Faculty Bibliography
Searched for:
person:pomarn01
in-biosketch:true
Total Results:
204
Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder
BACKGROUND:Inflammatory mechanisms are believed to contribute to the manifestation of major depressive disorder (MDD). Central cholinergic activity may moderate this effect. Here, we tested if volume of the cholinergic basal forebrain is associated with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglial activation in people with late life MDD. METHODS:Basal forebrain volume was determined from structural MRI scans and levels of CSF sTREM2 with immunoassay in 29 people with late-life MDD and 20 healthy older controls at baseline and 3 years follow-up. Associations were determined using Bayesian analysis of covariance. RESULTS:and total tau. Evidence was in favor of absence of an effect for baseline levels of CSF sTREM2 in MDD cases and for baseline and follow up data in controls. LIMITATIONS/CONCLUSIONS:The sample size of repeated CSF examinations was relatively small. Therefore, we used Bayesian sequential analysis to assess if effects were affected by sample size. Still, the number of cases was too small to stratify effects for different antidepressive treatments. CONCLUSIONS:Our data agree with the assumption that central cholinergic system integrity may contribute to regulation of microglia activity in late-life MDD.
PMID: 34246952
ISSN: 1573-2517
CID: 4936262
Brain Amyloid Deposition in Late-Life Depression [Letter]
PMID: 33189332
ISSN: 1873-2402
CID: 4672172
Evidence of upregulation of the cholinergic anti-inflammatory pathway in late-life depression
BACKGROUND:Decreased cholinergic tone associated with increased proinflammatory cytokines has been observed in several human diseases associated with low-grade inflammation. We examined if this attenuated cholinergic anti-inflammatory pathway (CAP) mechanism contributed to increased neuroinflammation observed in depression. METHODS:We measured cerebrospinal fluid (CSF) cholinergic markers (AChE and BChE activities) in 28 individuals with longstanding late-life major depression (LLMD) and 19 controls and their relationship to central and peripheral levels of pro-inflammatory cytokines (IL-6 and IL-8). Additionally, we examined if these cholinergic indices were related to CSF markers of microglial activation and neuroinflammation (sTREM2 and complement C3). RESULTS:Compared with controls, LLMD patients had a significant reduction in CSF BChE levels. Lower CSF BChE and AChE activities were associated with lower CSF markers of microglial and neuroinflammation (sTREM2 and C3). In addition, in LLMD patients we found an inverse relationship between peripheral marker of inflammation (plasma IL-6) and CSF BChE and AChE levels. CONCLUSIONS:Our results suggest an upregulation of the CAP mechanism in LLMD with an elevation in peripheral markers of inflammation and concomitant reduction in markers of glial activation associated with a higher cholinergic tone. Future studies should confirm these findings in a larger sample including individuals with acute and more severe depressive episodes and across all ages.
PMID: 33756305
ISSN: 1573-2517
CID: 4822602
Longitudinal increase in CSF strem2 is associated with increased markers of CSF ad pathology in late-life major depression potentially reflecting a compensatory mechanism [Meeting Abstract]
Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane innate immune receptor of the immunoglobulin family. In the brain, TREM2 is found exclusively on microglia and its stimulation has been associated with antiinflammatory and protective effects. Activation of TREM2 also results in the formation of a proteolytic soluble product (sTREM2). Higher baseline CSF sTREM2 concentrations have been associated with a slower rate of cognitive decline and decreased longitudinal brain amyloid deposition in Alzheimer's disease (AD). Thus, it has been proposed that CSF sTREM2 might reflect an antiinflammatory state. In a previous study by our group (ACNP presentation 2017), cognitively unimpaired individuals with latelife major depression (LLMD) which is associated with increased risk for AD, showed significant reductions in CSF sTREM2 levels and a lack of significant correlations with CSF AD biomarkers compared to controls, consistent with the aforementioned hypothesis and that TREM2- mediated anti-inflammatory microglia activation might be impaired in this disorder. In the current report, we examined the relationship between longitudinal changes in CSF sTREM2 during a 3-year period and their relationship to LLMD diagnosis and changes in AD and inflammatory markers.
