ReviewA systematic review of amyloid-β peptides as putative mediators of the association between affective disorders and Alzheimer׳s disease
Introduction
Affective disorders are incapacitating, highly prevalent and substantial contributors to the global burden of disease with an estimated lifetime prevalence of approximately 12% (Kessler et al., 2009). Empirically and epidemiologically founded evidence indicate significant heritability (Shih et al., 2004), high rates of non-recovery and recurrence that progressively enhance with each successive episode (Solomon et al., 2000) increased morbidity and mortality (Lauersen et al., 2007) a lifelong elevated risk of suicide (Rihmer, 2007), compromised psychosocial functioning and greatly reduced productivity that incurs immense healthcare costs to the society (Simon, 2003). Furthermore affective disorders are frequently associated with medical comorbidity and long-term population-based studies indicate that patients suffering from these mental illnesses also display an increased risk of developing dementia (Cruess et al., 2003, Musselman et al., 1998, Ownby et al., 2006, Spiegel and Giese-Davis, 2003).
Mood disorders are accompanied by cognitive abnormalities during depressive/manic episodes, but cognitive impairment is also prevalent among patients in remission, specifically within executive function and verbal memory (Bora et al., 2013, Robinson et al., 2006). Cognitive deficits have been linked to the number, duration and intensity of affective episodes and to the presence of mania or psychotic symptoms (Gorwood et al., 2008, Martinez-Aran et al., 2008, Zubieta et al., 2001), so that mood disorders in general would be expected to aggravate and accelerate the process of aging-related cognitive deterioration (Gualtieri and Johnson, 2008) and perhaps via synergistically interconnected pathophysiological processes eventually facilitate conversion to dementia.
Alzheimer׳s disease (AD) is the leading cause of progressive dementia. The histopathological hallmarks of AD, which begin decades prior to its clinical expression (Villemagne et al., 2013) encompass characteristic amyloid-β (Aβ) plaques derived from the larger amyloid precursor protein (APP), neurofibrillary tangles comprising a hyperphosphorylated form of tau proteins and neurodegeneration affecting several neurotransmitter systems (Blennow and Hampel, 2003). APP, if processed by the amyloidogenic pathway involving β- and γ-secretases, generates Aβ40, which is primarily associated with cerebral amyloid angiopathy, and Aβ42 – representing the major component of amyloid deposits (Blennow and Hampel, 2003). Amyloid markers can be measured in both cerebrospinal fluid (CSF) and in blood. While no consensus has been reached regarding plasma profiles, decreased levels of Aβ42 peptide combined with elevated tau (t-tau) and phosphorylated tau (p-tau) in CSF are sensitive and specific markers for AD and incipient AD (Blennow and Hampel, 2003, Zetterberg, 2008). To characterize the nature of cognitive impairment in affective disorder, several studies have measured these AD-related markers, both peripherally as well as in CSF. While tau markers are generally unchanged, Aβ42 shows significant alterations in several studies. To evaluate the strength of evidence for the association of Aβ alterations this review critically and systematically assesses studies that have measured Aβ markers in plasma/serum or CSF in samples from patients with affective disorder.
Section snippets
Search strategy and selection criteria
A systematic search was performed between July and August 2013 via the electronic databases PubMed and EMBASE, so as to identify and evaluate all available literature exploring the association between Aβ and affective disorders. Search profiles using various combinations of pertinent keywords: “Aβ”, “CSF”, “plasma”, “serum”, “depression”, “major depressive disorder”, “bipolar disorder”, “mood disorders”, “affective disorders” and “psychiatric disease”, were employed. Rigorous abstract
Population characteristics and study design
A total of 23 eligible, English-language articles (Baba et al., 2012, Blasko et al., 2006, Blasko et al., 2010, Bibl et al., 2007, Direk et al., 2013, Gudmundsson et al., 2007, Hertze et al., 2010, Hock et al., 1998, Jakobsson et al., 2013, Jensen et al., 1999, Kramberger et al., 2012, Metti et al., 2013, Moon et al., 2011, Piccinni et al., 2012, Pomara et al., 2006, Pomara et al., 2012, Portelius et al., 2010, Post et al., 2006, Reis et al., 2012, Schröder et al., 1997, Sjögren et al., 2000,
Longitudinal studies
One (Direk et al., 2013) of the four longitudinal studies included in this review, was considered of high research quality, whereas the remaining three (Blasko et al., 2010, Hertze et al., 2010, Metti et al., 2013) were of moderate quality. Methodological limitations/flaws included non-random sampling strategies (Hertze et al., 2010) missing Aβ40 measurements (Blasko et al., 2010) the use of non-diagnostic assessment tools for depression (Direk et al., 2013, Metti et al., 2013) and increased
Future research perspectives
Overall, results drawn from the 23 studies included in this review indicate that Aβ metabolism may be altered in patients with affective disorder but far from settles the issue. Thus, the exact correlation between AD and affective disorder remains elusive despite a clear clinico-epidemiological evidence of an increased incidence of cognitive impairment in patients suffering from affective disorders. Future research requires prospective, longitudinal studies, implemented in large study
Role of funding source
There were no funding sources in the writing of the manuscript or the decision to submit it for publication.
Conflict of interest
The authors have no conflicts of interest.
Acknowledgment
None.
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