Faculty Bibliography

Background: Several lines of evidence have implicated inflammatory pathways in major depressive disorder (MDD). These include reports of elevations in various pro-inflammatory cytokines including interleukin-6 (Il-6), interleukin-8 (IL-8), interleukin-1b (IL-1 beta). These cytokine elevations have also been reported in latelife depression and linked both to greater severity of baseline depressive symptoms and incident depression. A major drawback of existing cytokine studies is that they have been limited to determinations in plasma. Since these large molecules do not usually cross the blood-brain barrier, their relevance to neuroinflammation is not known. Most of these studies have also not included a neuroimaging component. This is particularly surprising, since white matter abnormalities implicated in depression may be especially sensitive to neuroinflammation. We examined a number of cytokines in both CSF and plasma in elderly individuals with MDD and healthy controls and hypothesized that elevations in certain cytokines would be found in MDD and would have a negative effect on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, IL-6, IL-8, IL-1 in were measured in CSF and plasma in 29 older subjects with MDD and 19 controls. MRI scans were performed to rule out structural brain abnormalities and to assess fractional anisotrophy (FA), a measure of white matter integrity. All had intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Results: Contrary to our prediction, there was no significant group difference in any of the CSF cytokines levels that we examined. However, consistent with previous reports, plasma IL-8 was elevated in individuals with MDD. Interestingly, in the entire sample, plasma IL-8 was negatively correlated with mean brain FA (r=-0.307; p=0.36). Conclusions: We found no evidence of CSF cytokine abnormalities in elderly subjects with MDD. However, there was an increase in plasma IL-8 in MDD, which merits further study because of its possible association with white matter pathology

Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer's disease (AD) have shown elevated levels of CSF NFL as compared to controls. However, the presence of the APOE epsilon4 allele, an established risk factor for AD, was not found to associate with higher CSF NFL concentrations. We examined whether TOMM40 variants, which have been reported to influence age of onset of AD and are in linkage disequilibrium with APOE, have an effect on CSF NFL levels, in 47 healthy, cognitively intact individuals with or without APOE epsilon4. Our results show that the presence of APOE epsilon4 alone does not affect CSF NFL levels significantly; however APOE and TOMM40 appear to interact. Subjects with APOE epsilon4 have higher CSF NFL levels than non-epsilon4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD, and may act as protective against the dose effect of epsilon4

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.

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been reported in subjects with Alzheimer's disease (AD) and may include increased cerebrospinal fluid (CSF) cortisol concentrations. Moreover, presence of the APOE varepsilon4 allele, which is an established risk factor for the development of AD, has been shown to associate with higher CSF cortisol levels, especially in AD sufferers. In this study, we examined whether TOMM40 variants, which have been reported to influence age of onset of AD, also had an effect on CSF cortisol levels, in healthy, cognitively intact individuals with or without APOE varepsilon4. In our results, the increase in CSF cortisol associated with the presence of the APOE varepsilon4 allele was only detected when a short TOMM40 poly-T variant, shown to associate with later age of onset of AD in varepsilon4 carriers, was not present. These results are consistent with previous reports (e.g., Roses et al., 2009) suggesting that TOMM40 poly-T variants influence the effects of APOE alleles

INTRODUCTION: Extensive evidence demonstrates that current cocaine abusers show hypoactivity in anterior cingulate and dorsolateral prefrontal cortex and respond poorly relative to drug-naive controls on tests of executive function. Relatively little is known about the cognitive sequelae of long-term abstinence in cocaine addicts. METHODS: Here, we use a GO-NOGO task in which successful performance necessitated withholding a prepotent response to assay cognitive control in short- and long-term abstinent cocaine users (1-5 weeks and 40-102 weeks, respectively). RESULTS: We report significantly greater activity in prefrontal, cingulate, cerebellar and inferior frontal gyrii in abstinent cocaine users for both successful response inhibitions and errors of commission. Moreover, this relative hyperactivity was present in both abstinent groups, which, in the presence of comparable behavioral performance, suggests a functional compensation. CONCLUSIONS: Differences between the short- and long-abstinence groups in the patterns of functional recruitment suggest different cognitive control demands at different stages in abstinence. Short-term abstinence showed increased inhibition-related dorsolateral and inferior frontal activity indicative of the need for increased inhibitory control while long-term abstinence showed increased error-related ACC activity indicative of heightened behavioral monitoring. The results suggest that the integrity of prefrontal systems that underlie cognitive control functions may be an important characteristic of successful long-term abstinence.