Method(s): Our baseline sample consisted of 51 subjects aged 60 years and older who completed a longitudinal observational study over three years and an optional lumbar puncture (LP). 38 of these individuals completed the LP at year 3 (20 with LLMD and 18 controls). We evaluated the effects of time on CSF TREM2 with related-samples Wilcoxon Signed Rank Test and the effect diagnosis on change in CSF sTREM2 with Mann Whitney U test. Correlations between change in CSF sTREM2 and CSF markers of AD (Abeta42, Abeta40, total-tau, p-tau181), inflammation (Il-6, Il-8), and Complement component 3 (C3) markers were run with Spearman's Rank test.
Result(s): Baseline CSF sTREM2 was significantly lower in the LLMD group vs controls (p = 0.03). There were no group differences in CSF sTREM2 from baseline to Year 3 (LLMD p = 0.82, Controls p = 0.18), nor did Year 3 differ between the LLMD and control group (p = 0.35). No differences were observed between controls and LLMD for the longitudinal change in CSF sTREM2, AD biomarkers and inflammatory markers. In the whole group, change in sTREM2 was significantly moderately correlated with change in CSF Abeta40 (rho = 0.54, p < 0.001), Abeta42 (rho = 0.48, p = 0.003), and PTau181 (rho = 0.34, p = 0.04). In the control group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.58, p = 0.01) and Abeta42 (rho = 0.56, p = 0.02). In the LLMD group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.50, p = 0.03), Tau (rho = 0.44, p = 0.05) and P-Tau181 (rho = 0.52, p = 0.02) but not with change in CSF Abeta42, a more specific marker of cerebral amyloidosis. Change in inflammatory markers (i.e., IL-6, IL-8) were not significantly correlated with change in sTREM2 (p > 0.05) for LLMD or controls, or the whole group. Change in sTREM2 was significantly correlated with C3 (rho = 0.35, p = 0.04) in the whole group.
Conclusion(s): There were no group differences in change in CSF sTREM2 during a 3-year period, nor any difference between baseline and year 3. The longitudinal increase in CSF sTREM2 during a 3-year period and its association with CSF AD biomarkers may reflect increased anti-inflammatory microglia activation and phagocytosis in response to pathological forms of AD biomarkers Abeta, tau, and p-tau 181. Interestingly, the CSF sTREM2 increase was associated with the increase CSF Abeta42 in controls, but not in LLMD. This finding suggests that upregulation of anti-inflammatory microglia and phagocytosis of brain amyloid deposits may be less efficient in LLMD. Similarly, the positive correlation between the longitudinal increase in CSF sTREM2 and the increase in CSF T-tau and Ptau181, which we found in the LLMD group but not in controls is also consistent with an upregulation of anti-inflammatory microglia in response to increased tau and neurofibrillary tangles, markers of neurodegeneration and AD, respectively. However, the change in CSF sTREM2 was correlated with the change in CSF C3 in the whole cohort; our group and others have also found positive correlations between CSF sTREM2 and CSF neurofilament light (NFL) protein, a biomarker of neuroaxonal damage. Taken together these results suggest that higher CSF sTREM2 concentrations may reflect not only upregulation of antiinflammatory microglia and phagocytosis in response to increased brain amyloid and tau pathology, but also increased neurotoxic effects which are possibly related to its reported intrinsic proinflammatory effects
Method(s): Our baseline sample consisted of 51 subjects aged 60 years and older who completed a longitudinal observational study over three years and an optional lumbar puncture (LP). 38 of these individuals completed the LP at year 3 (20 with LLMD and 18 controls). We evaluated the effects of time on CSF TREM2 with related-samples Wilcoxon Signed Rank Test and the effect diagnosis on change in CSF sTREM2 with Mann Whitney U test. Correlations between change in CSF sTREM2 and CSF markers of AD (Abeta42, Abeta40, total-tau, p-tau181), inflammation (Il-6, Il-8), and Complement component 3 (C3) markers were run with Spearman's Rank test.
