Circadian variation of rectal sensitivity and gastrointestinal peptides in healthy volunteers.

The aim of our study was to identify diurnal variation of perception of rectal distension and the release of gastroenteropancreatic hormones. In 12 healthy male volunteers (25 years, range 22-32), a rectal balloon distension was performed. Rectal perception thresholds (minimal, urge and pain) and rectal compliance were double-measured with a computer-controlled barostat at seven standardized time points during the day (from 16.00 to 14.00 hours the following day). Blood samples were taken 30 min before and after each rectal distension procedure to determine plasma levels of cholecystokinin (CCK), pancreatic polypeptide (PP) and motilin. Sensory thresholds for urge and pain varied significantly with the time of day, with higher threshold levels in the evening than in the morning hours. Bowel wall compliance showed as well-significant variance at pain threshold and was higher during daytime than in the evening or at night. In contrast to motilin, release of CCK and PP also showed a significant variation depending on daytime. Perception of rectal distension stimuli as well as compliance was independent of intake of food and peptide hormone levels, but CCK and PP levels increased with food, and PP levels decreased with rectal distension. Significant differences in the perception of rectal distension stimuli for urge and pain depending on daytime were found, but the release of gastrointestinal peptides seemed not to be involved. This circadian variation needs to be taken into account in patients and volunteer studies.

Effects of euglycemic hyperinsulinemia and lipid infusion on circulating cholecystokinin.

AIMS: Functions of the gut hormone cholecystokinin (CCK) include an important role in the regulation of gastric emptying, postprandial glucose homeostasis, and postmeal satiety. Postprandial CCK responses are significantly blunted in type 2 diabetic patients by unknown mechanisms. We hypothesized that hyperinsulinemia and lipid infusion influence circulating levels of biologically active CCK. METHODS: Eleven healthy subjects were studied in a cross-over design after 10-h overnight fasts, using euglycemic-hyperinsulinemic clamps for 443 min, with an additional infusion of lipid-heparin (1.25 ml.min(-1)) or saline (1.25 ml.min(-1)) for the last 300 min after constant plasma glucose levels were achieved. RESULTS: Euglycemic-hyperinsulinemia resulted in a sustained, up to 5-fold increase of plasma CCK (P < 0.001). When adding lipid infusion instead of saline, CCK concentrations rapidly declined and returned to baseline levels (CCK(300 min) 1.1 +/- 0.2 vs. 3.3 +/- 0.3 pmol/liter, P < 0.001). Partial intraclass correlation showed an independent correlation of plasma CCK with free fatty acids (r(ic) = -0.377, P < 0.001) but not with serum insulin (r(ic) = 0.077, P = 0.32). Whole-body insulin sensitivity decreased in lipid-exposed subjects (M value 7.1 +/- 0.7 vs. 5.6 +/- 0.9 mg.kg.min(-1), P = 0.017) but was not independently correlated with CCK (r(ic) = 0.040, P = 0.61). CONCLUSIONS: We report novel findings showing that circulating CCK markedly increased in the euglycemic-hyperinsulinemic state, possibly as a result of near-complete suppression of circulating free fatty acids. Moreover, raising blood lipids even moderately by lipid infusion rapidly and significantly interfered with this effect, suggesting that a negative feedback mechanism of blood lipids on circulating CCK might exist.

Peptide YY release in anorectic patients after liquid meal.

Fasting and postprandial levels of human peptide YY (PYY) were recently found to be lower in obesity. To investigate whether PYY levels are correspondingly high in patients with anorexia nervosa, PYY concentrations were analyzed under basal conditions and in response to a liquid meal. We investigated PYY plasma levels in 16 female anorectic (BMI 15.2+/-0.3 kg/m2) and seven lean subjects (BMI 21.3+/-0.6 kg/m2) before and after ingestion of a liquid meal (250 kcal; 15% protein, 55% carbohydrates, and 30% fat). PYY levels were analyzed using PYY ELISA (DSL, USA). Values are given as mean+/-SEM. Basal PYY levels in anorectic patients (89.0+/-14.4 pg/mL) were not significantly different from lean subjects (64.1+/-12.1 pg/mL). Postprandial PYY levels in healthy volunteers increased significantly after 20 and 60 min (80.4+/-12.7 and 96.0+/-19.9 pg/mL, respectively). In anorectic women PYY was increased at 20 min (137.9+/-19.5 pg/mL) and at 60 min (151.3+/-19.2 pg/mL). No difference was found between both groups. We conclude that basal and postprandial PYY levels in normal weight women are not different from anorectic patients. We could not confirm the recently published blunted postprandial PYY response in anorexia, a finding that merits further study.

mu-Opiate receptor agonist loperamide blocks bethanechol-induced gallbladder contraction, despite higher cholecystokinin plasma levels in man.

