A survey of subjective constipation in Parkinson’s disease patients in shanghai and literature review

Abstract Background Constipation is one of the most frequent non-motor symptoms (NMS) in Parkinson’s disease (PD) and the prevalence of constipation in PD patients varies among different studies. We designed this study to survey the prevalence and clinical characteristics of subjective constipation and the appearance chronology between the emergence of constipation and onset of motor symptoms in PD patients from Shanghai, China. Methods 268 PD patients were continuously recruited into this study. Parkinson’s related clinical information of the participants was collected. A spectrum of motor and nonmotor features was assessed with scales and questionnaires. Subjective constipation was defined by ROME III criteria. Results 54.10% PD patients suffer from constipation. Among them, there was 47.59% having constipation before onset of motor symptoms. Compared with patients without constipation, patients with constipation reported lower daily water intake and less exercise, and were dominated by bradykinetic-rigid motor phenotype at onset and were prone to have anxiety, depression and insomnia. The time span between constipation and the onset of motor symptoms was (6.62 ± 9.32) years. Constipation occurred more frequently between 2 and 10 years before onset of motor symptoms. Patients suffering with constipation were then divided into two groups according to the time sequence of constipation and motor onset: ‘constipation pre-motor sign’ group and ‘constipation post-motor sign’ group. Total timespan from earliest initial symptoms to present was similar. Compared with ‘constipation post-motor sign’ group, the patients in ‘constipation pre-motor sign’ group experienced an older motor symptoms onset age, less serious motor symptoms, more serious constipation and less daily levodopa dosage. Conclusions Our results supported that constipation could be a pre-motor symptom of PD. Different clinical characteristics were found in different constipation-loading time relative to motor symptoms. Research of constipation may be useful to better understand the early stages of PD and assessment of constipation with validated criteria may have utility as a risk factor for predicting PD in the prodromal phase

Intranasal LPS-mediated Parkinson's model challenges the pathogenesis of nasal cavity and environmental toxins.

Accumulating evidence implicates the relationship between neuroinflammation and pathogenesis in idiopathic Parkinson's disease (iPD). The nose has recently been considered a gate way to the brain which facilitates entry of environmental neurotoxin into the brain. Our study aims to build a PD model by a natural exposure route. In this report, we establish a new endotoxin-based PD model in mice by unilateral intranasal (i.n.) instillation of the lipopolysaccharides (LPS) every other day for 5 months. These mice display a progressive hypokinesia, selective loss of dopaminergic neurons, and reduction in striatal dopamine (DA) content, as well as α-synuclein aggregation in the SN, without systemic inflammatory and immune responses. This new PD model provides a tool for studying the inflammation-mediated chronic pathogenesis and searching for therapeutic intervention in glia-neuron pathway that will slow or halt neurodegeneration in PD

Western blot analyses of TH and ChAT in protein extracts from the left and right sides of the SN in mice challenged with right intranasal LPS (10 µg/every other day) or saline administration of for 5 months.

<p>Semi-quantification of relative TH and ChAT protein was obtained from among at least six different animals. *<i>P</i><0.05 and ***<i>P</i> <0.01 compared with the contralateral SN and saline control, respectively. </p

Pathological changes in the olfactory bulb in mice subjected to chronic i.n.

<div><p><b>LPS administration</b>. </p> <p>A) dopaminergic neurons (green) and α-synuclein accumulation (red) around the olfactory bulb in the mice challenged with right intranasal LPS administration of 10 µg/ every other day for 5 months. a) magnification of 4×, scale bar is 2mm; b),c),d) magnification of 10×, d) merge of a,b,c, scale bar is 500 μm; B) Immunohistochemical evidence for CD11b (red) expression in the olfactory bulb of mice challenged with right intranasal LPS administration of 10 µg/ every other day for 5 months. a) CD11b; b) nucleus; c) merged; scale bar is 500 μm.</p></div

Accumulation and aggregation of α-synuclein were determined by Western blot and immunostaining.

<p>a) Western blot, semi-quantification of α-synuclein protein was shown in histogram. b) Three-labeled immunofluorescence (Green=TH; Red=α-synuclein and Blue=Hochest) and quantitative analysis of α-synuclein⁺ cells within the rectangles; scale bar is 2 mm. c) Accumulation and aggregation of α-synuclein in the SN. The expression of insoluble α-synuclein (red) after PK treatment around the nucleus (blue); scale bar is 200 μm. Semi-quantification of α-synuclein protein was obtained from among at least six different animals. *<i>P</i><0.05 compared with the contralateral SN and saline control, respectively. </p

Behavioral alteration in mice with chronic i.n. LPS administration.

<p>a) The ambulatory motility (VM=voluntary movement), Motor behavior was analyzed in an open-field test at the 1st, 3rd and 5th months after LPS instillation. b) Adhesive removal test, the asymmetry of left and right movement was detected by the adhesive removal test at the 5th month after LPS instillation. c) Latency to find platforms (from day 1 to day 5), the cognition was measured by Morris water maze at the 5th month after LPS instillation. Left=time to remove adhesive dots from left forelimb; Right= time to remove adhesive dots from right forelimb. Bars indicate SD for 7-10 mice at each point. *<i>P</i><0.05 compared with the contralateral side and/or saline control, respectively. </p

Pathological changes in mice subjected to chronic i.n. LPS administration.

<p>a) Loss of dopaminergic neurons in the SN of mice challenged with right intranasal LPS administration of 10 µg/ every other day for 5 months; b) DA neurons in the VTA region on both sides; c) Representative photomicrographs illustrating TH immunoreactivity in the striatum; d) Neurons in the hippocampus and cortex were immunostained with anti-NeuN antibodies. Bars indicate SD for 7-10 mice. **<i>P</i><0.01 compared with contralateral side and saline control, respectively; scale bar is 2 mm. </p

The influence of peripheral immune on mice with chronic i.n. LPS.

<p>At the 5th month after LPS inoculation, mice were sacrificed and splenic mononuclear cells and the serum were isolated. The viability of T cells, oxidation products and inflammatory cytokines from spleens were detected in the presence and/or absence of α-synuclein stimulation by MTT, Nitrite and ELISA assays, respectively. Inflammatory cytokines from the serum were detected by ELISA assays. a) The viability of T cells; b) NO production, c) The secretion of inflammatory cytokines IL-1β, IL-6 and TNF-α; d) the secretion of Th1 IFN-γ, Th2 IL-10 and Th17 IL-17 and e) The secretion of inflammatory cytokines IL-1β, IL-6, IL-10 and TNF-α from the serum of the mice. There was no statistical significance between and within two groups. Determinations were performed in duplicate and results were expressed as mean±S.E.M. from at least six mice.</p