EPILOGUE
My research in the PhD program aimed to study in deep some neurobiological topics in the field of mood disorders through the investigation about the levels of putative blood biomarkers in groups of patients during affective episodes. All the investigated biomarkers (BDNF, Aβ40, Aβ42) are peptides involved in neuronal pathways of neuroplasticity and neurodegeneration. The previous chapters of this dissertation have reported three studies that I co-authored and published during the years of my PhD program, exploring the potential clinical correlates of BDNF and Aβ peptides levels such as severity of symptoms, illness course in terms of duration and number of episodes, response to treatment.
On the whole, the first study presented in this dissertation shows for the first time that plasma BDNF levels are significantly decreased also in the course of mixed episodes of BD.
Plasma BDNF of patients suffering from mixed episodes are lower than those of healthy controls but non significantly different from those of depressed patients. This is consistent with previous studies showing lower plasma BDNF concentrations in both depressed and manic patients, and further support the consistency of BDNF as a state-dependent marker of mood episodes. Most studies have shown that BDNF levels during manic or depressed episodes are lower in patients than in healthy subjects but they increase up to healthy subjects’ levels after specific and effective treatments (Fernandes et al., 2011; Polyakova et al., 2015). Moreover, comparable BDNF levels in manic, depressive and mixed states suggest a shared biological trait strengthening the hypothesis of a unitary model for mood disorders, as for the Kraepelinian description of a continuous manic-depressive spectrum (Cassano et al., 2004).
These findings are in line also with the last nosologic development which removed in the updated DSM-5 version mixed episodes leaving a specifier “with mixed features” for both depressive and manic episodes and virtually linking mood episodes of opposite polarity (APA, 2013).
The relative simplicity of the test and the highly consistent findings of our results suggest that the measure of plasma and/or serum BDNF levels may be a clinically useful biomarker.
However, the apparent lack of diagnostic specificity is likely to be a major drawback limiting the true clinical utility of this measure. Indeed, in addition to major depression, reduced serum and plasma BDNF levels have also recently been reported in several other disorders including schizophrenia, eating disorders, Huntington’s disease, Alzheimer’s disease, autism (Sen et al., 2008). Although the seemingly non-specific association linking reduced serum BDNF levels to
a broad range of disorders detracts from its appeal as a specific diagnostic biomarker, it may inform us about a common pathophysiological mechanism that is shared by several disease processes. Furthermore, it may also provide some insight into the high rates of comorbidity that exist between many of the disorders. A second potentially interesting application of peripheral BDNF measures could be as a surrogate biomarker of antidepressant efficacy. There is now strong evidence that serum BDNF levels increase following treatment with antidepressant medications, similar to what is seen with BDNF expression in specific brain regions in rodent models (Duman and Monteggia, 2006). This suggests that this measure may be used to screen novel antidepressant agents or possibly even predict an individual’s response to an antidepressant treatment if a relationship will be established between the change in BDNF levels and the clinical response. However, it is important to recognize that plasma and serum BDNF levels have also been shown to correlate with other events and activities such as food intake (Stanek et al., 2008), stress (Mitoma et al., 2007), and exercise (Tang et al., 2008), that all are likely to complicate the interpretation of the findings and possibly limit the true utility of the measure. On the other hand, it is worthy of note that some of these conditions are known either to exacerbate or precipitate depression (e.g., stress) or produce an antidepressant response (Duman and Monteggia, 2006). However, even if currently the real clinical utility of BDNF measure is limited, the whole body of preclinical and clinical studies in this field has provided novel insight into the pathophysiology of mood disorders.