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.

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer's disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production by far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Ab), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Ab40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Ab42. Plasma Ab40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Ab40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Ab40, but not Ab42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, we examined BDNF and Ab levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Results: Consistent with our prediction, Ab40 was inversely correlated with BDNF concentrations (P <.001), whereas Ab42 was independent (P = .231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Ab40 (P = .001) and so was performance in delayed recall (P = .029). Conclusions: In cognitively intact individuals, circulating Ab40 results in reduction in plasma BDNF, white matter integrity (FA), and memory performance. As such, it may have prognostic significance

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of depression. Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF within the brain. Exposure of these cells to amyloid beta (Abeta), which may play a role in the pathophysiology of late-life depression, results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Abeta40 into the carotid artery resulted in a disruption of endothelial cells, which was not observed with Abeta42 infusion. Therefore, we hypothesized that concentrations of plasma Abeta40, but not Abeta42, would have a negative effect on plasma BDNF levels. Methods: We examined BDNF and Abeta levels in plasma via immunoblotting and ELISA assays, respectively, from 88 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. As these subjects were originally recruited for a study on major depressive disorder (MDD), 45 had MDD and 43 were age-matched controls. Results: Consistent with our prediction, Abeta40 levels were inversely correlated with BDNF concentrations (p<.001), whereas Abeta42 levels were independent of BDNF expression (p=.231). This pattern was similar when MDD and control subjects were analyzed separately. Discussion: Our results are consistent with the hypothesis that cerebral endothelial cells are a contributing source of peripheral BDNF and that their disruption by circulating Abeta40 results in reduction in BDNF. However, these preliminary findings need confirmation, and the mechanisms for our observation, including Abeta40-induced cerebral endothelial cell dysfunction, will have to be clarified

A variable poly-T polymorphism in the TOMM40 gene, which is in linkage disequilibrium with APOE, was recently implicated with increased risk and earlier onset age for late-onset Alzheimer's disease in APOE epsilon3 carriers. To elucidate potential neurobiological mechanisms underlying this association, we compared the effect of TOMM40 poly-T variants to the effect of APOE, an established LOAD-risk modulator, on cerebrospinal fluid (CSF) amyloid beta (Abeta) and tau levels, in cognitively intact elderly subjects. APOE epsilon4 carriers showed significant reductions in Abeta 1-42 levels compared to non-epsilon4 carriers, but no differences were detected across TOMM40 variants. Neither Abeta 1-40 nor tau levels were affected by APOE or TOMM40

Current cocaine-dependent users show reductions in white matter (WM) integrity, especially in cortical regions associated with cognitive control that have been associated with inhibitory dysfunction. A key question is whether these white matter differences are present following abstinence from drug use. To address this, WM integrity was examined using diffusion tensor imaging (DTI) obtained on 43 cocaine abstinent patients (abstinence duration ranged between five days and 102 weeks) and 43 non-using controls. Additionally, a cross-sectional comparison separated the patients into three groups (short-term, mid-term and long-term) based upon duration of cocaine abstinence. The 43 cocaine abstinent patients showed lower fractional anisotropy (FA) in the left anterior callosal fibers, left genu of the corpus callosum, right superior longitudinal fasciculus, right callosal fibers and the superior corona radiata bilaterally when compared against non-using controls. Higher FA in the cocaine abstinent patients was observed in the splenium of the corpus callosum and right superior longitudinal fasciculus. Differences between the cocaine abstinent groups were observed bilaterally in the inferior longitudinal fasciculus, right anterior thalamic radiation, right ventral posterolateral nucleus of the thalamus, left superior corona radiata, superior longitudinal fasciculus bilaterally, right cingulum and the WM of the right precentral gyrus. The results identified WM differences between cocaine abstinent patients and controls as well as distinct differences between abstinent subgroups. The findings suggest that specific white matter differences persist throughout abstinence while other, spatially distinct, differences discriminate as a function of abstinence duration. These differences may, therefore, represent brain changes that mark recovery from addiction