UNLABELLED: mu-Opiate receptor agonists, such as loperamide, influence biliary excretion and suppress cholecystokinin (CCK)-induced gallbladder contraction. Loperamide decreases cholinergic mechanisms, like pancreatic polypeptide (PP) release, while muscarinic agonist (bethanechol)-induced PP release remains unaffected. The effects of loperamide on gallbladder contraction and peptide release were performed to resolve this discrepancy. METHODS: Six subjects (27.6 +/- 2.0 years) received bethanechol (12.5, 25 and 50 microg kg(-1) h(-1) continuously over 40 min) after oral 16 mg loperamide (vs placebo) in a crossover design. Gallbladder volume and plasma levels of CCK, PP, motilin, gastrin, neurotensin, cholylglycine were measured regularly. RESULTS: Bethanechol significantly reduced gallbladder volume (26.7 +/- 1.9 to a nadir of 15.3 +/- 2.2 mL, P < or = 0.05), and this action was inhibited by loperamide. Basal CCK levels increased significantly after loperamide. Incremental integrated CCK release after bethanechol was higher under loperamide (P < or = 0.05), as placebo CCK release was significantly decreased under bethanechol (2.0 +/- 0.4-0.8 +/- 0.3 pmol L(-1)). In both settings, PP levels were significantly increased after bethanechol, while release of neurotensin, motilin, gastrin and cholylglycine was unaffected. CONCLUSION: The mu-opiate receptor agonist loperamide inhibits bethanechol-induced gallbladder contraction. This effect is not mediated by inhibition of CCK release, as loperamide even enhances basal CCK plasma levels. As cholinergic mechanisms, like bethanechol-induced incremental PP release, were unaffected, mu-opiate agonists might influence gallbladder contraction via vagal-cholinergic pathways.

Gastric emptying of solid and liquid meals in healthy controls compared with long-term type-1 diabetes mellitus under optimal glucose control.

BACKGROUND: Neuropathy of the enteric nervous system and hyperglycaemia are regarded as the main causes of diabetic gastroparesis. PATIENTS AND METHODS: In ten patients with Type-1 diabetes mellitus and sensomotoric neuropathy gastric emptying half times were compared with ten healthy controls by employing the 13C-octanoic acid and the 13C-sodiumacetate breath test, resp., following the intake of equally composed and isocaloric liquid and solid meals. Plasma glucose concentrations were controlled by permanent intravenous administration of insulin. RESULTS: In diabetes mellitus gastric emptying half times after the intake of the liquid meal (p < 0.05) but not after ingestion of the solid meal were slightly prolonged. Gastric emptying half times in patients and controls were not different when liquid and solid meals were compared. CONCLUSIONS: Acute hyperglycaemia appears to be more important than the neuropathy of the enteric nervous system in the pathophysiology of diabetic gastroparesis. The rate of gastric emptying is obviously not dependent on the phase of a meal, but rather on the composition and the caloric content.

Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa.

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.

Post-prandial decrease of circulating human ghrelin levels.

Ghrelin, an endogenous ligand of the GH secretagogue-receptor, has recently been shown to stimulate GH secretion and to have orexigenic and adipogenic effects in rodents, but little is known about its regulation and biological function in humans. Gastric motor function is under control of the central nervous system; however, the afferent and efferent loops of this feedback control mechanism remain to be elucidated. In the study presented here we investigated the effect of nutrient intake on circulating human ghrelin levels, and a possible association between ghrelin levels and gastric emptying. Ten healthy volunteers received a standard meal after an overnight fast. Food intake significantly decreased plasma ghrelin levels from 248.5 +/- 15.0 to 179.5 +/- 17.9 fmol/ml (120 min after meal, p=0.047). Gastric emptying half-time (non-invasive 13C-octanoic acid breath test) was correlated with fasting plasma ghrelin levels (r=0.74, p=0.0013). Ghrelin appears to be one possible candidate to provide feedback signaling between nutrient intake, gastric motor function and the central nervous system.

Pavlovian conditioning of taste aversion using a motion sickness paradigm.

