| 1. |
- Abbasi, Rasha, et al.
(author)
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IceCube search for neutrinos from GRB 221009A
- 2023
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In: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
-
Conference paper (peer-reviewed)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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| 2. |
- Patterson, Nick, et al.
(author)
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Large-scale migration into Britain during the Middle to Late Bronze Age
- 2022
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594
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Journal article (peer-reviewed)abstract
- Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
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| 3. |
- Alawode, Deborah O T, et al.
(author)
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Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.
- 2021
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In: Journal of internal medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 290:3, s. 583-601
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. Whilst these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N), and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.
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| 4. |
- Allentoft, Morten E., et al.
(author)
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Population genomics of post-glacial western Eurasia
- 2024
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In: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Journal article (peer-reviewed)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 5. |
- Arber, Charles, et al.
(author)
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Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis.
- 2021
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In: Cell reports. - : Elsevier BV. - 2211-1247. ; 34:2
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Journal article (peer-reviewed)abstract
- Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer's disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease.
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| 6. |
- Banerjee, Gargi, et al.
(author)
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Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.
- 2020
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In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1189-1201
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Journal article (peer-reviewed)abstract
- There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p<0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p<0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n=5) and negative (n=5) scans, PET positive individuals had lower (p<0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile.CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.
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| 7. |
- Bateman, Randall J., et al.
(author)
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Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease
- 2023
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 389:20, s. 1862-1876
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Journal article (peer-reviewed)abstract
- Background: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. Methods: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. Results: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Conclusions: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline.
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| 8. |
- Chasman, Daniel I., et al.
(author)
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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
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Journal article (peer-reviewed)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 9. |
- Clarke, Mica T M, et al.
(author)
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CSF synaptic protein concentrations are raised in those with atypical Alzheimer's disease but not frontotemporal dementia.
- 2019
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In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11
-
Journal article (peer-reviewed)abstract
- Increased CSF levels of a number of synaptic markers have been reported in Alzheimer's disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1.CSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls. Patients were stratified by their tau to Aβ42 ratio: those with a ratio of >1 considered as having likely AD pathology, i.e. an atypical form of AD ('AD biomarker' group [n=18]), and <1 as likely FTD pathology ('FTD biomarker' group [n=48]). A subgroup analysis compared those in the FTD group with likely tau (n=7) and TDP-43 (n=18) pathology. Concentrations of neurogranin were measured using two different ELISAs (Ng22 and Ng36), and concentrations of two SNAP-25 fragments (SNAP-25tot and SNAP-25aa40) and synaptotagmin-1 were measured via mass spectrometry.The AD biomarker group had significantly higher concentrations of all synaptic proteins compared to controls except for synaptotagmin-1 where there was only a trend to increased levels-Ng22, AD mean 232.2 (standard deviation 138.9) pg/ml, controls 137.6 (95.9); Ng36, 225.5 (148.8) pg/ml, 130.0 (80.9); SNAP-25tot, 71.4 (27.9) pM, 53.5 (11.7); SNAP-25aa40, 14.0 (6.3), 7.9 (2.3) pM; and synaptotagmin-1, 287.7 (156.0) pM, 238.3 (71.4). All synaptic measures were significantly higher in the atypical AD group than the FTD biomarker group except for Ng36 where there was only a trend to increased levels-Ng22, 114.0 (117.5); Ng36, 171.1 (75.2); SNAP-25tot, 49.2 (16.7); SNAP-25aa40, 8.2 (3.4); and synaptotagmin-1, 197.1 (78.9). No markers were higher in the FTD biomarker group than controls. No significant differences were seen in the subgroup analysis, but there was a trend to increased levels in those with likely tau pathology.No CSF synaptic proteins have been shown to be abnormal in those with likely FTD pathologically. Higher CSF synaptic protein concentrations of neurogranin, SNAP-25, and synaptotagmin-1 appear to be related to AD pathology.
