Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-beta (A beta) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed A beta plaques in frontal cortical brain biopsy and 13 iNPH patients without A beta pathology. CSF Amyloid-beta(42) (A beta(42)), total tau (T-tau), phosphorylated tau (P-tau(181)), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but A beta(42) increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. A beta(42) instead showed divergent longitudinal decrease between A beta-positive and -negative patients in L-CSF, and thereafter increase in A beta-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (A beta(42) R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (A beta(42) 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only A beta(42) showed higher concentration in non-carriers of allele epsilon 4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy A beta pathology, while NFL normalized toward its pre-shunt levels. A beta(42) as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V-than L-CSF yet showing strong correlations.Peer reviewe

A placebo-controlled trial of the 5-HT1A agonist R-137696 on symptoms, visceral hypersensitivity and on impaired accommodation in functional dyspepsia

Acute studies suggested a therapeutic benefit for fundus-relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long-term studies are lacking. R-137696 is a serotonin-1A (5-HT(1A)) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R-137696 on symptoms in FD with VH or IA. Randomized, double-blind, placebo-controlled, parallel group study of 4 weeks R-137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty-three patients (33 VH and 20 IA), 18 men, mean age 40 +/- 13 years were recruited. Twenty-four received placebo and 29 received R-137696. In VH patients, both placebo and R-137696 improved total symptom scores, with a tendency for superiority of placebo (-1.12 vs-0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P <0.05). In IA, both placebo and R-137696 had no significant influence on total or individual symptom scores (-0.08 and -0.27). In VH, both placebo and R-137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R-137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4-week administration of the fundus-relaxing 5-HT(1A) agonist R-137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placeb

The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers

As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteer