1. Parkinson’s disease – diagnosis in the bowel? David Hilton Department of Cellular and Anatomical Pathology, Derriford Hospital, Plymouth

2. Parkinson’s disease Affects >100,000 in UK Progressive bradykinesia, tremor and rigidity Results in neuronal degeneration in regions of the brain with loss of dopamine Symptoms develop with 70-80% neuronal loss Rare genetic forms ?Toxins (MPTP, rotenone) Treatment with L-DOPA

3. Pathology Parkinson’s disease Normal  synuclein

4. Peripheral features Also postural hypotension, urinary urgency and erectile dysfunction Lewy bodies and  -synuclein accumulation in myenteric plexus (oesophagus-rectum), sympathetic ganglia, vagus nerve, cardiac sympathetic nerves, cutaneous fibres, adrenal and salivary glands ‘The bowels, which had been all along torpid, now, in most cases, demand stimulating medicines of very considerable power: the expulsion of the faeces from the rectum sometimes requiring mechanical aid’.

5. Aims Investigate the prevalence of  -synuclein pathology in gastrointestinal biopsies from PD patients, including in the preclinical phase, and assess its specificity.

6. Methods Identify PD patients from medical coding Cross reference with pathology database Identify matching controls All case notes reviewed to ensure clinical diagnosis of PD in cases and to exclude symptoms in controls Retrieve bowel biopsies taken post and pre diagnosis Immunocytochemistry antibodies to phosphorylated  -synuclein and to non-phosphorylated  -synuclein S100 protein used to confirm nerve fibres in biopsy All sections evaluated blind to diagnosis

7. PD10 Colonic biopsy 2010 - 4 years after onset pSN SN

8. PD10 Duodenal and colonic biopsies 2005 - 1 years prior to onset pSN

9. PD10 Colonic biopsy 1999 - 7 years prior to onset pSN

10. Results 133 case notes reviewed, 66 fulfilled criteria for PD, 4 patients excluded due to lack of nerve fibres in biopsies 117 gastrointestinal biopsies included from 62 patients with PD, and matching controls 12 positive biopsies (10%) from 7 PD cases (11%) All controls negative

11. CasePD diagnosisPositive biopsiesReason for biopsyAutonomic symptoms PD320071999 (gastric)Upper abdominal pain Postural hypotension 2007 Constipation 2010 PD102006 2010 (colonic) 2007 (rectal) 2005 (duodenal) 2005 (colonic) 1999 (colonic) Diarrhoea Anaemia Diarrhoea Postural hypotension 2005 Constipation 2007 PD30 2006 (tremor 2005) 2010 (colonic) Abdominal pain, weight loss Postural hypotension 2010 Constipation 2006 PD42 1995 (tremor 1993) 2010 (gastric)Reflux Postural hypotension 1995 Impotence 1995 PD85 2008 (tremor 2006) 2000 (gastric) 2006 (colonic) Vomiting Diarrhoea Postural hypotension 2005 PD100 2002 (tremor 2000) 2007 (colonic)Diarrhoea Postural hypotension 2001 Constipation 2008 PD11220092012 (duodenal)AnaemiaPostural hypotension 2009 Constipation 2009

12. SiteNumber testedPositive Oesophageal80 Gastric353 (9%) Duodenal152 (13%) Colorectal537 (13%) Gall bladder60

13. Time of biopsyNumber testedPositive Post-diagnosis656 (9%) 0-5 years pre-diagnosis293 (10%) 6-10 years pre-diagnosis183 (17%) >10 years pre-diagnosis50

14. Conclusions Bowel biopsy may be helpful in confirming the diagnosis of PD or identifying at risk individuals Bowel pathology occurs at least 8 years prior to the onset of classical PD symptoms Consistent with gastrointestinal origin for PD Bowel may offer a site to study the early phases of the disease and to monitor response to treatments

15. Acknowledgements Cellular Pathology Maddie Stephens Leanne Kirk Ross Potter Phil Edwards Neurology/PUPSMD John Zajicek Ellie Broughton Hannah Hagan Camille Carroll Grant from the South West Neurosciences Association