Faculty Bibliography
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163
Higher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer's disease
Neuroinflammation is associated with Alzheimer's disease, but the application of cerebrospinal fluid measures of inflammatory proteins may be limited by overlapping pathways and relationships between them. In this work, we measure 15 cerebrospinal proteins related to microglial and T-cell functions, and show them to reproducibly form functionally-related groups within and across diagnostic categories in 382 participants from the Alzheimer's Disease Neuro-imaging Initiative as well participants from two independent cohorts. We further show higher levels of proteins related to soluble tumor necrosis factor receptor 1 are associated with reduced risk of conversion to dementia in the multi-centered (p = 0.027) and independent (p = 0.038) cohorts of people with mild cognitive impairment due to predicted Alzheimer's disease, while higher soluble TREM2 levels associated with slower decline in the dementia stage of Alzheimer's disease. These inflammatory proteins thus provide prognostic information independent of established Alzheimer's markers.
PMCID:8238986
PMID: 34183654
ISSN: 2041-1723
CID: 5864702
Absence of Apolipoprotein E is associated with exacerbation of prion pathology and promotes microglial neurodegenerative phenotype
Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrPSc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrPSc mediated neurodegeneration. While clearance of PrPSc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrPSc mediated neurodegeneration. Apoe-/- mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe-/- mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrPSc and dying neurons by microglia in Apoe-/- mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrPSc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.
PMCID:8474943
PMID: 34565486
ISSN: 2051-5960
CID: 5061562
Segmented Linear Mixed Model Analysis Reveals Association of the APOEɛ4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression
BACKGROUND:APOEɛ4 allele carriers present with increased risk for late-onset Alzheimer's disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression. OBJECTIVE:To determine effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD. METHODS:A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer's Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia. RESULTS:ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI. CONCLUSION/CONCLUSIONS:Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.
PMID: 34120907
ISSN: 1875-8908
CID: 4911232
Challenges and Opportunities with Causal Discovery Algorithms: Application to Alzheimer's Pathophysiology
Causal Structure Discovery (CSD) is the problem of identifying causal relationships from large quantities of data through computational methods. With the limited ability of traditional association-based computational methods to discover causal relationships, CSD methodologies are gaining popularity. The goal of the study was to systematically examine whether (i) CSD methods can discover the known causal relationships from observational clinical data and (ii) to offer guidance to accurately discover known causal relationships. We used Alzheimer's disease (AD), a complex progressive disease, as a model because the well-established evidence provides a "gold-standard" causal graph for evaluation. We evaluated two CSD methods, Fast Causal Inference (FCI) and Fast Greedy Equivalence Search (FGES) in their ability to discover this structure from data collected by the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used structural equation models (which is not designed for CSD) as control. We applied these methods under three scenarios defined by increasing amounts of background knowledge provided to the methods. The methods were evaluated by comparing the resulting causal relationships with the "gold standard" graph that was constructed from literature. Dedicated CSD methods managed to discover graphs that nearly coincided with the gold standard. For best results, CSD algorithms should be used with longitudinal data providing as much prior knowledge as possible.
PMCID:7031278
PMID: 32076020
ISSN: 2045-2322
CID: 5864672
White matter atrophy in cerebral amyloid angiopathy
OBJECTIVE:We postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA. METHODS:White matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function. RESULTS:= 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function. CONCLUSIONS:Patients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.
PMCID:7455340
PMID: 32611644
ISSN: 1526-632x
CID: 5864692
The genetic architecture of the human cerebral cortex
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
PMID: 32193296
ISSN: 1095-9203
CID: 5864682
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
Detection of Cerebrovascular Loss in the Normal Aging C57BL/6 Mouse Brain Using in vivo Contrast-Enhanced Magnetic Resonance Angiography
Microvascular rarefaction, or the decrease in vascular density, has been described in the cerebrovasculature of aging humans, rats, and, more recently, mice in the presence and absence of age-dependent diseases. Given the wide use of mice in modeling age-dependent human diseases of the cerebrovasculature, visualization, and quantification of the global murine cerebrovasculature is necessary for establishing the baseline changes that occur with aging. To provide in vivo whole-brain imaging of the cerebrovasculature in aging C57BL/6 mice longitudinally, contrast-enhanced magnetic resonance angiography (CE-MRA) was employed using a house-made gadolinium-bearing micellar blood pool agent. Enhancement in the vascular space permitted quantification of the detectable, or apparent, cerebral blood volume (aCBV), which was analyzed over 2 years of aging and compared to histological analysis of the cerebrovascular density. A significant loss in the aCBV was detected by CE-MRA over the aging period. Histological analysis via vessel-probing immunohistochemistry confirmed a significant loss in the cerebrovascular density over the same 2-year aging period, validating the CE-MRA findings. While these techniques use widely different methods of assessment and spatial resolutions, their comparable findings in detected vascular loss corroborate the growing body of literature describing vascular rarefaction aging. These findings suggest that such age-dependent changes can contribute to cerebrovascular and neurodegenerative diseases, which are modeled using wild-type and transgenic laboratory rodents.
PMCID:7606987
PMID: 33192479
ISSN: 1663-4365
CID: 4671302
Peroxiredoxin 6 mediates protective function of astrocytes in Aβ proteostasis
BACKGROUND:) activities involved in repair of oxidatively damaged cell membrane lipids and cellular signaling. In the CNS, PRDX6 is uniquely expressed by astrocytes and its exact function remains unexplored. METHODS:AD transgenic mice were once crossed to mice overexpressing wild-type Prdx6 allele or to Prdx6 knock out mice. Aβ pathology and associated neuritic degeneration were assessed in mice aged 10 months. Laser scanning confocal microscopy was used to characterize Aβ plaque morphology and activation of plaque-associated astrocytes and microglia. Effect of Prdx6 gene dose on plaque seeding was assessed in mice aged six months. RESULTS:AD transgenic mice promotes selective enticement of astrocytes to Aβ plaques and penetration of plaques by astrocytic processes along with increased number and phagocytic activation of periplaque microglia. This effects suppression of nascent plaque seeding and remodeling of mature plaques consequently curtailing brain Aβ load and Aβ-associated neuritic degeneration. Conversely, Prdx6 haplodeficiency attenuates astro- and microglia activation around Aβ plaques promoting Aβ deposition and neuritic degeneration. CONCLUSIONS:We identify here PRDX6 as an important factor regulating response of astrocytes toward Aβ plaques. Demonstration that phagocytic activation of periplaque microglia vary directly with astrocytic PRDX6 expression level implies previously unappreciated astrocyte-guided microglia effect in Aβ proteostasis. Our showing that upregulation of PRDX6 attenuates Aβ pathology may be of therapeutic relevance for AD.
PMID: 32907613
ISSN: 1750-1326
CID: 4589342
Predicting Short-term MCI-to-AD Progression Using Imaging, CSF, Genetic Factors, Cognitive Resilience, and Demographics
In the Alzheimer's disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical management. Our goal was to develop generalizable multivariate models that integrate high-dimensional data (multimodal neuroimaging and cerebrospinal fluid biomarkers, genetic factors, and measures of cognitive resilience) for identification of MCI individuals who progress to AD within 3 years. Our main findings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments.
PMCID:6381141
PMID: 30783207
ISSN: 2045-2322
CID: 5864622
