Obtaining personalized predictions from a randomized controlled trial on Alzheimer's disease.

The purpose of this article is to infer patient level outcomes from population level randomized control trials (RCTs). In this pursuit, we utilize the recently proposed synthetic nearest neighbors (SNN) estimator. At its core, SNN leverages information across patients to impute missing data associated with each patient of interest.

Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.

Background: Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD).

Objectives: The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY).

Design: The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase.

Inferring the underlying multivariate structure from bivariate networks with highly correlated nodes.

Complex systems are often described mathematically as networks. Inferring the actual interactions from observed dynamics of the nodes of the networks is a challenging inverse task. It is crucial to distinguish direct and indirect interactions to allow for a robust identification of the underlying network.

Crossed cerebellar diaschisis in Alzheimer's disease.

Background: Crossed cerebellar diaschisis (CCD) is characterized by hypometabolism and hypoperfusion on molecular imaging in the cerebellum due to a supratentorial lesion on the contralateral side. CCD is a well-established phenomenon in acute or subacute conditions such as infarction but it has been less well described in chronic conditions such as neurodegenerative dementias. Here, we investigate CCD in a large sample of 830 people meeting research criteria for Alzheimer's disease (AD) using [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET).

Long-Term Hydromethylthionine Treatment Is Associated with Delayed Clinical Onset and Slowing of Cerebral Atrophy in a Pre-Symptomatic P301S MAPT Mutation Carrier.

One of the mutations in the microtubule-associated protein tau, P301S, is causative for dominantly inherited frontotemporal dementia characterized by extensive tau pathology for which no licensed treatment is available. Hydromethylthionine is a potent tau aggregation inhibitor. We report treatment of an asymptomatic carrier of the P301S mutation using hydromethylthionine over a 5-year period beginning at the mean age of onset of clinical decline in the family.

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS.

On the Validity of Neural Mass Models.

Modeling the dynamics of neural masses is a common approach in the study of neural populations. Various models have been proven useful to describe a plenitude of empirical observations including self-sustained local oscillations and patterns of distant synchronization. We discuss the extent to which mass models really resemble the mean dynamics of a neural population.

Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia.

Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.

Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.

Methods: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control).

Controversies on the network theory of epilepsy: Debates held during the ICTALS 2019 conference.

Debates on six controversial topics on the network theory of epilepsy were held during two debate sessions, as part of the International Conference for Technology and Analysis of Seizures, 2019 (ICTALS 2019) convened at the University of Exeter, UK, September 2-5 2019. The debate topics were (1) From pathologic to physiologic: is the epileptic network part of an existing large-scale brain network? (2) Are micro scale recordings pertinent for defining the epileptic network? (3) From seconds to years: do we need all temporal scales to define an epileptic network? (4) Is it necessary to fully define the epileptic network to control it? (5) Is controlling seizures sufficient to control the epileptic network? (6) Does the epileptic network want to be controlled? This article, written by the organizing committee for the debate sessions and the debaters, summarizes the arguments presented during the debates on these six topics.

Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer's Disease.

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.

The impact of physiological noise on hemodynamic-derived estimates of directed functional connectivity.

Measuring the strength of directed functional interactions between brain regions is fundamental to understand neural networks. Functional near-infrared spectroscopy (fNIRS) is a suitable method to map directed interactions between brain regions but is based on the neurovascular coupling. It, thus, relies on vasomotor reactivity and is potentially biased by non-neural physiological noise.

Quantitative assessment of cerebral connectivity deficiency and cognitive impairment in children with prenatal alcohol exposure.

It is common knowledge that alcohol consumption during pregnancy would cause cognitive impairment in children. However, recent works suggested that the risk of drinking during pregnancy may have been exaggerated. It is critical to determine whether and up to which amount the consumption of alcohol will affect the cognitive development of children.

Functionally dissociating ventro-dorsal components within the rostro-caudal hierarchical organization of the human prefrontal cortex.

