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    • Moreover a multiple regression analysis using the

    2023-08-30

    Moreover, a multiple regression analysis using the 1-year MMSE score as a dependent variable was conducted. The result showed that serum Protease Inhibitor Cocktail (EDTA-Free, 200X in DMSO) levels at admission did not affect the MMSE score 1 year later (β = 0.10, p = 0.639).
    Discussion In this study, serum Aβ42 levels were significantly lower, and Aβ40/Aβ42 ratios significantly higher, in patients with MDD compared with comparisons, consistent Protease Inhibitor Cocktail (EDTA-Free, 200X in DMSO) with our previous reports (Baba et al., 2012, Namekawa et al., 2013). At the time of admission, serum cortisol was not correlated with the serum Aβ levels, disagreeing with our hypothesis. However, serum cortisol levels at admission did correlate with serum Aβ42 levels and Aβ40/Aβ42 ratios 1 year later. Pomara and Murali Doraiswamy (2003) first raised the possibility of Aβ abnormalities in depression, and reported higher plasma Aβ42 levels in elderly patients with MDD. Moon et al. (2011) also found higher Aβ42 plasma levels in elderly patients with depressive symptoms. In contrast, Qiu et al. and Sun et al. reported lower plasma Aβ42 levels and higher Aβ40/Aβ42 ratios in a large sample of elderly depressive individuals (Qiu et al., 2007, Sun et al., 2007, Sun et al., 2008, Sun et al., 2009). However, these previous studies investigated elderly subjects, so it is possible that the subjects include patients in the early or preclinical stages of dementia. Our previous study demonstrated lower Aβ42 levels and higher Aβ40/Aβ42 ratios in 193 patients with MDD (age range, 27−84 years) compared with 413 healthy controls, and found similar findings even in younger subjects (Baba et al., 2012). The present study also examined patients with a wide age range (26−84 years), and these results are consistent with our previous reports. The current results show higher serum cortisol levels in patients with MDD than comparisons. Most studies have shown that patients with MDD have increased cortisol secretion (Pariante and Lightman, 2008, Marques et al., 2009), consistent with our results. Hyperactivity of the HPA axis is a common finding in patients with MDD (Pariante and Lightman, 2008, Marques et al., 2009), and dysregulation has also been observed in patients with AD (Rothman and Mattson, 2010). Increased cortisol levels have been reported in the CSF (Davis et al., 1986, Popp et al., 2009, Popp et al., 2015), plasma (Davis et al., 1986, Martignoni et al., 1990, Umegaki et al., 2000, Csernansky et al., 2006, Zverova et al., 2013), and serum (Rasmuson et al., 2002, Laske et al., 2009) in patients with AD. Increased plasma cortisol levels have been associated with more rapid increases in the symptoms of dementia and more rapid decreases in cognitive performance (Csernansky et al., 2006). Moreover, it has been reported that serum cortisol levels are significantly inversely correlated with CSF levels of total-tau, and phosphorylated-tau, and have a trend towards a positive correlation with CSF Aβ42 levels (Laske et al., 2009). Green et al.(Green et al., 2006) administered GC at levels relating to physiological stress into an AD mouse model. Their results revealed increased steady-state levels of amyloid precursor protein and β-secretase in GC-treated AD mouse, resulting in increased Aβ levels and Aβ deposition in the brain. They also found accelerated development of tau pathology as a result of GC administration. From these results, the authors suggested that GC may play an important role in the development and progression of AD. In the present study, the serum Aβ42 levels and Aβ40/Aβ42 ratios at admission were correlated with the number of depressive episodes. Thus, we speculate that facilitation of the HPA axis occurs with increasing numbers of depressive episodes. In this study, however, serum cortisol levels at admission were not related to simultaneous serum Aβ levels. However, serum cortisol levels at admission did correlate with serum Aβ42 levels and Aβ40/Aβ42 ratios 1 year later. Kulstad et al. (2005) chronically (12 months) administered high-dose GC (cortisol) and placebo to macaques. GC-treated macaques showed increased Aβ42 levels and decreased Aβ40 levels in the inferior frontal cortex, as well as decreased plasma Aβ42 levels. Moreover, the changes in plasma Aβ42 levels negatively correlated with CSF cortisol levels. The authors suggested that the plasma Aβ42 level decreases were provoked by increased GC, and that these changes may have a cumulative physiological impact when they persist over prolonged periods of time. Combining these previous reports and our results, we speculate that cortisol elevation in patients with MDD may affect the metabolism of Aβ, and that this change may gradually progress over a long time. Higher HAM-D scores and higher cortisol levels at admission were correlated with lower Aβ42 levels and higher Aβ40/Aβ42 ratios 1 year later. From these results, we speculate that longer-term exposure to higher levels of cortisol may be related to larger alterations in amyloid metabolism.