The role of neuroplasticity impairment in depression has been largely demonstrated and this could suggest novel targets for the development of therapeutic agents. Studies demonstrating that the cyclic adenosine monophosphate (cAMP) pathway and the BDNF-TrkB receptor system are up-regulated by chronic antidepressant system support the possibility that increasing the function of this intracellular systems may have therapeutic actions. For example, in the early 1980s, it was reported that rolipram, a specific phosphodisterase type IV (PDE-IV - the enzyme responsible for the breakdown of cAMP) inhibitor, has antidepressant efficacy in animal models of depression (Wachtel, 1983; Overstreet et al., 1989) and provokes a rapid increase of BDNF expression (Nibuya et al., 1996). A number of open and controlled clinical trial showed that rolipram indeed possesses antidepressant efficacy in patients with depression (Bertolino et al., 1988; Hebenstreit et al., 1989). Moreover, it is likely that rolipram has a faster onset of action than standard antidepressants do. However, its potential use for depression is limited because of side effects such as nausea and emesis. The several components of the BDNF-TrkB pathway such as the TrkB receptor itself or the mitogen-activated protein (MAP) kinases offer additional and unlimited potential targets for future drug development. The
investigation on intracellular targets could be particularly useful for those depressed patients which are resistant to standard monoaminergic antidepressants and in which it is hypothesized an impairment of the intracellular pathways linking monoamines receptor to BDNF gene expression.
The other two studies presented in this dissertation report that patients suffering from bipolar depression present lower plasma Aβ42, higher Aβ40 levels and Aβ40/Aβ42 ratio than healthy subjects. These findings are in line with those of previous studies exploring the alterations of peripheral Aβ peptides levels in depressed patients (Qiu et al., 2007; Sun et al., 2007, 2008; Baba et al., 2012). Our data also demonstrate that a negative correlation exists between plasma Aβ42 levels and the duration of illness as well as a positive correlation between Aβ40/Aβ42 ratio and the number of affective episodes. Moreover, the last presented study demonstrates that Aβ peptides levels do not change with ECT regardless of clinical response, that Aβ40/Aβ42 ratio is negatively correlated to the improvement of depressive and cognitive symptoms with treatment and that remitter patients shows a significantly lower Aβ40/Aβ42 ratio before ECT than non-remitter ones. Therefore, Aβ peptides and their ratio appear to be a useful tool to identify groups of bipolar patients with severe course of illness, poor response to treatments and at risk for cognitive decline. As regards cognitive functions, although the small sample size prevented us to perform reliable statistical analyses, we observed in the second presented study a trend towards higher Aβ40 levels and Aβ40/Aβ42 ratio in those patients (n=6) with a MMSE total score < 24, i.e. with a clinically significant cognitive impairment. This is in line with Sun's hypothesis of a cognitive impaired “amyloid-associated”
depression (Sun et al., 2008). In the ECT study, both Aβ40 and Aβ40/Aβ42 ratio resulted to be negatively correlated with MMSE score and Aβ40/Aβ42 ratio predicted a poor cognitive outcome after ECT. Another important point is the stability of Aβ levels across ECT that, differently from what happens for BDNF levels, let us to hypothesize with caution a role of Aβ peptides as trait marker of severity of illness course, poor response to treatments and risk for cognitive decline. This hypothesis needs to be examined by longitudinal studies.
The relevance of these data can be better understood by considering some previous clinical observations. Firstly, Aβ is a molecule notoriously involved in the pathophysiology of neurodegenerative disorders such as Alzheimer’s Disease (AD), being the main component of senile plaques but above all Aβ oligomers exerting a prolonged neurotoxic action from many years before the onset of dementia (Graff-Radford et al., 2007). Secondly, low Aβ42 levels and high Aβ40/Aβ42 ratio have been associated to risk for cognitive decline and dementia in follow-up studies on large general population cohorts (Graff-Radford et al., 2007; Okereke et
al., 2009; Seppala et al., 2010) especially in subjects with low cognitive reserve (low education and school attendance) and in carriers of apolipoprotein E e4 allele (Yaffe et al., 2011).
