Dataset Information

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

ABSTRACT: 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). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug. RESULTS:There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6?ng/ml at the 8?mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8?mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346?ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200?mg/day. CONCLUSIONS:Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8?mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60?mg/day. A confirmatory placebo-controlled trial is now planned.

SUBMITTER: Shiells H

PROVIDER: S-EPMC7306898 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Shiells Helen H Schelter Bjoern O BO Bentham Peter P Baddeley Thomas C TC Rubino Christopher M CM Ganesan Harish H Hammel Jeffrey J Vuksanovic Vesna V Staff Roger T RT Murray Alison D AD Bracoud Luc L Wischik Damon J DJ Riedel Gernot G Gauthier Serge S Jia Jianping J Moebius Hans J HJ Hardlund Jiri J Kipps Christopher M CM Kook Karin K Storey John M D JMD Harrington Charles R CR Wischik Claude M CM

Journal of Alzheimer's disease : JAD 20200101 2

<h4>Background</h4>Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.<h4>Objective</h4>To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.<h4>Methods</h4>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). The principal outcomes were change on the Addenbrookes C ...[more]

PMID: 32280089

Similar Datasets

Project description:bvFTD patients display an impairment in the attribution of cognitive and affective states to others, reflecting GM atrophy in brain regions associated with social cognition, such as amygdala, superior temporal cortex and posterior insula. Distinctive patterns of abnormal brain functioning at rest have been reported in bvFTD, but their relationship with defective attribution of affective states has not been investigated.To investigate the relationship among resting-state brain activity, gray matter (GM) atrophy and the attribution of mental states in the behavioral variant of fronto-temporal degeneration (bvFTD).We compared 12 bvFTD patients with 30 age- and education-matched healthy controls on a) performance in a task requiring the attribution of affective vs. cognitive mental states; b) metrics of resting-state activity in known functional networks; and c) the relationship between task-performances and resting-state metrics. In addition, we assessed a connection between abnormal resting-state metrics and GM atrophy.Compared with controls, bvFTD patients showed a reduction of intra-network coherent activity in several components, as well as decreased strength of activation in networks related to attentional processing. Anomalous resting-state activity involved networks which also displayed a significant reduction of GM density. In patients, compared with controls, higher affective mentalizing performance correlated with stronger functional connectivity between medial prefrontal sectors of the default-mode and attentional/performance monitoring networks, as well as with increased coherent activity in components of the executive, sensorimotor and fronto-limbic networks.Some of the observed effects may reflect specific compensatory mechanisms for the atrophic changes involving regions in charge of affective mentalizing. The analysis of specific resting-state networks thus highlights an intermediate level of analysis between abnormal brain structure and impaired behavioral performance in bvFTD, reflecting both dysfunction and compensation mechanisms.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets