| 1. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 2. |
- Rask, Eva, 1958-, et al.
(författare)
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Tissue-specific dysregulation of cortisol metabolism in human obesity
- 2001
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Williams & Wilkins Co.. - 0021-972X .- 1945-7197. ; 86:3, s. 1418-1421
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Tidskriftsartikel (refereegranskat)abstract
- Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local pre-receptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1). In obese Zucker rats 11 beta -HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin sensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from le participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r=0.47, p<0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r=0.43, p<0.02), and converted less cortisone to cortisol after oral administration (r=-0.49, p<0.01), suggesting impaired hepatic 11-HSD1 activity. By contrast, in vitro 11 beta -HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r=0.66, p<0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11 beta -HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.
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