Mechanisms underlying resilience in ageing Y Stern, G Chételat, C Habeck, EM Arenaza-Urquijo, P Vemuri, A Estanga, ...Nature Reviews Neuroscience 20 (4), 246-24

Acosta, Edward

Andrews, Howard F.

Bell, Karen L.

Deliyannides, Deborah A.

Devanand, Devangere P.

Gershon, Anne A.

Huey, Edward D.

Katsikoumbas, Mariasofia

Kreisl, William Charles

Mintz, Akiva

Pelton, Gregory H.

Pollina, Julianna

Prasad, K. M.

Razlighi, Qolamreza R.

Stern, Yaakov

Wisniewski, Thomas

BMJ Open

IntroductionAfter infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV1 may lead to neurodegeneration and Alzheimer’s disease (AD) pathology. HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid beta-protein (Aβ) aggregation and HSV1 DNA is common in amyloid plaques. Anti-HSV drugs reduce Aβ and phosphorylated tau accumulation in cell-culture models. Cognitive impairment is greater in patients with HSV seropositive, and antiviral drugs show robust efficacy against peripheral HSV infection. Recent studies of electronic health records databases demonstrate that HSV infections increase dementia risk, and that antiviral medication treatment reduces this risk. The generic antiviral drug valacyclovir was superior to placebo in improving memory in a schizophrenia pilot trial but has not been tested in AD.Methods and analysisIn patients with mild AD who test positive for HSV1 or HSV2 serum antibodies, valacyclovir, repurposed as an anti-AD drug, will be compared with placebo (lactose pills) in 130 patients (65 valacyclovir and 65 placebo) in a randomised, double-blind, 78-week phase II proof-of-concept trial. Patients on valacyclovir, dose-titrated from 2 g to a targeted oral dose of 4 g daily, compared with placebo, are hypothesised to show smaller cognitive and functional decline, and, using 18F-Florbetapir positron emission tomography (PET) and 18F-MK-6240 PET imaging, to show less amyloid and tau accumulation, respectively. In the lumbar puncture subsample, cerebrospinal fluid acyclovir will be assayed to assess central nervous system valacyclovir penetration.Ethics and disseminationThe trial is being overseen by the New York State Psychiatric Institute Institutional Review Board (protocol 7537), the National Institute on Ageing, and the Data Safety Monitoring Board. Written informed consent is obtained for all subjects. Results will be disseminated via publication, clinicaltrials.gov, media and conferences.Trial registration numberClinicalTrials.gov identifier (NCT03282916) Pre-results

Howard Andrews

D P Devanand

William C Kreisl

Qolamreza Razlighi

Anne Gershon

Yaakov Stern

Akiva Mintz

Thomas Wisniewski

Edward Acosta

Julianna Pollina

Mariasofia Katsikoumbas

Karen L Bell

Gregory H Pelton

Deborah Deliyannides

K M Prasad

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Antiviral therapy: Valacyclovir Treatment of Alzheimer’s Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial

Columbia University Academic Commons

Antiviral therapy: Valacyclovir Treatment of Alzheimer’s Disease (VALAD) Trial: protocol for a randomised, double-blind, placebo-controlled, treatment trial

https://academiccommons.columbia.edu/doi/10.7916/d8-ca42-ap20/download

Antiviral therapy: Valacyclovir Treatment of Alzheimer’s Disease (VALAD) Trial: protocol for a randomised, double-blind, placebo-controlled, treatment trial

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Directory of Open Access Journals

Columbia University Academic Commons