Faculty Bibliography

Depressed individuals are twice as likely to develop Alzheimer's disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β_1-40 (Aβ40) and amyloid-β_1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.

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.

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.

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

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.

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.

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

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

Individuals with Alzheimer's disease have been found to present a typical serial position curve in immediate recall tests, showing poor primacy performance and exaggerated recency recall. However, the recency advantage is usually lost after a delay. On this basis, we examined whether the recency ratio (Rr), calculated by dividing recency performance in an immediate memory task by recency performance in a delayed task, was a useful risk marker of cognitive decline. We tested whether change in Mini-Mental State Examination (MMSE) performance between baseline and follow-up was predicted by baseline Rr and found this to be the case (N = 245). From these analyses, we conclude that participants with high Rr scores, who show disproportionate recency recall in the immediate test compared to the delayed test, present signs of being at risk for cognitive decline or dysfunction.