Abstract. Accurate blood-based biomarkers of Alzheimer's disease (AD) could constitute simple, inexpensive, and non-invasive tools for the early diagnosis and treatment of this devastating neurodegenerative disease. We sought to develop a robust AD biomarker panel by identifying alterations in plasma metabolites that persist throughout the continuum of AD pathophysiology. Using a multicenter, cross-sectional study design, we based our analysis on metabolites whose levels were altered both in AD patients and in patients with amnestic mild cognitive impairment (aMCI), the earliest identifiable stage of AD. UPLC coupled to mass spectrometry was used to independently compare the levels of 495 plasma metabolites in aMCI (n = 58) and AD (n = 100) patients with those of normal cognition controls (NC, n = 93). Metabolite alterations common to both aMCI and AD patients were used to generate a logistic regression model that accurately distinguished AD from NC patients. The final panel consisted of seven metabolites: three amino acids (glutamic acid, alanine, and aspartic acid), one non-esterified fatty acid .918). Importantly, the model also distinguished aMCI from NC patients (AUC, 0.826), indicating its potential diagnostic utility in early disease stages. These findings describe a sensitive biomarker panel that may facilitate the specific detection of early-stage AD through the analysis of plasma samples.

SUMMARYTransmission in a pathway mediating presynaptic inhibition of soleus I a afferent terminals was assessed from the reduction of soleus muscle H reflex amplitude brought about by a short conditioning vibration pulse applied to the anterior tibialis muscle. In a group of young subjects (aged between 21 and 37 years) the mean reduction in reflex size with the limb relaxed was to 29-2 % of control, whereas in a group of older subjects (aged between 59 and 74 years) the reduction was significantly less, to 55 0% of control (P < 0 001, Student's t test). In the younger group the amount of presynaptic inhibition elicited was inversely related to the plantar-flexor torque produced by tonic contraction of gastrocnemius-soleus; often at higher torques no reduction in reflex size was seen. In contrast the older group showed only a slight reduction in presynaptic inhibition with increasing torque, so that at torques of 5 and 7 Nm the amount of presynaptic inhibition elicited was similar in the younger and older groups. The older subjects were not able to sustain the higher torques produced by the younger subjects. These results suggest that the control of transmission in this spinal pathway changes with increasing age.

Patients who were rapidly intensified achieved a maintained reduction in HbA1c faster than those with delayed intensification or no second-line therapy, despite a higher baseline HbA1c.

The possible role of changes in presynaptic inhibition of muscle spindle primary afferent terminals in Parkinson's disease was investigated. The pathway from tibialis anterior Ia afferents to soleus Ia terminals was assessed in 20 patients with Parkinson's disease and in 17 age matched controls, both at rest and during maintenance of tonic plantar flexing torques about the ankle. At all torques less presynaptic inhibition was present in the patients with Parkinson's disease than in the controls. The difference was significant at rest (p < 0.03) and at 2 Nm (p < 005) but not at 5 Nm and 7 Nm torque. The amount of presynaptic inhibition did not change with torque in either group. The observed alteration in presynaptic inhibition in Parkinson's disease is likely to make only a small contribution to the rigidity and impaired movement control.

The effects of intravenous infusion of the direct acting muscle relaxant, dantrolene sodium (5 mg kg−1), on tension, integrated EMG, soleus muscle motor unit discharge frequency and gamma nerve fibre discharge were measured in the decerebrate rat. Dantrolene sodium did not have any detectable direct effect upon the discharge of the gamma nerve fibres. The soleus muscle of the decerebrate preparations exhibited spontaneous tension and reflex responses. With the muscle held at constant length, dantrolene sodium caused an increase in the integrated EMG in 15 out of 18 experiments and a decrease in muscle tension in 15 out of 17. The results from these experiments showed great variability. Dantrolene sodium caused a slight reduction in the tension response to tonic stretch; this was accompanied by an increase in the integrated EMG. Dantrolene sodium also caused a shift in the relationship between tension and integrated EMG during the phasic component of the stretch reflex, with a greater integrated EMG being associated with a reduced tension. Motor unit discharge frequencies were found to increase but not sufficiently to overcome the action of dantrolene sodium. It is concluded that motor unit recruitment must play an important role in the compensation for the muscle weakening action of dantrolene sodium.