Result(s): Baseline CSF sTREM2 was significantly lower in the LLMD group vs controls (p = 0.03). There were no group differences in CSF sTREM2 from baseline to Year 3 (LLMD p = 0.82, Controls p = 0.18), nor did Year 3 differ between the LLMD and control group (p = 0.35). No differences were observed between controls and LLMD for the longitudinal change in CSF sTREM2, AD biomarkers and inflammatory markers. In the whole group, change in sTREM2 was significantly moderately correlated with change in CSF Abeta40 (rho = 0.54, p < 0.001), Abeta42 (rho = 0.48, p = 0.003), and PTau181 (rho = 0.34, p = 0.04). In the control group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.58, p = 0.01) and Abeta42 (rho = 0.56, p = 0.02). In the LLMD group, change in sTREM2 was significantly correlated with change in CSF Abeta40 (rho = 0.50, p = 0.03), Tau (rho = 0.44, p = 0.05) and P-Tau181 (rho = 0.52, p = 0.02) but not with change in CSF Abeta42, a more specific marker of cerebral amyloidosis. Change in inflammatory markers (i.e., IL-6, IL-8) were not significantly correlated with change in sTREM2 (p > 0.05) for LLMD or controls, or the whole group. Change in sTREM2 was significantly correlated with C3 (rho = 0.35, p = 0.04) in the whole group.
Conclusion(s): There were no group differences in change in CSF sTREM2 during a 3-year period, nor any difference between baseline and year 3. The longitudinal increase in CSF sTREM2 during a 3-year period and its association with CSF AD biomarkers may reflect increased anti-inflammatory microglia activation and phagocytosis in response to pathological forms of AD biomarkers Abeta, tau, and p-tau 181. Interestingly, the CSF sTREM2 increase was associated with the increase CSF Abeta42 in controls, but not in LLMD. This finding suggests that upregulation of anti-inflammatory microglia and phagocytosis of brain amyloid deposits may be less efficient in LLMD. Similarly, the positive correlation between the longitudinal increase in CSF sTREM2 and the increase in CSF T-tau and Ptau181, which we found in the LLMD group but not in controls is also consistent with an upregulation of anti-inflammatory microglia in response to increased tau and neurofibrillary tangles, markers of neurodegeneration and AD, respectively. However, the change in CSF sTREM2 was correlated with the change in CSF C3 in the whole cohort; our group and others have also found positive correlations between CSF sTREM2 and CSF neurofilament light (NFL) protein, a biomarker of neuroaxonal damage. Taken together these results suggest that higher CSF sTREM2 concentrations may reflect not only upregulation of antiinflammatory microglia and phagocytosis in response to increased brain amyloid and tau pathology, but also increased neurotoxic effects which are possibly related to its reported intrinsic proinflammatory effects
EMBASE:636646821
ISSN: 1740-634x
CID: 5089902
Impairment of the cholinergic anti-inflammatory pathway in older subjects with severe COVID-19 [Letter]
PMID: 33254578
ISSN: 1532-2777
CID: 4693952
Is there a relationship between morphological and functional platelet changes and depressive disorder?