OBJECTIVE: Pavlovian conditioning of taste aversion has rarely been investigated in healthy humans using motion sickness as the unconditioned stimulus (US). METHODS: Ninety subjects were pretested for susceptibility to illusory motion (vection) in a rotating drum. Thirty-two subjects susceptible to pseudomotion were assigned randomly to two groups and received either water 1 hour before rotation and a novel taste (elderberry juice, conditioned stimulus, [CS]) immediately before rotation in a rotating chair (conditioning group), or the sequence of water and juice was reversed (control group). During the test session 1 week later, all subjects were exposed to water 1 hour before and juice immediately before rotation. The amount of liquids ingested, nausea ratings, rotation tolerance, and blood levels of hormones (ACTH, ADH, PP) were evaluated. RESULTS: Subjects in the conditioning group developed taste aversion toward the novel taste, but not subjects in the control group. Postrotation nausea rating was affected marginally by conditioning, but rotation tolerance was not changed by conditioning. ACTH and ADH but not PP levels increased with rotation, but were unaffected by conditioning. CONCLUSIONS: Pavlovian conditioning of behavioral, but not of endocrine, indicators was effective in susceptible subjects using a rotating chair as US and a single CS-US pairing.

Accuracy of 13C-urea breath test in clinical use for diagnosis of Helicobacter pylori infection.

UNLABELLED: The 13C-urea breath test (UBT) is a noninvasive test for diagnosis of Helicobacter pylori infection of gastric mucosa. The aim of this prospective study was to assess the accuracy of a simple UBT in clinical routine use. METHODS: The study population comprised of 100 patients (49 f, 51 m) requiring diagnostic upper GI endoscopy. One biopsy specimen was taken from the gastric antrum, body and fundus, respectively, for standard histological examination and one additional specimen from each location was transformed into transport medium for cultivation of H. pylori. After vaccination of the culture plates the biopsies were tested for urease activity (UAT). After recovery from endoscopy the patients had to pass an one liter endexspiratory breath sample before and 15 min after drinking 200 ml orange juice, pH 3.6, containing 75 mg of 13C-urea. 13CO2 was measured in the breath samples using isotope-selective nondispersive infrared spectrometry. RESULTS: Defining gold standard groups with all biopsy tests (from antrum and corpus) positive or negative the 13CO2 delta over baseline (DOB) cut-off level of UBT was set at 6.5/1000 in order to best discriminate positive from negative patients (ROC analysis). UBT was positive in 37% of all subjects. Taken UAT and histological examination together (positive when both tests were positive) UBT displayed a sensitivity of 92%, a specificity of 94%, a positive predictive value of 89%, and a negative predictive value of 94%. When including the results of culture sensitivity and negative predictive value reached almost 100%. The mean of the 13CO2-DOB values from H. pylori-positive duodenal or gastric ulcer patients did not differ from controls (H. pylori-positive patients without lesions). The 13CO2-DOB values of the ulcer group were correlated significantly with the active inflammatory component of gastritis in antrum, corpus, and fundus. CONCLUSION: UBT with this setup detects H. pylori infection in clinical routine use with high accuracy. The increase of exhaled 13CO2 does not predict ulcer disease but reflects the degree of active inflammation of gastric mucosa.

Noninvasive (13)C-octanoic acid breath test shows delayed gastric emptying in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons. However, ALS has been recognized to also involve non-motor systems. Subclinical involvement of the autonomic system in ALS has been described. The recently developed (13)C-octanoic acid breath test allows the noninvasive measurement of gastric emptying. With this new technique we investigated 18 patients with ALS and 14 healthy volunteers. None of the patients had diabetes mellitus or other disorders known to cause autonomic dysfunction. The participants received a solid standard test meal labeled with (13)C-octanoic acid. Breath samples were taken at 15-min intervals for 5 h and were analyzed for (13)CO(2) by isotope selective nondispersive infrared spectrometry. Gastric emptying peak time (t(peak)) and emptying half time (t(1/2)) were determined. All healthy volunteers displayed normal gastric emptying with a mean emptying t(1/2) of 138 +/- 34 (range 68-172) min. Gastric emptying was delayed (t(1/2) > 160 min) in 15 of 18 patients with ALS. Emptying t(1/2) in ALS patients was 218 +/- 48 (range 126-278) min (p < 0.001). These results are compatible with autonomic involvement in patients with ALS, causing delayed gastric emptying of solids and encouraging the theory that ALS is a multisystem disease rather than a disease of the motor neurons only.

Gastrointestinal dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of motor neurons. However, ALS has been recognized to involve several non-motor systems. Subclinical involvement of the autonomic system (i.e. of cardial or sudomotor regulation) has been described in ALS. Gastrointestinal motor dysfunction can occur in amyotrophic lateral sclerosis, even if patients do not complain of gastrointestinal symptoms. New techniques in non-invasive evaluation of gastrointestinal function showed delayed gastric emptying and delayed colonic transit times in patients with ALS.

