Changes of peripheral TGF-β1 depend on monocytes-derived macrophages in Huntington disease.

Background: Huntington Disease (HD) is a neurodegenerative disorder resulting from the expansion of polyglutamine stretch in the huntingtin protein (Htt). Mutant HTT (mHtt) leads to progressive impairment of several molecular pathways that have been linked to disease pathogenesis. Defects in the production of a number of neurotrophic factors have been described as important determinants contributing to the development of HD. We have previously demonstrated that production of transforming growth factor-beta 1 (TGF-beta 1) is also deregulated in HD. Peripheral levels of TGF-beta 1 were markedly reduced early in the disease and returned to normal levels with disease severity. However, the cause and the biochemical origin of such abnormalities are still unclear. Results: We report here that the abnormal production of peripheral TGF-beta 1 depends on the changes in the percentage of TGF-beta 1-producing macrophages along disease course. Variation in the number of TGF-beta 1-producing macrophages resulted from differential activation state of the same cells, which displayed phenotypic and functional heterogeneity throughout the clinical course of HD. We further demonstrated that, similar to the periphery, the number of TGF-beta 1-immunoreactive cells in human post-mortem brain with HD, varied with neuropathological changes. Conclusions: Our data indicate that reduced bioavailability of TGF-beta 1 in the serum of HD subjects is attributable to the variation of the number of TGF-beta 1-producing macrophages. Macrophages display a differential ability to produce TGF-beta 1, which reflects diversity in cells polarization throughout the disease course. Besides elucidating the biochemical origin of TGF-beta 1 fluctuations in HD, our study highlights an interesting parallelism between periphery and central compartment and underlines the potential of TGF-beta 1 as a possible indicator suitable for prediction of disease onset in HD

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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

Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration

10.1212/WNL.0000000000200142NEUROLOGY9816E1605-E161

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