Late life depression with cognitive impairment: Evaluation and treatment

Older adults with depression often present with signs and symptoms indicative of functional or cognitive impairment. These somatic symptoms make evaluating and treating depression in older adults more complex. Late life depression (LLD), depression in adults over the age of 65, is more frequently associated with cognitive changes. Cognitive impairment in LLD may be a result of the depressive disorder or an underlying dementing condition. Memory complaints are also common in older adults with depression. There is a wide range of cognitive impairment in LLD including decreased central processing speed, executive dysfunction, and impaired short-term memory. The etiology of cognitive impairment in LLD may include cerebrovascular disease, a significant risk factor for LLD, which likely interrupts key pathways between frontal white matter and subcortical structures important in mood regulation. Because depressive symptoms often coexist with dementia, it is important to determine the temporal relationship between depressive symptoms and cognitive change. If depressive symptoms pre-date the cognitive impairment and cognitive symptoms are mild and temporary, LLD is the likely etiology of the cognitive impairment. If cognitive changes appear prior to depressive symptoms and persist after LLD is successfully treated, an underlying dementia is more likely. Clinicians should be exclude common conditions such as thyroid disease which can contribute to depressive symptoms and cognitive impairment prior to treating LLD. Both antidepressants and psychotherapy can be effective in treating LLD. Subsequent evaluations following treatment should also reassess cognition

Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo

BACKGROUND: The aggregation of amyloid-β (Aβ) into insoluble plaques is a hallmark pathology of Alzheimer’s disease (AD). Previous work has shown increasing serotonin levels with selective serotonin re-uptake inhibitor (SSRI) compounds reduces Aβ in the brain interstitial fluid (ISF) in a mouse model of AD and in the cerebrospinal fluid of humans. We investigated which serotonin receptor (5-HTR) subtypes and downstream effectors were responsible for this reduction. RESULTS: Agonists of 5-HT(4)R, 5-HT(6)R, and 5-HT(7)R significantly reduced ISF Aβ, but agonists of other receptor subtypes did not. Additionally, inhibition of Protein Kinase A (PKA) blocked the effects of citalopram, an SSRI, on ISF Aβ levels. Serotonin signaling does not appear to change gene expression to reduce Aβ levels in acute timeframes, but likely acts within the cytoplasm to increase α-secretase enzymatic activity. Broad pharmacological inhibition of putative α-secretases increased ISF Aβ and blocked the effects of citalopram. CONCLUSIONS: In total, these studies map the major signaling components linking serotonin receptors to suppression of brain ISF Aβ. These results suggest the reduction in ISF Aβ is mediated by a select group of 5-HTRs and open future avenues for targeted therapy of AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-016-0112-5) contains supplementary material, which is available to authorized users

Frontal White Matter Anisotropy and Antidepressant Remission in Late-Life Depression

10.1371/journal.pone.0003267PLoS ONE39

Altered emotional interference processing in the amygdala and insula in women with Post-Traumatic Stress Disorder

AbstractBackgroundPost-Traumatic Stress Disorder (PTSD) is characterized by distinct behavioral and physiological changes. Given the significant impairments related to PTSD, examination of the biological underpinnings is crucial to the development of theoretical models and improved treatments of PTSD.MethodsWe used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 32 women with PTSD (based on an interpersonal trauma) and 21 matched controls were tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli.ResultsCompared to controls, patients with PTSD showed hyperactivity in several brain regions, including the amygdala, insula, as well as dorsal lateral and ventral PFC regions.ConclusionsThese results are consistent with previous studies that have higher amygdala and insular activation in PTSD subjects. However, inhibition of suppression of PFC regions is inconsistent with the fear circuitry model hypothesized by prior research. We suggest that the specific emotional conflict task used appears to target implicit or automatic emotional regulation instead of explicit or effortful emotional regulation. This is particularly relevant as it posited that emotional regulatory difficulties in anxiety disorders such as PTSD appear to occur in implicit forms of emotion regulation

APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42

Identifying high risk populations is an important component of disease prevention strategies. One approach is examining neuroimaging parameters that differ in Alzheimer’s disease (AD), including functional connections known to be disrupted within the “default mode network” (DMN). We have previously shown these same disruptions in cognitively normal elderly, who have amyloid-beta (Aβ) plaques detected using PIB PET imaging, suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aβ plaque toxicity by examining resting state fMRI functional connectivity (fcMRI ) in participants without preclinical fibrillar amyloid deposition (PIB−). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB− were categorized into those with and without an APOE 4 allele and studied using fcMRI. APOE 4 allele carriers (E4+) differed significantly from E4− in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed prior to any manifestations of cognitive changes and in the absence of brain fibrillar amyloid-beta (Aβ) plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity

Childhood Trauma History Is Linked To Abnormal Brain Connectivity In Major Depression

Patients with major depressive disorder (MDD) present with heterogeneous symptom profiles, while neurobiological mechanisms are still largely unknown. Brain network studies consistently report disruptions of resting-state networks (RSNs) in patients with MDD, including hypoconnectivity in the frontoparietal network (FPN), hyperconnectivity in the default mode network (DMN), and increased connection between the DMN and FPN. Using a large, multisite fMRI dataset ( n = 189 patients with MDD, n = 39 controls), we investigated network connectivity differences within and between RSNs in patients with MDD and healthy controls. We found that MDD could be characterized by a network model with the following abnormalities relative to controls: ( i ) lower within-network connectivity in three task-positive RSNs [FPN, dorsal attention network (DAN), and cingulo-opercular network (CON)], ( ii ) higher within-network connectivity in two intrinsic networks [DMN and salience network (SAN)], and ( iii ) higher within-network connectivity in two sensory networks [sensorimotor network (SMN) and visual network (VIS)]. Furthermore, we found significant alterations in connectivity between a number of these networks. Among patients with MDD, a history of childhood trauma and current symptoms quantified by clinical assessments were associated with a multivariate pattern of seven different within- and between-network connectivities involving the DAN, FPN, CON, subcortical regions, ventral attention network (VAN), auditory network (AUD), VIS, and SMN. Overall, our study showed that traumatic childhood experiences and dimensional symptoms are linked to abnormal network architecture in MDD. Our results suggest that RSN connectivity may explain underlying neurobiological mechanisms of MDD symptoms and has the potential to serve as an effective diagnostic biomarker