PMID: 33092669
ISSN: 1092-8529
CID: 4642482
CSF α-synuclein correlates with CSF neurogranin in late-life depression
Purpose/aim of the study: Major depressive disorder (MDD) in late life is linked to increased risk of subsequent dementia, but it is still unclear exactly what pathophysiological mechanisms underpin this link. A potential mechanism related to elevated risk of dementia in MDD is increased levels of α-synuclein (α-Syn), a protein found in presynaptic neuronal terminals.Materials and methods: In this study, we examined cerebrospinal fluid (CSF) levels of α-Syn in conjunction with biomarkers of neurodegeneration (amyloid-β 42, total and phospho tau) and synaptic dysfunction (neurogranin), and measures of memory ability, in 27 cognitively intact older individuals with MDD and 19 controls.Results: Our results show that CSF α-Syn levels did not significantly differ across depressed and control participants, but α-Syn was directly associated with neurogranin levels, and indirectly linked to poorer memory ability.Conclusions: All in all, we found that α-Syn may be implicated in the association between late life MDD and synaptic dysfunction, although further research is needed to confirm these results.
PMID: 32228205
ISSN: 1563-5279
CID: 4370092
FAM222A encodes a protein which accumulates in plaques in Alzheimer's disease
Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.
PMCID:6972869
PMID: 31964863
ISSN: 2041-1723
CID: 5134432
Complement component 3 levels in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder
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.
PMCID:6961956
PMID: 31942568
ISSN: 2666-1446
CID: 4263682
Cerebrospinal fluid alpha-synuclein in late-life depression and neurobiological correlates [Meeting Abstract]
Background: Misfolding of the pre-synaptic protein, alpha-synuclein (alpha-Syn), and formation of abnormal cytoplasmic aggregates, have been implicated in the progressive degeneration and synaptic dysfunction associated with Parkinson's disease (PD) and a number of related disorders. Several lines of evidence have also implicated disturbances in alpha-synuclein in the pathophysiology of depression. For example, depression is highly prevalent in PD and other synucleopathies, and often precedes motor symptoms. In preclinical experiments overexpression of human alpha-Syn has been linked to a depressive-like phenotype, and with factors implicated in depression including disruption of monoamine transporters, degeneration of dopamine neurons and microglial and HPA-axis activation and release of proinflammatory cytokines. Despite these findings, there are no studies that have examined CSF alpha-Syn concentration in depression and its relationship to symptoms, monoaminergic indices and markers of synaptic dysfunction such as neurogranin (Ng) and neuroinflammation (IL-6, IL-8).
Method(s): A total of 51 individuals participated in a 3-year longitudinal study examining possible Abeta disturbances in depression and agreed to have a lumbar puncture. Of these 51 individuals, 47 showed (28 MDD and 19 controls) no MRI evidence of confluent deep or periventricular white matter hyperintensities and had a Mini-Mental State Examination (MMSE) score of 28 or above were included in this study. Participants completed a clinical evaluation including the Hamilton Depression Scale (HAMD) and neuropsychological evaluations. Memory performance from the neuropsychological assessment was determined by Total Recall on the Buschke Selective Reminding Test, Delayed Recall, and the Recency Ratio. CSF alpha-Syn (ng/mL), Ng (pg/mL), HVA, 5-HIAA, MHPG, IL-6, and IL-8, cortisol (ug/dL) were determined using previously published methods. Mann-U Whitney tests were conducted to compare depressed and controls. Spearman correlations were computed for depressed subjects and controls, separately, and results for the depress subjects only are reported below.
Result(s): There were no significant differences in alpha-Syn (p = 0.21), Ng (p = 0.35), IL6 (p = 0.213), IL8 (p = 0.633), HVA (p = 0.665), 5-HIAA (p = 0.442) and MHPG (p = 0.845) between the depressed and the control group. In depressed subjects only, alpha-Syn was significantly positively correlated with Ng (rho = 0.783, p < 0.001), and negatively correlated with cortisol (rho =-0.425, p = 0.024) and IL-8 (rho =-0.435, p = 0.021), with a trend for IL-6 (rho =-0.355, p = 0.064). Interestingly, there was no significant relationship with depressive symptoms at Baseline (p = .36). alpha-Syn was not correlated with memory performance on the selected assessments (p values >= 0.400). Ng displayed a trend correlation with Rr (rho = 0.482, p = 0.009, adjusted p = 0.081), consistent with expectations, but was not otherwise correlated with the other variables (adjusted p values >= 0.350).
