| 1. |
- Murray, Christopher J. L., et al.
(author)
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Population and fertility by age and sex for 195 countries and territories, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017
- 2018
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In: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1995-2051
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Journal article (peer-reviewed)abstract
- Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49·4% (95% uncertainty interval [UI] 46·4–52·0). The TFR decreased from 4·7 livebirths (4·5–4·9) to 2·4 livebirths (2·2–2·5), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83·8 million people per year since 1985. The global population increased by 197·2% (193·3–200·8) since 1950, from 2·6 billion (2·5–2·6) to 7·6 billion (7·4–7·9) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2·0%; this rate then remained nearly constant until 1970 and then decreased to 1·1% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2·5% in 1963 to 0·7% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2·7%. The global average age increased from 26·6 years in 1950 to 32·1 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59·9% to 65·3%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1·0 livebirths (95% UI 0·9–1·2) in Cyprus to a high of 7·1 livebirths (6·8–7·4) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0·08 livebirths (0·07–0·09) in South Korea to 2·4 livebirths (2·2–2·6) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0·3 livebirths (0·3–0·4) in Puerto Rico to a high of 3·1 livebirths (3·0–3·2) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2·0% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation.
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| 2. |
- Alves, Guido, et al.
(author)
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CSF amyloid-β and tau proteins, and cognitive performance, in early and untreated Parkinson's Disease: the Norwegian ParkWest study
- 2010
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 81:10, s. 1080-1086
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Journal article (peer-reviewed)abstract
- Background Alzheimer's disease (AD) pathology is found in a considerable portion of patients with Parkinson's disease (PD), particularly those with early dementia (PDD). Altered cerebrospinal fluid (CSF) levels of amyloid-beta (Abeta) and tau proteins have been found in PDD, with intermediate changes for Abeta42 in non-demented PD. The authors investigated whether AD-related CSF protein levels are altered and relate to neuropsychological performance in early, untreated PD. Methods CSF concentrations of Abeta42, Abeta40 and Abeta38 were measured by electrochemiluminiscene and levels of total tau (T-tau) and phosphorylated tau (P-tau) by ELISA in 109 newly diagnosed, unmedicated, non-demented, community-based PD patients who had undergone comprehensive neuropsychological testing, and were compared with those of 36 age-matched normal controls and 20 subjects with mild AD. Results PD patients displayed significant reductions in Abeta42 (19%; p=0.009), Abeta40 (15.5%; p=0.008) and Abeta38 (23%; p=0.004) but not T-tau (p=0.816) or P-tau (p=0.531) compared with controls. CSF Abeta42 reductions in PD were less marked than in AD (53%; p=0.002). Sequential regression analyses demonstrated significant associations between CSF levels of Abeta42 (beta=0.205; p=0.019), Abeta40 (beta=0.378; p<0.001) and Abeta38 (beta=0.288; p=0.001) and memory impairment, but not executive-attentional or visuospatial dysfunction. Tau protein levels did not correlate with cognitive measures. Conclusion CSF Abeta levels are altered in a subset of patients with early PD and relate to memory impairment. Our study suggests that alterations in Abeta protein metabolism may contribute to the heterogeneity in pattern and course of cognitive decline associated with PD. Longitudinal studies are needed to clarify the clinical significance of CSF Abeta peptides as prognostic biomarkers in PD.
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| 3. |
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| 4. |
- Mattsson, Niklas, 1979, et al.
(author)
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CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
- 2009
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In: JAMA : the journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 302:4, s. 385-93
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Journal article (peer-reviewed)abstract
- CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
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| 5. |
- Mokdad, Ali H., et al.
(author)
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Diabetes mellitus and chronic kidney disease in the Eastern Mediterranean Region : findings from the Global Burden of Disease 2015 study
- 2018
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In: International Journal of Public Health. - : SPRINGER BASEL AG. - 1661-8556 .- 1661-8564. ; 63, s. 177-186
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Journal article (peer-reviewed)abstract
- We used findings from the Global Burden of Disease 2015 study to update our previous publication on the burden of diabetes and chronic kidney disease due to diabetes (CKD-DM) during 1990-2015. We extracted GBD 2015 estimates for prevalence, mortality, and disability-adjusted life years (DALYs) of diabetes (including burden of low vision due to diabetes, neuropathy, and amputations and CKD-DM for 22 countries of the EMR from the GBD visualization tools. In 2015, 135,230 (95% UI 123,034-148,184) individuals died from diabetes and 16,470 (95% UI 13,977-18,961) from CKD-DM, 216 and 179% increases, respectively, compared to 1990. The total number of people with diabetes was 42.3 million (95% UI 38.6-46.4 million) in 2015. DALY rates of diabetes in 2015 were significantly higher than the expected rates based on Socio-demographic Index (SDI). Our study showed a large and increasing burden of diabetes in the region. There is an urgency in dealing with diabetes and its consequences, and these efforts should be at the forefront of health prevention and promotion.
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| 6. |
- Mulugeta, Ezra, et al.
(author)
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Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates.
- 2011
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In: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2011
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Journal article (peer-reviewed)abstract
- We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.
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| 7. |
- Mulugeta, Ezra, et al.
(author)
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CSF amyloid {beta}38 as a novel diagnostic marker for dementia with Lewy bodies.