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| 10. |
- Dubois, Bruno, et al.
(author)
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Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.
- 2014
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In: Lancet neurology. - 1474-4465. ; 13:6, s. 614-29
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Research review (peer-reviewed)abstract
- In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.
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| 11. |
- Escott-Price, Valentina, et al.
(author)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Journal article (peer-reviewed)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 12. |
- Ferrari, Raffaele, et al.
(author)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
-
In: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
-
Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 13. |
- Foiani, Martha S, et al.
(author)
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Plasma tau is increased in frontotemporal dementia.
- 2018
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In: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 89:8, s. 804-807
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Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations inGRN,MAPTandC9orf72being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life.This study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in eitherMAPT(n=12),GRN(n=9) orC9orf72(n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression.Higher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only theMAPTgroup had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration.Plasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only inMAPTmutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.
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| 14. |
- Gallagher, Michael D., et al.
(author)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Journal article (peer-reviewed)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 15. |
- Hampel, Harald, et al.
(author)
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Biomarkers for Alzheimer's disease therapeutic trials.
- 2011
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In: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4, s. 579-593
-
Research review (peer-reviewed)abstract
- The development of disease-modifying treatments for Alzheimer's disease requires innovative trials with large numbers of subjects and long observation periods. The use of blood, cerebrospinal fluid or neuroimaging biomarkers is critical for the demonstration of disease-modifying therapy effects on the brain. Suitable biomarkers are those which reflect the progression of AD related molecular mechanisms and neuropathology, including amyloidogenic processing and aggregation, hyperphosphorylation, accumulation of tau and neurofibrillary tangles, progressive functional, metabolic and structural decline, leading to neurodegeneration, loss of brain tissue and cognitive symptoms. Biomarkers should be used throughout clinical trial phases I-III of AD drug development. They can be used to enhance inclusion and exclusion criteria, or as baseline predictors to increase the statistical power of trials. Validated and qualified biomarkers may be used as outcome measures to detect treatment effects in pivotal clinical trials. Finally, biomarkers can be used to identify adverse effects. Questions regarding which biomarkers should be used in clinical trials, and how, are currently far from resolved. The Oxford Task Force continues and expands the work of our previous international expert task forces on disease-modifying trials and on endpoints for Alzheimer's disease clinical trials. The aim of this initiative was to bring together a selected number of key international opinion leaders and experts from academia, regulatory agencies and industry to condense the current knowledge and state of the art regarding the best use of biological markers in Alzheimer's disease therapy trials and to propose practical recommendations for the planning of future AD trials.
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| 16. |
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| 17. |
- Hoelscher, Kristian, et al.
(author)
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Urbanization and political change in Africa
- 2023
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In: AFRICAN AFFAIRS. - 0001-9909 .- 1468-2621. ; 122:488, s. 353-376
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Journal article (peer-reviewed)abstract
- Urbanization is transforming the human and political geography of Africa. While a growing body of research explores the urban dimensions of clientelism, contentious action, and social mobilization, there has been less attention given to the ways in which this demographic megatrend is influencing political change more broadly. We argue that the political implications of African urbanization are contingent on local conditions and experiences; there are no deterministic associations between urbanization and political change. To better understand the mechanisms linking urbanization to politics, we argue that a place-based approach is needed. We illustrate this by reviewing and highlighting how urbanization may affect (i) the nature and balance of citizen preferences; (ii) the composition, interests, and influence of elite actors; (iii) forms of political mobilization; (iv) shifting gender roles; (v) the role of civil society in political processes; and (vi) the likelihood and manifestations of contentious collective action. We conclude with a discussion of directions for further research.
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| 18. |
- Ingala, Silvia, et al.
(author)
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Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.
- 2021
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:7, s. 1189-1204
-
Journal article (peer-reviewed)abstract
- We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 =0.98, P<0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P<0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P<0.001).In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
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| 19. |
- James, Sarah-Naomi, et al.
