Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease

INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The first‐in‐indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: PEGASUS enrolled 95 participants (intent‐to‐treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin‐15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau‐181 (p‐tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein‐3 (FABP3); and gliosis biomarker chitinase 3‐like protein 1 (YKL‐40), while the oxidative stress marker 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) increased. Between‐group differences were observed for the Aβ42/40 ratio, p‐tau181, total tau, neurogranin, FABP3, YKL‐40, interleukin‐15, and 8‐OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While between‐group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD). Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms. The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets. PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration. Supports further clinical development of PB and TURSO in neurodegenerative diseases

Recruiting US Chinese Elders Into Clinical Research for Dementia

Forenzička psihijatrija bavi se među ostalim liječenjem neubrojivih počinitelja protupravnih djela. Te osobe sud upućuje na prisilno liječenje. Liječnik koji ih liječi redovito izvješćuje sud o napretku u liječenju. Iz toga proizlaze problemi dinamički orijentirane grupne psihoterapije forenzičkih pacijenata. Rad se bavi specifičnim pitanjima provođenja dinamički orijentirane grupne psihoterapije u forenzičkim uvjetima: kako voditi grupnu analizu u uvjetima prisilnoga liječenja, koje su specifične kontratransferne reakcije s obzirom na činjenicu da su članovi grupe počinili protupravna djela, uvođenje trećeg (suda) u terapijski proces, homogenost grupe s obzirom na dijagnostičke kategorije, velik broj osoba s antisocijalnim poremećajem ličnosti, osjećaj (ne)sigurnosti u grupi počinitelja. Iskustvo je autora da, unatoč mnogobrojnim specifičnostima grupne psihoterapije forenzičkih pacijenata osnovna terapijska tehnika ostaje ista, uz potrebu pomnijeg praćenja vlastitih (kontratransfernih) emocionalnih reakcija.Forensic psychiatry deals with a treatment of offenders of unlawful deeds that were assessed as not guilty by reason of insanity. These people are sent for aninvoluntary treatment by the court. Therapists who treat these people are obliged to inform the court about the process of treatment. These two characteristics are basic problems in the dynamic group psychotherapy of forensic patients. This manuscript deals with specific issues of dynamic group psychotherapy in forensic settings: how to do dynamic group psychotherapy in involuntary treatment setting, what are specific countertransferential reactions due to the fact that group members all committed an unlawful deed, the introduction of the third party (the court) in the therapeutic process, homogenous group in regard of diagnostic categories, large number of group members with antisocial personality disorder, feelings of (in)security in a group of perpetrators. The author’s experience is that, although there are many specificities of group psychotherapy with forensic patients, the basic therapeutic techniques are the same, with the important task of continuous and thorough analysis of own (countertransferential) emotional reactions