J. Michael Ryan

Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales

OBJECTIVEnThis paper provides a case study of reverse translational research, in which empirical clinical trials focused on relieving psychopathological symptoms of Alzheimers disease (AD) ultimately led to mechanism-based trials addressing aspects of the underlying pathophysiology of Alzheimers disease. AD is multi-dimensional in nature, characterized not only by cognitive and functional decline but by neuropsychiatric symptoms that develop commonly and are associated with considerable morbidity. There have been a large number of empirical trials of various pharmacological agents to reduce these symptoms, such as agitation. Although antipsychotics are used most frequently for agitation, the usual effect size is modest, and there is a range of tolerability and/or safety issues, leading to the hope that alternatives can be found. Furthermore, most clinical trials addressing psychopathology have not been mechanism-based and none have attempted an alternative approach, namely, to delay or prevent the emergence of psychopathology.nnnFINDINGSnThe evidence of clinical trials is reviewed regarding the safety, tolerability, and apparent efficacy of the mood stabilizers carbamazepine and valproate for agitation associated with AD. Possible mechanisms of action of valproate are reviewed, leading to the surprising conclusion that neuroprotective properties may account for some of its clinical effects. These mechanisms (including activation of wnt-dependent signaling and upregulation of bcl-2, among others) may be particularly relevant for long-term treatment of AD.nnnCONCLUSIONSnThese clinical and mechanistic findings were combined in the development of a novel clinical trial examining whether chronic valproate therapy can attenuate the clinical progression of AD, which will be implemented by the Alzheimers Disease Cooperative Study. The design addresses valproates potential to delay or prevent the onset of agitation in patients lacking agitation to begin with, as well as to slow progressive decline in cognition and daily functioning.

Pharmacologic therapy for behavioral symptoms of alzheimer's disease

Behavioral signs and symptoms in dementia are common, morbid, classifiable, and treatable. The current state-of-the-art approach is to evaluate carefully for social or environmental causes, intercurrent medical conditions, or other triggers of the behavior and attempt to deal with those directly. When these conservative steps fail, there may be a role for medication. A rational approach typically hinges on matching the most dominant behavioral target symptoms to the most relevant medication class, the key information of which is summarized.

PHASE 1 STUDY IN HEALTHY VOLUNTEERS OF THE O-GLCNACASE INHIBITOR ASN120290 AS A NOVEL THERAPY FOR PROGRESSIVE SUPRANUCLEAR PALSY AND RELATED TAUOPATHIES

O1-12-05 PHASE 1 STUDY IN HEALTHY VOLUNTEERS OF THE O-GLCNACASE INHIBITOR ASN120290 AS A NOVEL THERAPY FOR PROGRESSIVE SUPRANUCLEAR PALSYAND RELATED TAUOPATHIES J.Michael Ryan, AnnaQuattropani, Khalid Abd-Elaziz, Izaak den Daas, Manfred Schneider, Solenne Ousson, Maud Neny, Astrid Sand, Jennifer Hantson, Bruno Permanne, Christoph Wiessner, Dirk Beher, Asceneuron SA, Lausanne, Switzerland; Asceneuron SA, Lausanne, Switzerland; QPS Netherlands BV, Groningen, Netherlands. Contact e-mail: dirk.beher@asceneuron.com