(author)
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A population-based study of head injury, cognitive function and pathological markers.
- 2021
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In: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 8:4, s. 842-856
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Journal article (peer-reviewed)abstract
- To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals.Participants (n=502, age=69-71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18 F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer's disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15years prior to the scan (ii) anytime up to age 71.Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15years prior (16%, n=80) performed worse on cognitive tests at age 69-71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p>0.01).Having a LOC HI aged 50's and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).
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| 20. |
- Jones, Lesley, et al.
(author)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Journal article (peer-reviewed)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 21. |
- Kanoni, Stavroula, et al.
(author)
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Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant : a 14-cohort meta-analysis
- 2011
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In: Diabetes. - Alexandria : American diabetes association. - 0012-1797 .- 1939-327X. ; 60:9, s. 2407-2416
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Journal article (peer-reviewed)abstract
- OBJECTIVE Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.RESEARCH DESIGN AND METHODS We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.RESULTS We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
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| 22. |
- Keshavan, Ashvini, et al.
(author)
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Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays.
- 2020
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In: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 12:1
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Journal article (peer-reviewed)abstract
- We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET).In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays, and inter-platform Pearson correlations were derived. Logistic regressions and receiver-operating characteristic analysis generated CSF cut-points optimizing concordance with 18F-florbetapir amyloid PET status (n=63).Measurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84-.94, P<.0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57-0.79, P<.0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.110 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40, and 25.3 for Lumipulse Aβ42/p-tau181.The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.
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| 23. |
- Keshavan, Ashvini, et al.
(author)
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CSF biomarkers for dementia.
- 2022
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In: Practical neurology. - : BMJ. - 1474-7766 .- 1474-7758. ; 22:4, s. 285-294
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Journal article (peer-reviewed)abstract
- Although cerebrospinal fluid (CSF) biomarker testing is incorporated into some current guidelines for the diagnosis of dementia (such as England's National Institute for Health and Care Excellence (NICE)), it is not widely accessible for most patients for whom biomarkers could potentially change management. Here we share our experience of running a clinical cognitive CSF service and discuss recent developments in laboratory testing including the use of the CSF amyloid-β 42/40 ratio and automated assay platforms. We highlight the importance of collaborative working between clinicians and laboratory staff, of preanalytical sample handling, and discuss the various factors influencing interpretation of the results in appropriate clinical contexts. We advocate for broadening access to CSF biomarkers by sharing clinical expertise, protocols and interpretation with colleagues working in psychiatry and elderly care, especially when access to CSF may be part of a pathway to disease-modifying treatments for Alzheimer's disease and other forms of dementia.
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| 24. |
- Keshavan, Ashvini, et al.
(author)
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Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.
- 2021
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In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 144:2, s. 434-449
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Journal article (peer-reviewed)abstract
- Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770-0.864 and amyloid-β composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.
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| 25. |
- Kingsley, Jonathan, et al.
(author)
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Pandemic gardening: A narrative review, vignettes and implications for future research
- 2023
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In: Urban Forestry & Urban Greening. - : ELSEVIER GMBH. - 1618-8667 .- 1610-8167. ; 87
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Research review (peer-reviewed)abstract
- There is a significant amount of evidence highlighting the health, wellbeing and social benefits of gardening during previous periods of crises. These benefits were also evident during the COVID-19 pandemic. This paper presents a narrative review exploring gardening during the early stages of the COVID-19 pandemic to understand the different forms of gardening that took place during this crisis and key elements of this activity. Research about gardening during the pandemic focused on food (in)security and disrupted food systems, the health and wellbeing benefits of gardening, and the social dimensions of gardening. We offer three vignettes of our own research to highlight key insights from local, national and international perspectives of gardening during the pandemic. The papers conclusion outlines how researchers, policy makers and public health practitioners can harness what has been learned from gardening during the pandemic to ensure these benefits are more widely available and do not exacerbate already entrenched health inequalities in society.
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