Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial

Previous investigations on arithmetic stress with verbalization showed that spectral measures of heart rate variability (HRV) did not assess changes in autonomic modulation, although the heart rate (HR) increased. In this study non-linear measures of HRV are determined and linear measures are re-examined in order to understand this apparent discrepancy between HR and HRV changes. In 23 healthy subjects 5-min electrocardiograms (ECGs) were recorded at rest and during arithmetic stress aloud. We determined non-linear (short-term scaling exponent, sensitivity to the initial condition and signal complexity) and linear (low-frequency and high-frequency spectral powers) measures. Our results showed that averaging concealed out an opposite effect of mental stress aloud on spectral measures and that this could be the main reason why the effect was not quantified. We found that increase of HR upon mental stress aloud could be achieved through the decreased as well as increased modulation in high-frequency band (HF). We also showed that non-linear measures distinguished this opposite effect of mental stress aloud on linear measures. Decreased HF power is associated with increase in short-term scaling exponent and decrease in signal complexity, while increased HF power increased sensitivity to the initial conditions. Apart from their opposite response to the mental stress, the two groups differed in baseline in sensitivity to the initial conditions. We suggest that variety of changes in HR dynamics upon different perturbation could be due to some differences in intrinsic properties of the system.

We apply wavelet-based time-localized phase coherence to investigate the relationship between blood flow and skin temperature, and between blood flow and instantaneous heart rate (IHR), during vasoconstriction and vasodilation provoked by local cooling or heating of the skin. A temperature-controlled metal plate (approximately 10 cm2) placed on the volar side of the left arm was used to provide the heating and cooling. Beneath the plate, the blood flow was measured by laser Doppler flowmetry and the adjacent skin temperature by a thermistor. Two 1 h datasets were collected from each of the ten subjects. In each case a 30 min basal recording was followed by a step change in plate temperature, to either 24 °C or 42 °C. The IHR was derived from simultaneously recorded ECG. We confirm the changes in the energy and frequency of blood flow oscillations during cooling and heating reported earlier. That is, during cooling, there was a significant decrease in the average frequency of myogenic blood flow oscillations (p < 0.05) and the myogenic spectral peak became more prominent. During heating, there was a significant (p < 0.05) general increase in spectral energy, associated with vasodilation, except in the myogenic interval. Weak phase coherence between temperature and blood flow was observed for unperturbed skin, but it increased in all frequency intervals as a result of heating. It was not significantly affected by cooling. We also show that significant (p < 0.05) phase coherence exists between blood flow and IHR in the respiratory and myogenic frequency intervals. Cooling did not affect this phase coherence in any of the frequency intervals, whereas heating enhanced the phase coherence in the respiratory and myogenic intervals. This can be explained by the reduction in vascular resistance produced by heating, a process where myogenic mechanisms play a key role. We conclude that the mechanisms of vasodilation and vasoconstriction, in response to temperature change, are oscillatory in nature and are independent of central sources of variability.

The functional magnetic resonance imaging (fMRI) blood oxygenation level‐dependent (BOLD) signal is regularly used to assign neuronal activity to cognitive function. Recent analyses have shown that the local field potential (LFP) gamma power is a better predictor of the fMRI BOLD signal than spiking activity. However, LFP gamma power and spiking activity are usually correlated, clouding the analysis of the neural basis of the BOLD signal. We show that changes in LFP gamma power and spiking activity in the primary visual cortex (V1) of the awake primate can be dissociated by using grating and plaid pattern stimuli, which differentially engage surround suppression and cross‐orientation inhibition/facilitation within and between cortical columns. Grating presentation yielded substantial V1 LFP gamma frequency oscillations and significant multi‐unit activity. Plaid pattern presentation significantly reduced the LFP gamma power while increasing population multi‐unit activity. The fMRI BOLD activity followed the LFP gamma power changes, not the multi‐unit activity. Inference of neuronal activity from the fMRI BOLD signal thus requires detailed a priori knowledge of how different stimuli or tasks activate the cortical network.

Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response relationships for steady state plasma levels in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit. Conclusions: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.