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Structural brain networks in remitted psychotic depression

Neufeld, Nicholas H; Kaczkurkin, Antonia N; Sotiras, Aristeidis; Mulsant, Benoit H; Dickie, Erin W; Flint, Alastair J; Meyers, Barnett S; Alexopoulos, George S; Rothschild, Anthony J; Whyte, Ellen M; Mah, Linda; Nierenberg, Jay; Hoptman, Matthew J; Davatzikos, Christos; Satterthwaite, Theodore D; Voineskos, Aristotle N
Major depressive disorder with psychotic features (psychotic depression) is a severe disorder. Compared with other psychotic disorders such as schizophrenia, relatively few studies on the neurobiology of psychotic depression have been pursued. Neuroimaging studies investigating psychotic depression have provided evidence for distributed structural brain abnormalities implicating the insular cortex and limbic system. We examined structural brain networks in participants (N = 245) using magnetic resonance imaging. This sample included healthy controls (n = 159) and the largest cross-sectional sample of patients with remitted psychotic depression (n = 86) collected to date. All patients participated in the Study of Pharmacotherapy of Psychotic Depression II randomized controlled trial. We used a novel, whole-brain, data-driven parcellation technique-non-negative matrix factorization-and applied it to cortical thickness data to derive structural covariance networks. We compared patients with remitted psychotic depression to healthy controls and found that patients had significantly thinner cortex in five structural covariance networks (insular-limbic, occipito-temporal, temporal, parahippocampal-limbic, and inferior fronto-temporal), confirming our hypothesis that affected brain networks would incorporate cortico-limbic regions. We also found that cross-sectional depression and severity scores at the time of scanning were associated with the insular-limbic network. Furthermore, the insular-limbic network predicted future severity scores that were collected at the time of recurrence of psychotic depression or sustained remission. Overall, decreased cortical thickness was found in five structural brain networks in patients with remitted psychotic depression and brain-behavior relationships were observed, particularly between the insular-limbic network and illness severity.
PMID: 32109935
ISSN: 1740-634x
CID: 4324472

Complement component 3 levels in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder

Pillai, Anilkumar; Bruno, Davide; Nierenberg, Jay; Pandya, Chirayu; Feng, Tami; Reichert, Chelsea; Ramos-Cejudo, Jaime; Osorio, Ricardo; Zetterberg, Henrik; Blennow, Kaj; Pomara, Nunzio
Late-life major depression (LLMD) is a risk factor for the development of mild cognitive impairment and dementia, including Alzheimer's disease (AD) and vascular dementia. Immune dysregulation and changes in innate immune responses in particular, have been implicated in the pathophysiology of both LLMD and AD. Complement system, a key component of the innate immune mechanism, is known to play an important role in synaptic plasticity and cognitive functions. However, its role in LLMD remains unknown. In the present study, we examined the levels of complement component 3 (C3, the convergence point of all complement activation pathways) in the cerebrospinal fluid (CSF) of elderly depressed subjects compared to healthy controls; as well as the relationship of CSF C3 levels with amyloid-beta (Aβ42 and Aβ40), total tau (T-tau) and phosphorylated tau (P-tau) proteins and cognition scores. CSF was obtained from 50 cognitively intact volunteers (major depression group, N = 30; comparison group, N = 20) and analyzed for levels of C3 by ELISA. C3 levels were marginally lower in the major depression group relative to the comparison group. We did not find any significant association of C3 with the AD biomarkers Aβ42 reflecting plaque pathology, P-tau related to tau pathology or the neurodegeneration biomarker T-tau. In contrast, C3 was positively correlated with CSF Aβ40, which may reflect Aβ deposition in cerebral vessel walls. We observed a negative correlation between C3 levels and Total Recall on the Buschke Selective Reminding Test (BSRT) for memory performance in the depressed subjects when controlling for education. This initial evidence on C3 status in LLMD subjects may have implications for our understanding of the pathophysiology of major depression especially in late life.
PMID: 31942568
ISSN: 2666-1446
CID: 4263682

CSF butyrylcholinesterase and acetyl-cholinesterase activity and their relationship to pro-inflammatory cytokines in late-life major depression [Meeting Abstract]

Pomara, N.; Bruno, D.; Nierenberg, J.; Reichert, C.; Fu, M.; Zetterberg, H.; Blennow, K.
ISSN: 0924-977x
CID: 3827672

Use of Functional Magnetic Resonance Imaging to Identify Risk Factors for Relapse in Patients With Stimulant Use Disorders: Bridging the Gap Between Research and Clinical Practice

Nierenberg, Jay
PMID: 30646324
ISSN: 2574-3805
CID: 3594802

Reduction in CSF STREM2, a biomarker of microglia activation, in elderly depressives [Meeting Abstract]

