

28 Gluecocerbrosidase mutations The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 28

29 Early diagnosis is it possible? Clinical i l evaluation Imaging Gene testing Biochemistry (urate) GPSRC CNS RTG 29

30 Common pathways underlying PD pathogenesis The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 30

31 Early diagnosis is it possible? Clinical evaluation Imaging Gene testing Biochemistry GPSRC CNS RTG 31

32 Incidence rate line graph The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 32

33 Kempster graph The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS RTG 33

34 Conclusions Even with current criteria, diagnosis of PD is only 75% accurate at presentation Certain non-motor features precede motor deficits, but none are specific for PD Combinations help enrich a population, but numbers converting to PD are small Genetic factors are uncommon and penetrance variable Heterogenicity of PD aetiology will confound early markers Ultimately, PD risk will likely be estimated by a complex of genetic and phenotypic (clinical and biochemical) markers and imaging GPSRC CNS RTG 34

35 Copyright statements Slide 16 Slide , reproduced with permission from Wolters Kluwer Health 2008, reproduced with permission from Elsevier 35