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  • Hyperactivity of the hypothalamus pituitary adrenal HPA axis

    2022-12-01

    Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is well described in MDD (Pariante and Lightman, 2008, Marques et al., 2009), is also observed in AD and results in increased glucocorticoid Fmoc-Phe-OH receptor (GC, cortisol in primates) levels in blood and CSF (Davis et al., 1986, Martignoni et al., 1990, Rasmuson et al., 2001, Rasmuson et al., 2002, Crochemore et al., 2005, Krishnan and Nestler, 2008, Popp et al., 2009, Popp et al., 2015, Caraci et al., 2010, Chi et al., 2014). Stressful stimuli induce hyperactivity of the HPA-axis and result in an increase of GC secretion from the adrenal cortex. Normally, the GC increase is transient due to a negative-feedback system (Sapolsky et al., 1986). In patients with depression and AD, impairment of the negative-feedback system has been suggested to occur. Excessively increased GC may damage neural Fmoc-Phe-OH receptor in the hippocampus, inducing hippocampal volume loss and memory impairment (Butters et al., 2008, Sierksma et al., 2010, Byers and Yaffe, 2011). Interestingly, some studies have demonstrated that GC administration increases Aβ and tau pathology in a mouse model of AD (Green et al., 2006), and that chronic GC administration decreases plasma Aβ42 levels in a macaque (Kulstad et al., 2005).
    Methods
    Results The detailed demographic and clinical features of participants, serum Aβ40 and Aβ42 levels, Aβ40/Aβ42 ratios, and cortisol levels at admission are shown in Table 1. No significant differences in education, MMSE scores or ApoE4 frequencies were identified between MDD patients and healthy comparisons. Comparisons were significantly younger than MDD patients (p < 0.001), and there were significantly more female comparisons than female with MDD (p < 0.001). There were no differences in serum Aβ40 levels between patients with MDD and comparisons. However, serum Aβ42 levels were significantly lower (p < 0.001), and Aβ40/Aβ42 ratios significantly higher (p < 0.001), in patients with MDD compared with comparisons. Cortisol levels were significantly higher (p = 0.003) in patients with MDD compared with comparisons. Multiple regression analysis showed that Aβ40 levels at admission were not correlated with any variables. Aβ42 levels at admission did correlate with the number of depressive episodes (β = 0.25, p = 0.012) and tended to relate to cortisol level (β = −0.17, p = 0.074). Aβ40/Aβ42 ratios at admission did correlate with the number of depressive episodes (β = −0.24, p = 0.015) but not cortisol levels (β = 0.31, p = 0.181) (Table 3). Similar results were found in non-ApoE4 carriers (data not shown). When a multiple regression analysis was conducted including ApoE4 as a dependent variable, ApoE4 did not influence the Aβs results (data not shown), suggesting that the relationship between Aβ and cortisol was independent of ApoE4. To exclude the possible influence of preclinical dementia, the analysis was performed using only patients under 65 years (n = 129), giving similar results (data not shown). Of the patients with MDD, 27 were followed for 1 year and their Aβs re-assessed (most patients transited to another hospital or clinic from our university hospital, and several patients refused re-examination). All the follow-up patients were in remission (HAM-D < 7) at the time of re-assessment. The admission data of only 27 patients who were re-assessed 1 year later were used for comparison of Aßs between admission and 1 year later. The comparison data of Aβs in these 27 patients of the MDD group at admission and 1 year after are indicated in Table 2. Aβ40/Aβ42 ratios 1 year later were significantly lower compared with those at admission (p = 0.001). The Aβs of these 27 patients were compared with those of the healthy comparisons using the Mann–Whitney U test. In this small number of patients, the serum levels of Aβ40 at admission were not different from those of the healthy comparisons (p = 0.444); 1 year later, however, the Aβ40 levels were significantly lower than those in the healthy comparisons (p = 0.033). At admission, the levels of serum Aβ42 were lower (p = 0.001) and Aβ40/Aβ42 ratios were higher (p = 0.025) in patients compared with healthy comparisons. For patients were tested 1 year later, however, Aβ42 levels (p = 0.067) and Aβ40/Aβ42 ratios (p = 0.061) did not differ significantly from comparisons. We conducted multiple regression analysis using the 1-year Aβ results as dependent variables, and the same independent variables as previously, including cortisol level at admission. Aβ40 levels 1 year later were not significantly correlated with any variable. Aβ42 levels 1 year later were significantly and negatively correlated with HAM-D scores (β = −0.62, p = 0.015) and cortisol levels (β = −0.43, p = 0.046) at admission. Aβ40/Aβ42 ratios at 1 year were significantly and positively correlated with HAM-D scores (β = 0.64, p = 0.011) and cortisol levels (β = 0.62, p = 0.005) at admission. Higher cortisol levels at admission were correlated with lower Aβ42 levels and higher Aβ40/Aβ42 ratios 1 year later. Additionally, higher HAM-D scores at admission were correlated with lower Aβ42 levels and higher Aβ40/Aβ42 ratios 1 year later.