Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene ...concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS) approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10(-9)). Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841) in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.
PURPOSEMagnetic resonance imaging (MRI) scanner-specific geometric distortions may contribute to scanner induced variability and decrease volumetric measurement precision for multi-site studies. The ...purpose of this study was to determine whether geometric distortion correction increases the precision of brain volumetric measurements in a multi-site multi-scanner study. METHODSGeometric distortion variation was quantified over a one-year period at 10 sites using the distortion fields estimated from monthly 3D T1-weighted MRI geometrical phantom scans. The variability of volume and distance measurements were quantified using synthetic volumes and a standard quantitative MRI (qMRI) phantom. The effects of geometric distortion corrections on MRI derived volumetric measurements of the human brain were assessed in two subjects scanned on each of the 10 MRI scanners and in 150 subjects with cerebrovascaular disease (CVD) acquired across imaging sites. RESULTSGeometric distortions were found to vary substantially between different MRI scanners but were relatively stable on each scanner over a one-year interval. Geometric distortions varied spatially, increasing in severity with distance from the magnet isocenter. In measurements made with the qMRI phantom, the geometric distortion correction decreased the standard deviation of volumetric assessments by 35% and distance measurements by 42%. The average coefficient of variance decreased by 16% in gray matter and white matter volume estimates in the two subjects scanned on the 10 MRI scanners. CONCLUSIONGeometric distortion correction using an up-to-date correction field is recommended to increase precision in volumetric measurements made from MRI images.
It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease ...and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity WMH volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition (18F‐AV45 positron emission tomography PET) and neurodegeneration (cortical thickness or 18F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid‐independent pathway in which vascular burden affects cognitive function via localized neurodegeneration.
Highlights
Alzheimer's disease often co‐exists with vascular pathology.
We studied a unique cohort enriched for high white matter hyperintensities (WMH).
High WMH related to cognitive impairment of semantic fluency and executive function.
This relationship was mediated via temporo‐parietal atrophy rather than metabolism.
This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.
White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is ...understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy FA). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.
INTRODUCTION
Cerebral small vessel disease (SVD) and amyloid beta (Aβ) pathology frequently co‐exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of ...memory impacted early and extensively in dementia, remains poorly understood.
METHODS
In a unique cohort of mixed Alzheimer's disease and moderate–severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aβ, as assessed by 18F‐AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape.
RESULTS
Frontal WMH, occipital WMH, and Aβ were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aβ. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aβ‐vulnerable subregions.
DISCUSSION
Hippocampal degeneration is differentially sensitive to SVD and Aβ pathology. The pattern of hippocampal atrophy could serve as a disease‐specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.
The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score.
Fifty-seven subjects with ...significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB.
F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score.
Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.
Background
Small vessel disease (SVD) often co‐exists with Alzheimer’s disease (AD) pathology (up to 60%) and may facilitate AD progression. However, SVD is currently not integrated as a pathological ...factor within the ATN research criteria. Up to now, the majority of studies that investigated effects of SVD on brain atrophy and cognition were limited to either AD cohorts with low SVD burden (e.g., ADNI) or cognitively normal elderly with high SVD burden. Thus, there is a need to investigate the effects of SVD in a cohort spanning low to severe SVD and amyloid‐beta pathology.
Method
Our study included 118 subjects in total. Fifty‐nine subjects were recruited in a multi‐site study (MITNEC) from dementia and SVD‐stroke clinics (64% amyloid‐beta+) who had severe SVD burden as quantified by white matter hyperintensity volumes WMH; median(IQR): 30.2(22.2)cm3 and Fazekas score 2.5‐3. In addition, we included 59 cognitively normal/early‐MCI subjects from ADNI (44% amyloid‐beta+) with low‐to‐moderate WMH median(IQR): 5.8(9.1)cm3. We performed vertex‐wise regressions, investigating associations of cortical thickness with amyloid‐beta (18F‐florbetapir‐SUVRpons) or vascular burden (WMH), corrected for WMH or amyloid‐beta, respectively, and age, sex, education. Further, mediation analyses investigated whether the effects of amyloid‐beta or vascular burden on cognition (MMSE, MoCA, Trails‐B, semantic fluency, ANART, and Boston‐naming) were mediated by cortical thickness.
