Faculty Bibliography
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217
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
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
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
Drug-induced reductions in brain amyloid-β levels may adversely affect cognition and behavior by a disruption of functional connectivity homeostasis
PMID: 31337272
ISSN: 1758-2032
CID: 3987072
The recency ratio is related to CSF Amyloid Beta 1-42 levels in MCI-AD
OBJECTIVE:As anti-amyloid therapeutic interventions shift from enrolling patients with Alzheimer's disease (AD) dementia to individuals with pre-clinical disease, the need for sensitive measures that allow for non-invasive, fast, disseminable and cost-effective identification of preclinical status increases in importance. The recency ratio (Rr) is a memory measure that relies on analysis of serial position performance, which has been found to predict cognitive decline and conversion to early mild cognitive impairment (MCI). The aim of this study was to test Rr's sensitivity to cerebrospinal fluid (CSF) levels of the core AD biomarkers in individuals with MCI-AD and controls. METHODS:Baseline data from 126 (110 controls and 16 MCI-AD) participants from the Wisconsin Alzheimer's Disease Research Center were analysed. Partial correlations adjusting for demographics were carried out between CSF measure of amyloid beta (Aβ40, Aβ42 and the 40/42 ratio) and tau (total and phosphorylated), and memory measures (Rr, delayed recall and total recall) derived from the Rey's Auditory Verbal Learning Test. RESULTS:Results indicated that Rr was the most sensitive memory score to Aβ42 levels in MCI-AD, while no memory score correlated significantly with any biomarker in controls. CONCLUSIONS:This study shows that Rr is a sensitive cognitive index of underlying Amyloid β pathology in MCI-AD.
PMID: 30430632
ISSN: 1099-1166
CID: 3457562
Basal Forebrain Resting Functional Activity Associated with Brain Amyloid-β Burden in ε4 Carriers and Older Women: Possible Implications for Baseline Cognition and Response to Amyloid-β-based Preventive Trials
PMID: 30720398
ISSN: 1527-1315
CID: 3632042
CSF butyrylcholinesterase and acetyl-cholinesterase activity and their relationship to pro-inflammatory cytokines in late-life major depression [Meeting Abstract]
ISI:000458400500124
ISSN: 0924-977x
CID: 3827672
Multimodal Hippocampal Subfield Grading For Alzheimer's Disease Classification
ISI:000487586600036
ISSN: 2045-2322
CID: 4155602
The recency ratio as predictor of early MCI
ABSTRACTObjectives:Individuals with Alzheimer's disease (AD) present poor immediate primacy recall accompanied by intact or exaggerated recency, which then tends to decline after a delay. Bruno et al. (Journal of Clinical and Experimental Neuropsychology, Vol. 38, 2016, pp. 967-973) have shown that higher ratio scores between immediate and delayed recency (i.e. the recency ratio; Rr) are associated with cognitive decline in high-functioning older individuals. We tested whether Rr predicted conversion to early mild cognitive impairment (early MCI) from a cognitively healthy baseline.
PMID: 29667564
ISSN: 1741-203x
CID: 3056222
Pathological Increases in Neuronal Hyperactivity in Selective Cholinergic and Noradrenergic Pathways May Limit the Efficacy of Amyloid-β-Based Interventions in Mild Cognitive Impairment and Alzheimer's Disease
In spite of compelling evidence linking amyloid-β (Aβ) disturbances to the pathophysiology of Alzheimer's disease (AD), Aβ-based treatments have consistently failed to produce any beneficial effects both in mild cognitive impairment (MCI) and AD, even with successful reductions of toxic aggregated and soluble Aβ species. Before abandoning both the hypothesis and approach, there is a need to examine some overlooked factors that may have contributed to the lack of efficacy, such as the potential drug-induced increases in neuronal hyperactivity leading to adverse cognitive effects. In particular, we posit that selective cholinergic and noradrenergic pathways will be especially vulnerable to this adverse effect. If confirmed, this idea could help identify a potentially preventable and treatable obstacle for enhancing the efficacy of therapeutic agents in MCI and AD.
PMID: 30480259
ISSN: 2542-4823
CID: 3500562