Pancreatic bicarbonate response to intraduodenal tryptophan in dogs: role of muscarinic M1-receptors and cholecystokinin.

CONCLUSIONS: In dogs, 1. Activation of cholecystokinin-receptors is needed for an adequate pancreatic bicarbonate response to secretin; 2. Cholinergic nerve fibers ending on M1-receptors are probably of little or no importance for the bicarbonate response to secretin in the given dose; 3. The bicarbonate response to tryptophan, given with a secretin background, is controlled by cholinergic M1-fibers and by cholecystokinin; 4. M1-fibers mainly mediate the bicarbonate response to low loads of tryptophan, whereas cholecystokinin controls the response to low and high loads of tryptophan; and 5. Both mediators interact in a synergistic manner. METHODS: In six conscious dogs with chronic gastric and duodenal fistulas, we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol/kg/h), the cholecystokinin-receptor antagonist L-364,718 (0.025-0.1 mg/kg/h), and combinations of both on the pancreatic bicarbonate response to graded loads of intraduodenal tryptophan (0.37-10.0 mmol/h), given against a background of secretin (20.5 pmol/kg/h). RESULTS: Secretin significantly (p < 0.05) stimulated the pancreatic bicarbonate output above basal levels. All doses of L-374,718, but not telenzepine, significantly decreased the bicarbonate response to secretin by up to 64%. Additional administration of telenzepine together with L-364,718 had no further inhibitory effect on the secretin-stimulated bicarbonate output as compared to L-364,718 given alone. All loads of tryptophan significantly increased the bicarbonate output over that seen with secretin alone (= incremental bicarbonate response to tryptophan). Telenzepine significantly decreased the incremental bicarbonate response to the two lower loads (0.37-1.1 mmol/h) of tryptophan (by 82-124%); L-364,718 decreased the incremental bicarbonate response to all loads of tryptophan (by 50-118%). The incremental bicarbonate output, as well as the 180-min integrated bicarbonate response to all loads of tryptophan, were abolished by all combinations of both antagonists.

Effects of telenzepine and L-364,718 on canine pancreatic secretion before and after vagotomy.

In six conscious dogs we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol.kg-1.h-1), the cholecystokinin (CCK) antagonist L-364,718 (0.025-0.1 mg.kg-1.h-1), and combinations of both on the pancreatic secretory response to intraduodenal tryptophan, given against a secretin background before and after truncal vagotomy. Before vagotomy, the higher doses of telenzepine and of L-364,718 significantly (P < 0.05) decreased the protein response to tryptophan by up to 97%. After vagotomy, all doses of L-364,718 abolished the protein response, whereas telenzepine had no further effect. Before and after vagotomy, all combinations abolished the protein response. The plasma CCK-like immunoreactivity basally, during secretin, and in response to tryptophan was not altered by vagotomy, telenzepine, and/or L-364,718. These findings indicate that in dogs 1) potentiation exists between M1 receptors and CCK for stimulation of the pancreatic enzyme response to intraduodenal tryptophan, 2) the cholinergic fibers of the enteropancreatic reflex activated by tryptophan run within the vagus nerves and end at least in part on M1 receptors, 3) CCK acts in part independently of the vagal nerves, and 4) the CCK release by intestinal tryptophan is not influenced by vagotomy, telenzepine, and/or L-364,718.

Gastric emptying following pylorus-preserving Whipple and duodenum-preserving pancreatic head resection in patients with chronic pancreatitis.

BACKGROUND: After pylorus-preserving Whipple (PPW), delayed gastric emptying (DGE) is reported in up to 50% of these patients. We analyzed gastric emptying and hormonal adaptation of cholecystokinin (CCK), pancreatic polypeptide (PP), and gastrin following two surgical procedures for chronic pancreatitis (CP): the PPW and the duodenum-preserving pancreatic head resection (DPPHR). METHODS: Ten patients underwent DPPHR and 10 underwent PPW for CP. Preoperatively and 10 days and 6 months postoperatively, gastric emptying (paracetamol absorption test) and CCK, gastrin, and PP were measured using a test meal stimulation. RESULTS: The area under the serum paracetamol time curve for 0 to 120 minutes (AUC) showed no preoperative difference. Ten days postoperatively, the AUC was significantly reduced (P <0.05) after PPW but not after DPPHR. Six months postoperatively, AUC was comparable with the preoperative findings in DPPHR and PPW. The integrated 180-minute PP release was significantly reduced 10 days and 6 months postoperatively in both groups. The integrated 180-minute CCK release was decreased 10 days after PPW, but failed to be significant (P = 0.053). Gastrin levels were postoperatively unchanged. CONCLUSION: Following DPPHR we found no delay in gastric emptying. In contrast, DGE occurs early after PPW. Our data may help explain the slower recovery in PPW patients with regard to weight gain and relief from pain, which may be due to the functional alteration of gastric emptying and motility after this type of surgery.