Result
We observed a significant effect of vascular burden on cortical thickness independent of amyloid‐beta. This effect was stronger than the vascular‐independent effect of amyloid‐beta on thickness (Fig. 1). Furthermore, we observed additive effects of vascular burden and amyloid‐beta on cognition (semantic fluency: ß=‐0.29 p=0.002 and ß=‐0.27 p=0.001, respectively; Trails‐B: ß=+0.18 p=0.03 and ß=+0.22 p=0.02, respectively). Here, the effects on semantic fluency were significantly mediated by cortical thickness (vascular→thickness→semantic: 35% mediation, 95%CI‐0.19,‐0.02; amyloid‐beta→thickness→semantic: 19% mediation, 95%CI‐0.11,‐0.003) (Fig. 1).
Conclusion
In our study of mixed AD/SVD and control subjects, the effect of SVD burden (WMH) exceeded the effect of amyloid‐beta on neurodegeneration alone. Furthermore, vascular burden contributed to semantic loss both directly and through its impact on neurodegeneration. As such, the presence of cerebrovascular comorbidities supports the idea of combinational therapeutic approaches where SVD factors may be targeted alongside amyloid‐beta to halt neurodegeneration and cognitive decline.
Summary Background & aims Chronic inflammation impairs recovery among the 1.6 million people who suffer from hip fracture annually. Vitamin E and the carotenoids are two classes of dietary ...antioxidants with profound anti-inflammatory effects, and the goal of this study was to assess whether higher post-fracture concentrations of these antioxidants were associated with lower levels of interleukin 6 (IL-6) and the soluble receptor for tumor necrosis factor-alpha (sTNF-αR1), two common markers of inflammation. Methods Serum concentrations of the dietary antioxidants and inflammatory markers were assessed at baseline and 2, 6, and 12 month follow-up visits among 148 hip fracture patients from The Baltimore Hip Studies. Generalized estimating equations modeled the relationship between baseline and time-varying antioxidant concentrations and inflammatory markers. Results Higher post-fracture concentrations of vitamin E and the carotenoids were associated with lower levels of inflammatory markers. Associations were strongest at baseline, particularly between the α-tocopherol form of vitamin E and sTNF-αR1 ( p = 0.05) and total carotenoids and both sTNF-αR1( p = 0.01) and IL-6 ( p = 0.05). Higher baseline and time-varying α-carotene and time-varying lutein concentrations were also associated with lower sTNF-αR1 at all post-fracture visits ( p ≤ 0.05). Conclusions These findings suggest that a clinical trial increasing post-fracture intake of vitamin E and the carotenoids may be warranted.
Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males ...displaying clinical features of early-onset parkinsonism and intellectual disability identified a ∼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.503C>A p.Thr168Lys) in RAB39B in an unrelated Wisconsin kindred affected by a similar clinical phenotype. In silico and in vitro studies demonstrated that the mutation destabilized the protein, consistent with loss of function. In vitro small-hairpin-RNA-mediated knockdown of Rab39b resulted in a reduction in the density of α-synuclein immunoreactive puncta in dendritic processes of cultured neurons. In addition, in multiple cell models, we demonstrated that knockdown of Rab39b was associated with reduced steady-state levels of α-synuclein. Post mortem studies demonstrated that loss of RAB39B resulted in pathologically confirmed Parkinson disease. There was extensive dopaminergic neuron loss in the substantia nigra and widespread classic Lewy body pathology. Additional pathological features included cortical Lewy bodies, brain iron accumulation, tau immunoreactivity, and axonal spheroids. Overall, we have shown that loss-of-function mutations in RAB39B cause intellectual disability and pathologically confirmed early-onset Parkinson disease. The loss of RAB39B results in dysregulation of α-synuclein homeostasis and a spectrum of neuropathological features that implicate RAB39B in the pathogenesis of Parkinson disease and potentially other neurodegenerative disorders.
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