Converging evidence suggests that psychotic Alzheimer's disease (AD + P) is associated with an acceleration of frontal degeneration, with tau pathology playing a primary role. Previous histopathologic and biomarker studies have specifically implicated tau pathology in this condition. To precisely quantify tau abnormalities in the frontal cortex in AD + P, we used a sensitive biochemical assay of total tau and 4 epitopes of phospho-tau relevant in AD pathology in a postmortem sample of AD + P and AD − P. Samples of superior frontal gyrus from 26 AD subjects without psychosis and 45 AD + P subjects with psychosis were analyzed. Results of enzyme-linked immunosorbent assay demonstrate that AD + P females, but not males, had significantly higher levels of phosphorylated tau in the frontal cortex. In males, but not females, AD + P was associated with the presence of α-synuclein pathology. These results support a gender dissociation of pathology in AD + P. The design of future studies aimed at the elucidation of cognitive and/or functional outcomes; regional brain metabolic deficits; or genetic correlates of AD + P should take gender into consideration.
Evidence garnered from genetic(Hollingworth et al., 2007, Sweet et al., 2010 and Sweet et al., 2000) longitudinal (below), and imaging (below) studies of Alzheimer's disease (AD) complicated by a psychotic course (AD + P) support its syndromal distinction from its nonpsychotic counterpart (AD − P); very recent work on the neurobiology of the disorder point toward frontal systems deficits and an overrepresentation of one of the pathologic protein hallmarks of the disease as potentially etiologically related to the development of psychosis. The identification of a specific neuropathological etiology of psychosis could pave the way to new treatment approaches for a condition that currently relies on the use of antipsychotic medication that have been reported to contribute to an exacerbation of cognitive impairment (Schneider and Dagerman, 2004 and Vigen et al., 2011) and that carry a “black box warning” for use in the elderly with AD(FDA, 2005).
Converging evidence suggests that AD + P may represent a relative acceleration of frontal pathology, with tau pathology playing a primary role. AD + P can be distinguished from AD − P in its association with a greater burden of cognitive impairment and a more rapid cognitive decline, as concluded by a review of 55 studies of AD+P (Ropacki and Jeste, 2005). This association has subsequently been confirmed in more recent studies (Sweet et al., 2000, Sweet et al., 2012 and Wilkosz et al., 2010); the decline has consistently been found to predate the onset of psychosis, suggesting a pathologic process that finds expression in both deterioration and psychosis.(FDA, 2005, Paulsen et al., 2000 and Weamer et al., 2009) The contribution of neurodegenerative pathology to the psychotic course of AD is suggested by a hastened mortality.(Lopez et al., 2013, Scarmeas et al., 2005 and Wilson et al., 2005) The constellation of aggravated cognitive deficits in AD + P suggests disruption of frontal systems (Jeste et al., 1992 and Paulsen et al., 2000) with working memory tasks particularly affected. (Koppel et al., 2012, Koppel et al., 2013c and Murray et al., 2013a) Computer-assisted tomography, magnetic resonance imaging, single-photon emission computed tomography, and [18F]-fluorodexyglucose positron emission tomography studies of AD + P also consistently but not exclusively implicate frontal systems (Murray et al., 2013b).
A number of reports suggest that tau may be a unique contributor to the putative neurodegenerative process in AD + P. Neurofibrillary tangles (NFTs) are one of the pathologic hallmarks of AD whose distribution correlates with the severity of disease (Arriagada et al., 1992). Tau is abnormally phosphorylated in AD, a critical event leading to abnormal folding and cleavage with aggregation of the protein and the eventual development of NFT pathology (Goedert, 1993 and Mondragon-Rodriguez et al., 2008). Tau is hyperphosphorylated in AD at 19 specific amino acid sequences, with evidence indicating that phosphorylation at particular sites correlate with the maturity of pathology and that individual sites may be critical for conformational changes from pre-tangles leading to neuronal tangles to eventual extracellular tangles.(Augustinack et al., 2002 and Kimura et al., 1996) Previous studies have reported an increased burden of NFT pathology in frontal cortex in AD + P, although these studies have relied on semi-quantitative transformation of histochemical detection of fibrillar tau. (Emanuel et al., 2011 and Zubenko et al., 1991) A recent neuropathological correlation study of pre-frontal cortical sections from a postmortem AD + P sample used quantitative fluorescence microsopy and observed an increased burden of intraneuronal tau phosphorylated at Ser199/Ser202/Thr205 (Murray et al., 2013a). In a study conducted on a data sample drawn from the Alzheimer's Disease Neuroimaging Initiative, cerebrospinal fluid (CSF) biomarkers of AD (total tau, Thr181 phospho-tau, and amyloid-beta [Aβ]) were explored as predictors of the development of psychosis. Elevation of total tau was associated with the future development of AD + P (Koppel et al., 2013a). An association of CSF total and Thr181 phospho-tau with gender was also observed when the genders were separated; females but not males with subsequent development of AD + P manifested baseline elevations of Thr181 phosho-tau and total tau.
No previous studies have used a biochemical approach to precisely quantify concentrations of pathogenic tau in brains of those with AD + P, or explored whether particular tau phosphorylation sites predominate in AD + P that could distinguish it from AD − P. To quantify tau abnormalities in the frontal cortex in AD + P across a range of phosphorylation sites, and to explore the impact of gender on those abnormalities, we used a sensitive biochemical assay of 4 epitopes of phospho-tau (Ser396/404; Ser202; Thr231; Ser199/202/Thr205) using monoclonal antibodies known to recognize a wide range of tau pathology in a postmortem sample of AD + P and AD − P.
