State-dependent alterations in cerebrospinal fluid Aß42 levels in cognitively intact elderly with late-life major depression.

Depression has been linked to Alzheimer's disease as either an increased risk factor for its development or as a prodromal symptom. The neurobiological basis for such an association, however, remains poorly understood. Numerous studies have examined whether changes in amyloid beta (Aß) metabolism, which are implicated in the pathogenesis of Alzheimer's disease, are also found in depression. In this paper, we investigated the relationship between depressive symptoms and cerebrospinal fluid (CSF) Aß indices in otherwise healthy, cognitively normal elderly with late-life major depression (LLMD) and controls using a longitudinal approach, which is a novel contribution toward the literature. Significantly lower levels of CSF Aß42 were observed in the LLMD group at baseline and were associated with more severe depressive symptoms. During longitudinal follow-up, the depressed group remained cognitively unchanged, but was significantly less depressed than at baseline. A greater improvement in depressive symptoms was associated with increases in CSF Aß42 levels in both groups. Increases in CSF Aß42 and Aß40 were also associated with increased CSF total-tau levels. Our results suggest that LLMD may be associated with state-dependent effects of CSF Aß42 levels. Future studies should determine whether the association reflects state-dependent changes in neuronal activity and/or brain amyloid burden in depression.

Lower CSF amyloid beta peptides and higher F2-isoprostanes in cognitively intact elderly individuals with major depressive disorder.

OBJECTIVE: Major depressive disorder is common in the elderly, and symptoms are often not responsive to conventional antidepressant treatment, especially in the long term. Soluble oligomeric and aggregated forms of amyloid beta peptides, especially amyloid beta 42, impair neuronal and synaptic function. Amyloid beta 42 is the main component of plaques and is implicated in Alzheimer's disease. Amyloid beta peptides also induce a depressive state in rodents and disrupt major neurotransmitter systems linked to depression. The authors assessed whether major depression was associated with CSF levels of amyloid beta, tau protein, and F2-isoprostanes in elderly individuals with major depressive disorder and age-matched nondepressed comparison subjects. METHOD: CSF was obtained from 47 cognitively intact volunteers (major depression group, N=28; comparison group, N=19) and analyzed for levels of soluble amyloid beta, total and phosphorylated tau proteins, and isoprostanes. RESULTS: Amyloid beta 42 levels were significantly lower in the major depression group relative to the comparison group, and amyloid beta 40 levels were lower but only approaching statistical significance. In contrast, isoprostane levels were higher in the major depression group. No differences were observed in total and phosphorylated tau proteins across conditions. Antidepressant use was not associated with differences in amyloid beta 42 levels. CONCLUSIONS: Reduction in CSF levels of amyloid beta 42 may be related to increased brain amyloid beta plaques or decreased soluble amyloid beta production in elderly individuals with major depression relative to nondepressed comparison subjects. These results may have implications for our understanding of the pathophysiology of major depression and for the development of treatment strategies.

Plasma BDNF levels vary in relation to body weight in females.

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted.

Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly.

OBJECTIVES: The objectives of this study were to examine the relationship between APOE epsilon4 and subjective effects of trihexyphenidyl on measures reflecting sedation and confusion and to investigate the relationship between trihexyphenidyl-induced subjective effects and objective memory performance. METHODS: This study comprised 24 cognitively intact, health elderly adults (12 APOE epsilon4 carriers) at an outpatient geriatric psychiatry research clinic. This was a randomized, double blind, placebo-controlled, three-way, crossover experimental design. All participants received 1.0 mg or 2.0 mg trihexyphenidyl or placebo administered in counterbalanced sequences over a period of three consecutive weeks. Bond and Lader's visual analog scales and alternate versions of the Buschke Selective Reminding Test were administered in a repeated measures design at baseline, 1, 2.5, and 5 hours postdrug administration. RESULTS: A 2.0-mg oral dose of trihexyphenidyl resulted in increased subjective ratings of mental slowness in carriers of the APOE epsilon4 allele only. Drug effects as determined by difference scores between 2.0 mg trihexyphenidyl and placebo on ratings of mental slowness significantly correlated with total and delayed recall on the Buschke Selective Reminding Test in carriers of the APOE epsilon4 allele only. However, no significant effects were found with other visual analog scales reflecting subjective sedation and clear-headedness. CONCLUSION: The epsilon4 allele in healthy elderly was associated with increased subjective mental slowing after trihexyphenidyl anticholinergic challenge.

The effect of mifepristone (RU 486) on plasma cortisol in Alzheimer's disease.

The glucocorticoid receptor (GR) antagonist mifepristone (RU-486) has been reported to increase early morning plasma ACTH/cortisol in diverse non-demented populations. This pilot study examined the cortisol response to RU 486 in patients with Alzheimer's disease (AD), a condition associated with abnormalities in various aspects of the hypothalamic-pituitary-adrenal (HPA) axis. Nine AD subjects were randomized in a placebo-controlled parallel study: 4 in the placebo group and 5 in the RU 486 group. Subjects received oral doses of RU 486 (200 mg) or placebo daily for 6-weeks. Morning plasma cortisol was determined at baseline, at 12 h following the first study drug dose, and weekly thereafter. RU 486 resulted in a significant increase in cortisol levels [F(1,6)=65.32; P<0.001]. The magnitude of this increase grew over the course of the study [F(1,6)=63.17; P<0.001], was not related to cortisol suppression after dexamethasone and appeared greater than that reported in the literature in younger populations in response to the same drug regimen. However, further studies with age-matched controls should be done to determine possible AD related changes in this response.