Conclusion(s): In depressed subjects only, CSF alpha-Syn was significantly positively related with CSF Ng. Similar correlations have been reported in PD and together with reductions in CSF levels ascribed to impaired synaptic activity in that population from increased brain deposits. Given that CSF alpha-Syn did not correlate with cognitive and depressive symptoms, the significance of this finding, if any, remains to be determined. Lower CSF alpha-Syn in PD and Lewy-Body Dementia have been attributed to its entrapment in brain parenchyma. Therefore, the negative correlations between CSF alpha-Syn and proinflammatory cytokines and cortisol in depressed subjects only are consistent with increased glial and HPA-axis activation, secondary to greater alpha-Syn brain deposits. This preliminary finding complements reports of increased serum alpha-Syn levels and its mRNA expression associated with severity of depressive symptoms in younger populations
Method(s): A total of 51 individuals participated in a 3-year longitudinal study examining possible Abeta disturbances in depression and agreed to have a lumbar puncture. Of these 51 individuals, 47 showed (28 MDD and 19 controls) no MRI evidence of confluent deep or periventricular white matter hyperintensities and had a Mini-Mental State Examination (MMSE) score of 28 or above were included in this study. Participants completed a clinical evaluation including the Hamilton Depression Scale (HAMD) and neuropsychological evaluations. Memory performance from the neuropsychological assessment was determined by Total Recall on the Buschke Selective Reminding Test, Delayed Recall, and the Recency Ratio. CSF alpha-Syn (ng/mL), Ng (pg/mL), HVA, 5-HIAA, MHPG, IL-6, and IL-8, cortisol (ug/dL) were determined using previously published methods. Mann-U Whitney tests were conducted to compare depressed and controls. Spearman correlations were computed for depressed subjects and controls, separately, and results for the depress subjects only are reported below.
Result(s): There were no significant differences in alpha-Syn (p = 0.21), Ng (p = 0.35), IL6 (p = 0.213), IL8 (p = 0.633), HVA (p = 0.665), 5-HIAA (p = 0.442) and MHPG (p = 0.845) between the depressed and the control group. In depressed subjects only, alpha-Syn was significantly positively correlated with Ng (rho = 0.783, p < 0.001), and negatively correlated with cortisol (rho =-0.425, p = 0.024) and IL-8 (rho =-0.435, p = 0.021), with a trend for IL-6 (rho =-0.355, p = 0.064). Interestingly, there was no significant relationship with depressive symptoms at Baseline (p = .36). alpha-Syn was not correlated with memory performance on the selected assessments (p values >= 0.400). Ng displayed a trend correlation with Rr (rho = 0.482, p = 0.009, adjusted p = 0.081), consistent with expectations, but was not otherwise correlated with the other variables (adjusted p values >= 0.350).
Conclusion(s): In depressed subjects only, CSF alpha-Syn was significantly positively related with CSF Ng. Similar correlations have been reported in PD and together with reductions in CSF levels ascribed to impaired synaptic activity in that population from increased brain deposits. Given that CSF alpha-Syn did not correlate with cognitive and depressive symptoms, the significance of this finding, if any, remains to be determined. Lower CSF alpha-Syn in PD and Lewy-Body Dementia have been attributed to its entrapment in brain parenchyma. Therefore, the negative correlations between CSF alpha-Syn and proinflammatory cytokines and cortisol in depressed subjects only are consistent with increased glial and HPA-axis activation, secondary to greater alpha-Syn brain deposits. This preliminary finding complements reports of increased serum alpha-Syn levels and its mRNA expression associated with severity of depressive symptoms in younger populations
EMBASE:631798928
ISSN: 1740-634x
CID: 4456542