Pomara, N; Bruno, D; Nierenberg, J; Zetterberg, H; Blennow, K; Heslegrave, A; Foiani, M
Background: Both intense microglia activation and senescence, which respectively lead to marked and reduced inflammatory responses, have each been implicated in the etiology of depression. However, to date, results from postmortem and PET studies of microglial status have been negative or inconclusive, perhaps reflecting the heterogeneity of microglia dysfunction in this disorder, and the lack of specificity of the neuroimaging ligands for microglia. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane innate immune receptor of the immunoglobulin family; in brain, it is found exclusively on microglia. TREM2 variants have been associated with increased risk for AD and other degenerative disorders. It undergoes proteolytic cleavage generating a soluble form (sTREM2), found in CSF, and emerging data suggest that its levels may reflect microglia activation. These considerations prompted us to determine if elderly cognitively-intact individuals with a DSM-IV diagnosis of late-life major depression (LLMD) differ from healthy controls with respect to CSF sTREM2 and its relationship to depressive symptoms. Additionally, because of the association between depression and increased risk for AD, we also determined its relationship to CSF AD biomarkers. Methods: CSF was obtained from 47 older subjects with intact cognition having an MMSE score of at least 28 and no gross MRI abnormalities other than white matter hyperintensities (28 LLMDs, 19 Healthy controls). CSF sTREM2 was determined using an electrochemiluminescence immunoassay. Severity of depression was determined at the baseline and screening visits using the HAM-D. Results: CSF sTREM2 was significantly (p<.05) reduced in LLMD compared to controls. CSF sTREM2 was significantly (negatively) correlated with baseline HAM-D scores in the entire sample and in the depressed group separately. As previously reported in cognitively-intact populations, CSF sTREM2 was significantly (positively) correlated with CSF Abeta42, Abeta40, tau and p-tau. Antidepressant treatment and APOE-e4 status had no effect on CSF sTREM2. Conclusions: The reduction in CSF sTREM2 level in LLMD and its association with more depressive symptoms suggest that decreased rather than increased microglia activation may contribute to the pathophysiology of this disorder. Future studies should determine how lower CSF sTREM2 levels may relate to activated M1 (pro-inflammatory) or M2 (anti-inflammatory) microglia phenotypes and to inflammatory and AD brain PET biomarkers
ISSN: 1740-634x
CID: 2955442

Basal forebrain mediated increase in brain CRF is associated with increased cholinergic tone and depression

Gollan, Jackie K; Dong, Hongxin; Bruno, Davide; Nierenberg, Jay; Nobrega, Jose N; Grothe, Michel J; Pollock, Bruce G; Marmar, Charles R; Teipel, Stefan; Csernansky, John G; Pomara, Nunzio
PMID: 28477491
ISSN: 1872-7123
CID: 2548752

Increased levels of ascorbic acid in the cerebrospinal fluid of cognitively intact elderly patients with major depression: a preliminary study

Hashimoto, Kenji; Ishima, Tamaki; Sato, Yasunori; Bruno, Davide; Nierenberg, Jay; Marmar, Charles R; Zetterberg, Henrik; Blennow, Kaj; Pomara, Nunzio
Major depressive disorder (MDD) in the elderly is a risk factor for dementia, but the precise biological basis remains unknown, hampering the search for novel biomarkers and treatments. In this study, we performed metabolomics analysis of cerebrospinal fluid (CSF) from cognitively intact elderly patients (N = 28) with MDD and age- and gender-matched healthy controls (N = 18). The CSF levels of 177 substances were measured, while 288 substances were below the detection limit. Only ascorbic acid was significantly different, with higher levels in the MDD group at baseline. There were no correlations between CSF ascorbic acid levels and clinical variables in MDD patients at baseline. At the 3-year follow-up, there was no difference of CSF ascorbic acid levels between the two groups. There was a negative correlation between CSF ascorbic acid and CSF amyloid-beta42 levels in all subjects. However, there were no correlations between ascorbic acid and other biomarkers (e.g., amyloid-beta40, total and phosphorylated tau protein). This preliminary study suggests that abnormalities in the transport and/or release of ascorbic acid might play a role in the pathogenesis of late-life depression.
PMID: 28615661
ISSN: 2045-2322
CID: 2593722

The recency ratio is associated with reduced CSF glutamate in late-life depression

