Hyperphosphorylated Tau is Elevated in Alzheimer's Disease with Psychosis

Article type: Research Article

Authors: Murray, Patrick S.^{a; b} | Kirkwood, Caitlin M.^a | Gray, Megan C.^a | Fish, Kenneth N.^a | Ikonomovic, Milos D.^{a; c; d} | Hamilton, Ronald L.^e | Kofler, Julia K.^e | Klunk, William E.^{a; c} | Lopez, Oscar L.^{a; c} | Sweet, Robert A.^{a; b; c; *}

Affiliations: [a] Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [b] VISN 4 Mental Illness Research, Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA | [c] Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [d] Geriatric Research Educational and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA | [e] Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: Robert A. Sweet, Biomedical Science Tower, W1645, 3811 O'Hara St., Pittsburgh, PA 15213, USA. Tel.: +1 412 624 0064; Fax: +1 412 624 9910; E-mail: [email protected].

Abstract: Psychosis occurs in 40–60% of Alzheimer's disease (AD) subjects, is heritable, and indicates a more rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scores on the Mini-Mental State Examination and Digit Span Backwards test. These novel findings indicate that tau phosphorylation may be accelerated in AD with psychosis, indicating a more dynamic, exaggerated pathology in AD with psychosis.

Keywords: Alzheimer's disease, Braak stage, Mini-Mental State Examination, psychosis, tau

DOI: 10.3233/JAD-131166

Journal: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 759-773, 2014