- 2011
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 82:2, s. 160-4
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Journal article (peer-reviewed)abstract
- Background The clinical distinction between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is sometimes difficult, particularly in mild cases. Although CSF markers such as amyloid β42 (Aβ42) and P-tau can distinguish between AD and normal controls, their ability to distinguish between AD and DLB is not adequate. Objective This study aims to investigate whether CSF markers, in particular levels of Aβ38, can differentiate between mild AD and DLB. Methods 85 individuals were included after standardised diagnostic procedures: 30 diagnosed as probable AD, 23 probable DLB, 20 probable Parkinson's disease dementia and 12 non-demented control subjects. CSF levels of Aβ38, Aβ40 and Aβ42 were determined using commercially available ultra-sensitive multi-array kit assay (MSD) for human Aβ peptides. Total tau (T-tau) and phosphorylated tau (P-tau) were analysed using ELISA (Innotest). In addition, combinations (Aβ42/Aβ38, Aβ42/Aβ40, Aβ42/P-tau and Aβ42/Aβ38/P-tau) were assessed. Results Significant between group differences were found for all CSF measures, and all except Aβ40, Aβ42 and Aβ42/P-tau differed between AD and DLB. The Aβ42/Aβ38 ratio was the measure that best discriminated between AD and DLB (AUC 0.765; p<0.005), with a sensitivity of 78% and a specificity of 67%. Conclusion This study suggests that the level of Aβ38 can potentially contribute in the diagnostic distinction between AD and DLB when combined with Aβ42. Single measures had low diagnostic accuracy, suggesting that developing a panel of markers is the most promising strategy. Studies with independent and larger samples and a priori cut-offs are needed to test this hypothesis.
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| 8. |
- Mulugeta, Ezra
(author)
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Muscarinic M1 and M4 receptor subtypes in normal and pathological conditions in the central nervous system : studies on human and animal tissues using subtype selective ligands
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Snake venoms from different mamba species contain toxins that bind to muscarinic acetylcholine receptors (mAChR). The toxins MT-1 (selective for M1 after iodination), M1 toxin-1 (also known as MT7, selective for MI) and M4 toxin-1 (also known as MT3, selective for M4 receptors) were isolated and used to study M1 and M4 receptor subtypes in normal and pathological conditions. The pharmacological profile of M1 toxin-1 was determined in functional assays using cloned human M1- M4 receptors expressed in CHO cells. It was clearly demonstrated that M1 toxin-1 acts as a selective noncompetitive antagonist of the muscarinic M1 receptors by binding stably to an allosteric site. Age-related loss of mAChRs in rat hippocampus and neocortex is still controversial. The effect of ageing on the level of M1 and M4 mAChR subtypes was investigated in the hippocampus and entorhinal cortex of young (21 days), adult (3 months) and old (25 months) rats. A significant increase in muscarinic M1 receptor binding in all areas of the hippocampus and a significant loss in M4 binding only in the CA1 region and entorhinal cortex have been observed in 25 months compared to 21-day-old rats. The increase of M1 receptors in (old aged) rats could be due to compensatory processes as a result of the changes in M4 receptors. The decrease in M4 receptors in the entorhinal cortex and in the CA1 area of the hippocampus of (old aged) rats could be one of the factors leading to impaired cognitive function. Administration of mAChR agonists or acetylcholinesterase inhibitors produces effective pain relief However, the mAChR subtype(s) involved in the spinal cord are not fully defined. The levels of M1 and M4 receptor subtypes in spinal cord of acute and chronic arthritic rats were investigated. No M1- toxin 1 binding was observed, indicating an absence of M1 receptors. However, the binding Of M4- toxin 1 was reduced between 87-90 % in the Rexed laminae I to X of the spinal cord both in acute and chronic pain as compared to controls. These findings suggest that the mAChR M4 subtype may have a role in cholinergic mechanisms of analgesia. Alzheimers disease (AD) related loss of mAChR subtype has been controversial. Muscarinic M1, M2 and M4 receptor subtype changes in the hippocampus of AD and control brains were evaluated. A significant decrease in M4 receptors was observed in the dentate gyrus and CA4 regions of brain sections from AD patients compared to controls. These findings suggest that, relative to other mAChR subtype, the M4 receptor could be the subtype that is selectively compromised in AD. Long-term adrenalectomy (ADX) has been reported to cause significant loss of cells in the dentate gyrus and CA1-CA4 fields of the hippocampus resulting in impairment of cognitive functions. The effect of ADX on muscarinic M1 and M4 receptors levels in the hippocampus and entorhinal cortex of 3, 14, 30, 90 and 150 days adrenalectomized male Wistar rats was studied. A significant loss Of M4 but not M1 receptors was observed in the different areas of the hippocampus and entorhinal cortex which varied with time after ADX. The vulnerability is in the order entorhinal cortex > dentate gyrus, CA4 > CA3 > CA2, CAI. Our results show that M1 and M4 receptors are differentially affected after ADX and indicate that the M4 receptor subtype is influenced by adrenal hormones and suggest that the M4 receptor might be the subtype linked to memory functions in the hippocampus. In conclusion, the studies from the five papers (Papers I - V) constituting this thesis demonstrate that selective ligands like the muscarinic toxins are valuable tools to establish the roles of the different mAChR subtypes involved in normal and pathological conditions in the CNS. These findings suggest that, relative to the M1, the M4 receptor could be the subtype that is selectively compromised in Alzheimer's disease and in pain response. These findings might lead to new therapeutic strategies in the treatment of pain and Alzheimer's disease.
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| 9. |
- Stanaway, Jeffrey D., et al.
(author)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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In: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Journal article (peer-reviewed)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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| 10. |
- Öhrfelt Olsson, Annika, 1973, et al.
(author)
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Identification of Novel α-Synuclein Isoforms in Human Brain Tissue by using an Online NanoLC-ESI-FTICR-MS Method.
- 2011
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In: Neurochemical research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 36:11, s. 2029-2042
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Journal article (peer-reviewed)abstract
- Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn(1-140)) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn(1-139) and Ac-α-syn(1-103)) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA).
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