Neuropathological analisys and clinical correlates of chronic constipation in patients with parkinson’s disease

Chronic constipation (CC) represents one of the most common gastrointestinal (GI) complaint in Parkinson’s disease (PD), being diagnosed in about 80% of patients. Furthermore, CC is one of the earlier manifestations of PD, often preceding the somatic motor impairment. The enteric nervous system (ENS), controlling gut functions, can be a target of the PDrelated degenerative processes as Lewy bodies and neurites can be detected in myenteric and submucosal neurons of PD tissue specimens. However, the precise neurochemical ENS abnormalities underlying CC/PD patients remain largely unknown. Our aims in CC/PD patients were to: 1) characterize constipation by assessing colonic transit time (TT) and anorectal manometry (AM); 2) analyze colonic submucosal neurons of PD patients vs controls, particularly assessing the secretomotor neuron component. GI symptoms were evaluated by the Rome III questionnaire, while PD was established by a Unified Parkinson’s Disease Rating Scale (part III). CC was completely studied in 16 PD patients (7F, 9M; age range: 64-85 yrs) by TT and AM and colonoscopy; 10 control subjects (3F, 7M; age range: 33-77 yrs) undergoing screening colonoscopy were also enrolled in the study. Using routine biopsies during colonoscopy, we obtained submucosal specimens with related neural network in 10 CC/PD patients and 10 controls. The submucosal plexus was studied by immunohistochemistry on whole mount preparations using a mouse monoclonal anti-HuC/D as pan-neuronal marker (Invitrogen, 1:50) and a rabbit polyclonal anti-VIP (vasoactive intestinal peptide-7913; CURE/DDRC, UCLA, 1:2500) antibodies. Four groups of CC/PD patients were characterized: a) 47% showed a delayed TT and altered AM; b) 20% had only a delayed TT; c) 20% only an altered AM; d) the remaining 13% had no evident functional impairment. There were no significant differences in the number of HuC/D immunoreactive (-IR) neurons/ ganglion between CC/PD (3.6±1.2) and controls (3.8±1.9); however, a reduced number of VIP-IR neurons was found in CC/PD (74.4±19.9) vs controls (91.0±11.5). Most (87%) of CC/PD patients has a marked impairment of colonic motor and rectal sensory functions. Neurochemical changes in a subset of secretomotor neurons suggest that altered secretory mechanisms may accompany sensorymotor dysfunction in PD-related CC pathophysiolog