18 research outputs found
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Meningomyeloencephalitis secondary to Mycobacterium haemophilum infection in AIDS
Infections by opportunistic non-tuberculous mycobacteria (ntm) are rising in global incidence
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Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups.
Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10-8), PVRL2 (Score = 125.86, P = 1.64 × 10-9), TOMM40 (Score = - 18.58, P = 4.61 × 10-8), and APOE (Score = 75.12, P = 7.26 × 10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW
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Abstract WP127: Cerebral Microbleeds, Cerebral Amyloid Angiopathy, And Their Relationships To Quantitative Markers Of Neurodegeneration
Introduction:
Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer’s disease. In the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA impact volumetric changed in the brain related to neurodegenerative disease remains unclear.
Methods:
We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between two related markers of cerebrovascular disease – MRI-based CMBs and autopsy-based CAA, as independent variables, and volumetric markers of neurodegeneration, as dependent variables.
Results:
We included 2657 participants with available MRI data and 82 autopsy cases from the BARS. In a meta-analysis of NOMAS, ADNI and EDIS, superficial CMBs were associated with larger gray (β=4.49 ± 1.13, P=0.04) and white (β=4.72 ± 2.1, P=0.03) matter volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with one CMB (B=5.17 ± 2.47, P=0.04) than in those with ≥ 2 CMBs (β=1.97 ± 3.41, P=0.56). In the BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3, P=0.016) but not with increased brain weight (β=1.54 ± 1.29, P=0.26).
Discussion:
Superficial CMBs are associated with larger morphometric brain measures. This association is strongest in brains with fewer CMBs, suggesting that the CMBs/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease
Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration
Background and Objectives Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear. Methods We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease-MRI-based CMBs and autopsy-based CAA-as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55-90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples. Results We included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (beta = 4.49 +/- 1.13, p = 0.04) and white matter (beta = 4.72 +/- 2.1, p = 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (beta = 5.17 +/- 2.47, p = 0.04) than in those with >= 2 CMBs (beta = 1.97 +/- 3.41, p = 0.56). In BARS, CAA was associated with increased cortical thickness (beta = 6.5 +/- 2.3, p = 0.016) but not with increased brain weight (beta = 1.54 +/- 1.29, p = 0.26). Discussion Superficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease
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Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration
10.1212/WNL.0000000000200142NEUROLOGY9816E1605-E161