Bruno, Davide; Nierenberg, Jay; Cooper, Thomas B; Marmar, Charles R; Zetterberg, Henrik; Blennow, Kaj; Hashimoto, Kenji; Pomara, Nunzio
Glutamate is the principal excitatory neurotransmitter in the central nervous system, and is thought to be involved in the process of memory encoding and storage. Glutamate disturbances have also been reported in psychiatric disorders, such as schizophrenia and major depressive disorder (MDD), and in Alzheimer's disease. In this paper, we set out to study the relationship between cerebrospinal fluid (CSF) glutamate levels and memory performance, which we believe has not been reported previously. In particular, we focused on recall performance broken down by serial position. Our prediction was that the recency ratio (Rr), a novel cognitive marker of intellectual impairment, would be linked with CSF glutamate levels. We studied data from a group of cognitively intact elderly individuals, 28 of whom had MDD, while 19 were controls. Study results indicated that Rr levels, but no other memory score, were inversely correlated with CSF glutamate levels, although this was found only in individuals with late-life MDD. For comparison, glutamine or GABA were not correlated with any memory performance measure.
PMID: 28323201
ISSN: 1095-9564
CID: 3080692

Selective and state-dependent changes in CSF abeta42 levels in cognitively-intact elderly with late life major depression [Meeting Abstract]

Pomara, N; Nierenberg, J; Bruno, D; Reichert, C; Osorio, R; Sarreal, A; Hernando, R; Marmar, C; Wisniewski, T; Zetterberg, H; Blennow, K
Background: Numerous studies have linked depressive symptoms, or syndromal depression, to increased risk for Alzheimer's disease (AD) irrespective of its onset age. The neurobiological basis for this association, however, remains poorly understood. Studies which have examined biomarkers of AD in peripheral and central tissues in depression, including CSF Abeta42 (Abeta42) and brain amyloid using PET ligands, have provided conflicting results. These discrepant results may have been due to methodological differences across studies, including heterogeneity in study populations (e.g., inclusion of individuals with mild cognitive impairment) and the use of approaches for detecting depression (e.g., patients' self-ratings) that lack diagnostic specificity. In addition, only a few studies have employed structured interviews based on DSM diagnostic criteria or standardized pre-analytical and laboratory procedures for quantifying Abeta. Finally, all of the existing studies have been limited to cross sectional comparisons based on a single Abeta determination; thus, it is not known if these abnormalities persist over time and if depressive symptoms influence Abeta levels. The current study was conducted to address the aforementioned limitations. Methods: Our baseline sample consisted of 47 subjects aged 60 years and older; 28 with LMDD and 19 controls. Of the 47 older subjects, 31 were e4 non-carriers and 16 were e4 carriers. All subjects were cognitively-intact and had a) no evidence of dementia, b) a Mini-Mental State Exam score of at least 28, and c) no gross MRI abnormalities other than white matter hyperintensities. CSF collection was repeated after 3 years for 36 of these individuals: 19 with LLMD and 17 controls. We evaluated the effects of diagnosis and time on Abeta42 levels with 2 x 2 repeated measures ANOVA. Results: Longitudinal comparisons of controls and LLMD revealed that the LLMD group was significantly less depressed at follow up than at baseline, as determined by the HAM-D, whereas controls remained unchanged. There was a significant interaction between diagnosis and time on CSF Abeta42 levels. Importantly, the reductions in depressive symptoms observed over time were significantly correlated with increases in CSF Abeta42 levels, both in the entire cohort (r =-.451, p =.006) and within the LLMD group (r =-.547, p =.015), but not in the control group (p =.809). The same relationship was not significant with Abeta40 (Pomara et al., 2016). Performance on cognitive indices remained unchanged and was not significantly correlated with changes in AD Biomarkers. Conclusions: Cognitively-intact, elderly individuals with LLMD, who were more depressed at baseline, but less depressed at the 3 year follow-up, showed both a reduction in baseline CSF Abeta42 (Pomara et al., 2012) and elevation in Abeta42 at 3 year follow-up. In addition, changes in CSF Abeta42 were correlated with changes in depressive symptoms. Future studies should determine if these state-dependent changes in Abeta42 mediate the increased risk of AD contributed by LLMD. If this is the case, the need for more aggressive treatment of LLMD cannot be underestimated
ISSN: 1740-634x
CID: 2397672

State-dependent alterations in cerebrospinal fluid Abeta42 levels in cognitively intact elderly with late-life major depression

Pomara, Nunzio; Bruno, Davide; Osorio, Ricardo S; Reichert, Chelsea; Nierenberg, Jay; Sarreal, Antero S; Hernando, Raymundo T; Marmar, Charles R; Wisniewski, Thomas; Zetterberg, Henrik; Blennow, Kaj
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 (Abeta) 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) Abeta 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 Abeta42 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 Abeta42 levels in both groups. Increases in CSF Abeta42 and Abeta40 were also associated with increased CSF total-tau levels. Our results suggest that LLMD may be associated with state-dependent effects of CSF Abeta42 levels. Future studies should determine whether the association reflects state-dependent changes in neuronal activity and/or brain amyloid burden in depression.
PMID: 27508979
ISSN: 1473-558x
CID: 2213652