Alcoholic beverages produced by alcoholic fermentation but not by distillation are powerful stimulants of gastric acid secretion in humans.

BACKGROUND: The effect of commonly ingested alcoholic beverages on gastric acid output and release of gastrin in humans is unknown. AIM AND METHODS: In 16 healthy humans the effect of some commonly ingested alcoholic beverages produced by fermentation plus distillation (for example, whisky, cognac, calvados, armagnac, and rum) or by alcoholic fermentation (beer, wine, champagne, martini, and sherry) on gastric acid output and release of gastrin was studied. Gastric acid output was determined by the method of intragastric titration. Plasma gastrin was measured using a specific radioimmunoassay. RESULTS: None of the alcoholic beverages produced by fermentation plus distillation had any significant effect on gastric acid output and release of gastrin compared with control (isotonic glucose and distilled water). Alcoholic beverages produced only by fermentation significantly (p < 0.05) increased the gastric acid output by 57% to 95% of maximal acid output (MAO) and release of gastrin up to 5.1-fold compared with control. If beer, wine, and sherry were distilled, only their remaining parts increased gastric acid output by 53% to 76% of MAO and increased release of gastrin up to 4.3-fold compared with control. CONCLUSIONS: (1) Alcoholic beverages produced by fermentation but not by distillation are powerful stimulants of gastric acid output and release of gastrin; (2) the alcoholic beverage constituents that stimulate gastric acid output and release of gastrin are most probably produced during the process of fermentation and removed during the following process of distillation.

Mediators of exocrine pancreatic secretion induced by intraduodenal application of bile and taurodeoxycholate in man.

The aim of the study was to investigate whether cholecystokinin, neurotensin, and cholinergic mechanisms act as mediators of bile salt-stimulated exocrine pancreatic secretion. Ten fasting healthy subjects provided with a double-lumen tube received 2, 4, and 6 g cattle bile and 200, 400, and 600 mg Na-taurodeoxycholate (TDC) into the duodenum at 65-min intervals, respectively. The application of TDC was repeated in another 10 subjects after intravenous bolus injection of 2.5 micrograms/kg b.w. atropine followed by continuous infusion of 5 micrograms/kg.h. Secretions of volume, bicarbonate, trypsin, and lipase were determined in 10-min fractions of duodenal juice. Plasma samples were analysed for cholecystokinin-like immunoreactivity (CCK-LI) and neurotensin with radioimmunoassays. Volume, bicarbonate, trypsin, and lipase secretion rates were significantly increased by 4 g and 6 g bile and by all doses of TDC. Incremental volume and bicarbonate output was dose-dependently enhanced by bile and TDC, and trypsin and lipase output by bile. Atropine significantly decreased the baseline values and all responses to TDC. Plasma concentrations and integrated CCK-LI and neurotensin significantly increased after 4 and 6 g bile and after 400 and 600 mg TDC. Atropine did not significantly influence peptide release. It is concluded that both hydrokinetic and ecbolic pancreatic secretion stimulated by intraduodenal bile and TDC are dependent on a cholinergic tone. CCK and probably also neurotensin act as further mediators of the ecbolic effect.

Delayed colonic transit times in amyotrophic lateral sclerosis assessed with radio-opaque markers.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of motor neurons. However, ALS has been recognized to involve several non-motor systems, subclinically. Cardiac and sudomotor autonomic involvement in ALS has been described. Recently, delayed gastric emptying was reported. The aim of this study was to assess colonic transit time in patients with ALS. Therefore, measurement of total and segmental colonic transit times using radio-opaque markers was performed in 14 patients with ALS and 14 healthy age-matched volunteers. Multiple-ingestion, single-radiograph technique was used. Segmental and colonic transit times were calculated from the number of retained markers. Nine of 14 patients with ALS showed markedly delayed colonic transit times if compared to healthy controls. Colonic transit in ALS patients was significantly delayed in the right and left colon; the rectosigmoid transit did not show major delay. The colonic transit times did not correlate with bulbar involvement, Norris score, walking disability or duration of the disease. In summary, colonic dysfunction in ALS may be a result of inactivity or inadequate fiber intake. However, it also may represent a gastrointestinal autonomic involvement due to nerval degeneration. Considering ALS as a multisystem disorder including the autonomic nervous system may have implications for research into pathogenesis and therapy of neurodegenerative disease.