Another longitudinal study of 988 community-dwelling elders demonstrated an association between high plasma Aβ40/Aβ42 and increased risk of incident depression over 9 years among those with one or more apolipoprotein E e4 allele. This implies a synergistic relationship similar to that found with dementia (Metti et al., 2013). Finally, bipolar patients are known to present high risk for cognitive impairment (for review see: Goodwin et al., 2008), particularly in case of a severe illness course (Kessing and Andersen, 2004; Robinson et al., 2006;
Geerlings et al., 2008). In line with the “neuroprogression” hypothesis, clinical and preclinical evidence suggest that multiple mood episodes disrupt the homeostasis between neurodegenerative and neuroprotective mechanisms and lead over the course of disease to brain atrophy, progressive decline in mental health and psychosocial functioning and ultimately to cognitive impairment (for review see: Bauer et al., 2014).
These issues stimulate some pathophysiological speculations. Considering the model of AD, it is worth noting that mild cognitive decline and reduction of peripheral Aβ42 levels may be also found several years before the diagnosis of dementia and the formation of senile plaques (Graff-Radford et al., 2007; Amieva et al., 2008). It has been argued that the peripheral reduction may be due to Aβ42 deposition and concentration of the brain (Graff-Radford et al., 2007). A recent study compared Aβ40 and 42 production and clearance between AD patients and healthy control subjects, reporting similar cerebral production rates in the two groups but lower clearance rates in AD patients (Mawuenyega et al., 2010). In addition, different preclinical data showed impairment in the clearance operated by the blood-brain barrier as an early event in Aβ-mediated neurotoxicity (Deane et al., 2009). In fact, the concentration of the Aβ peptides in the brain is regulated not only by their synthesis from amyloid precursor protein (APP), but also by their crossing through the blood-brain barrier (BBB), which is mediated by active transports. The receptor for advanced glycation endproducts (RAGE) mainly regulates the entry of the Aβ soluble peptides through the BBB (Deane et al., 2003), while the LRP-1 (protein-1 relative to the receptor of the low-density lipoproteins) regulates their exit from the brain (Shibata et al., 2000, Deane et al., 2004; Deane and Zlokovic, 2004).
The expression of RAGE in the cerebral vessels endothelium is increased in AD mouse models and AD patients (Deane et al., 2003; Donahue et al., 2006; Miles et al., 2008), while LRP-1 expression is reduced (Shibata et al., 2000; Deane et al., 2004; Donahue et al., 2006). These changes would contribute to an Aβ increase in the brain, to its consequent oligomerization and, thus, to higher levels of the amyloid neurotoxic form. Given these findings, it would be
interesting to study whether and how the blood-brain barrier functionality is also affected during the illness course in patients with mood disorders. Some very recent PET studies demonstrated increased binding values in multiple cortical areas of patients with lifetime history of major depression relative to comparison healthy subjects (Wu et al., 2014) and that lifetime history of depression predicts increased amyloid-β accumulation in patients with MCI (Chung et al., 2015).
In any case, our finding of plasma Aβ alterations in bipolar patients leads us to investigate about possible neurodegenerative phenomena involved in bipolar disorder pathophysiology.
Further studies are needed in order to understand whether Aβ-mediated neurotoxicity might increase the risk for dementia and cognitive decline in our patients. It would be important to clarify whether a primarily “amyloid-associated” mood disorder with resistance to treatment and risk for cognitive decline exists, or whether neurodegenerative processes, mediated by Aβ and triggered by recurrence of affective episodes, represent an epiphenomenon in all patients with mood disorders. At the same time, further research should realize if plasmatic Aβ peptides may represent a good and reliable bio-marker of neurodegeneration and cognitive deterioration in depressed and bipolar patients, especially in those with high illness recurrence.
However, is mandatory to integrate an accurate cognitive assessment during the follow-up of patients suffering from mood disorders, particularly from bipolar disorder, in order to allow the early recognition of cognitive impairment. This represents an important issue to design adequate therapeutic treatments. Along this view, treatments potentiating the dopaminergic transmission and modulating the glutamatergic transmission should be considered for cognitive impaired bipolar patients.
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