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

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

Pathology Parkinson’s disease Normal  synuclein

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’.

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

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

PD10 Colonic biopsy years after onset pSN SN

PD10 Duodenal and colonic biopsies years prior to onset pSN

PD10 Colonic biopsy years prior to onset pSN

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

CasePD diagnosisPositive biopsiesReason for biopsyAutonomic symptoms PD (gastric)Upper abdominal pain Postural hypotension 2007 Constipation 2010 PD (colonic) 2007 (rectal) 2005 (duodenal) 2005 (colonic) 1999 (colonic) Diarrhoea Anaemia Diarrhoea Postural hypotension 2005 Constipation 2007 PD (tremor 2005) 2010 (colonic) Abdominal pain, weight loss Postural hypotension 2010 Constipation 2006 PD (tremor 1993) 2010 (gastric)Reflux Postural hypotension 1995 Impotence 1995 PD (tremor 2006) 2000 (gastric) 2006 (colonic) Vomiting Diarrhoea Postural hypotension 2005 PD (tremor 2000) 2007 (colonic)Diarrhoea Postural hypotension 2001 Constipation 2008 PD (duodenal)AnaemiaPostural hypotension 2009 Constipation 2009

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

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

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

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