Cognitive control is proposed to rely on a rostral-to-caudal hierarchy of neural processing within the prefrontal cortex (PFC), with more rostral parts exerting control over more caudal parts. Anatomical and functional data suggest that this hierarchical organization of the PFC may be separated into a ventral and a dorsal component. Furthermore, recent studies indicate that the apex of the hierarchy resides within the mid-lateral rather the rostral PFC.

Analytical approach to network inference: Investigating degree distribution.

When the network is reconstructed, two types of errors can occur: false positive and false negative errors about the presence or absence of links. In this paper, the influence of these two errors on the vertex degree distribution is analytically analyzed. Moreover, an analytic formula of the density of the biased vertex degree distribution is found.

Seizure prediction - ready for a new era.

Epilepsy is a common disorder characterized by recurrent seizures. An overwhelming majority of people with epilepsy regard the unpredictability of seizures as a major issue. More than 30 years of international effort have been devoted to the prediction of seizures, aiming to remove the burden of unpredictability and to couple novel, time-specific treatment to seizure prediction technology.

Improving network inference: The impact of false positive and false negative conclusions about the presence or absence of links.

Background: A reliable inference of networks from data is of key interest in the Neurosciences. Several methods have been suggested in the literature to reliably determine links in a network. To decide about the presence of links, these techniques rely on statistical inference, typically controlling the number of false positives, paying little attention to false negatives.

Detection of time-, frequency- and direction-resolved communication within brain networks.

Electroencephalography (EEG) records fast-changing neuronal signalling and communication and thus can offer a deep understanding of cognitive processes. However, traditional data analyses which employ the Fast-Fourier Transform (FFT) have been of limited use as they do not allow time- and frequency-resolved tracking of brain activity and detection of directional connectivity. Here, we applied advanced qEEG tools using autoregressive (AR) modelling, alongside traditional approaches, to murine data sets from common research scenarios: (a) the effect of age on resting EEG; (b) drug actions on non-rapid eye movement (NREM) sleep EEG (pharmaco-EEG); and (c) dynamic EEG profiles during correct vs incorrect spontaneous alternation responses in the Y-maze.

Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development.

Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.

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 in mild AD.

Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

Background: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease.

Networks: On the relation of bi- and multivariate measures.

A reliable inference of networks from observations of the nodes' dynamics is a major challenge in physics. Interdependence measures such as a the correlation coefficient or more advanced methods based on, e.g.

Granger causal time-dependent source connectivity in the somatosensory network.

Exploration of transient Granger causal interactions in neural sources of electrophysiological activities provides deeper insights into brain information processing mechanisms. However, the underlying neural patterns are confounded by time-dependent dynamics, non-stationarity and observational noise contamination. Here we investigate transient Granger causal interactions using source time-series of somatosensory evoked magnetoencephalographic (MEG) elicited by air puff stimulation of right index finger and recorded using 306-channel MEG from 21 healthy subjects.

Assessing parameter identifiability for dynamic causal modeling of fMRI data.

Deterministic dynamic causal modeling (DCM) for fMRI data is a sophisticated approach to analyse effective connectivity in terms of directed interactions between brain regions of interest. To date it is difficult to know if acquired fMRI data will yield precise estimation of DCM parameters. Focusing on parameter identifiability, an important prerequisite for research questions on directed connectivity, we present an approach inferring if parameters of an envisaged DCM are identifiable based on information from fMRI data.

Network inference in the presence of latent confounders: the role of instantaneous causalities.

Background: Detecting causal interactions in multivariate systems, in terms of Granger-causality, is of major interest in the Neurosciences. Typically, it is almost impossible to observe all components of the system. Missing certain components can lead to the appearance of spurious interactions.

Electrical stimulation for cortical mapping reduces the density of high frequency oscillations.

Background: High frequency oscillations (HFOs, 80-500 Hz) are EEG biomarkers for epileptogenic areas. HFOs are also indicators of disease activity as HFO rates increase after reduction of antiepileptic medication. Electrical stimulation (ES) can be used for diagnostic purposes as well as therapy in patients with refractory epilepsy.