| 1. |
- Vogel, Jacob W., et al.
(author)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Wang, Li-San, et al.
(author)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Journal article (peer-reviewed)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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| 6. |
- Zhou, XP, et al.
(author)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 7. |
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| 8. |
- Scott, G. D., et al.
(author)
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Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium
- 2022
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
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Journal article (peer-reviewed)abstract
- The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.
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| 9. |
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| 10. |
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| 11. |
- Filioglo, A, et al.
(author)
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Outcomes after reperfusion therapies in patients with ACA stroke: A multicenter cohort study from the EVATRISP collaboration.
- 2022
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In: Journal of the neurological sciences. - : Elsevier BV. - 1878-5883 .- 0022-510X. ; 432
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Journal article (peer-reviewed)abstract
- Patients with stroke secondary to occlusions of the anterior cerebral artery (ACA) often have poor outcomes. The optimal acute therapeutic intervention for these patients remains unknown.Patients with isolated ACA-stroke were identified from 10 centers participating in the EndoVascular treatment And ThRombolysis in Ischemic Stroke Patients (EVATRISP) prospective registry. Patients treated with endovascular thrombectomy (EVT) were compared to those treated with intravenous thrombolysis (IVT). Odds ratios with 95% confidence intervals (OR; 95%CI) were calculated using multivariate regression analysis.Included were 92 patients with ACA-stroke. Of the 92 ACA patients, 55 (60%) were treated with IVT only and 37 (40%) with EVT (±bridging IVT). ACA patients treated with EVT had more often wake-up stroke (24% vs. 6%, p=0.044) and proximal ACA occlusions (43% vs. 24%, p=0.047) and tended to have higher stroke severity on admission [NIHSS: 10.0 vs 7.0, p=0.054). However, odds for favorable outcome, mortality or symptomatic intracranial hemorrhage did not differ significantly between both groups. Exploration of the effect of clot location inside the ACA showed that in patients with A1 or A2/A3 ACA occlusions the chances of favorable outcome were not influenced by treatment allocation to IVT or EVT.Treatment with either IVT or EVT could be safe with similar effect in patients with ACA-strokes and these effects may be independent of clot location within the occluded ACA.
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| 12. |
- Guerreiro, R., et al.
(author)
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Heritability and genetic variance of dementia with Lewy bodies
- 2019
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 127, s. 492-501
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Journal article (peer-reviewed)abstract
- Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants. © 2019 Elsevier Inc.
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| 13. |
- Guerreiro, R., et al.
(author)
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Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
- 2018
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In: Lancet Neurology. - 1474-4422. ; 17:1, s. 64-74
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Journal article (peer-reviewed)abstract
- Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
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| 14. |
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| 15. |
- Bianchini, F, et al.
(author)
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Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein
- 2023
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In: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 8:81, s. eade0958-
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Journal article (peer-reviewed)abstract
- Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2′ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.
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| 16. |
- Filioglo, A., et al.
(author)
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Tandem occlusions involving the internal carotid and anterior cerebral arteries-A rare form of stroke: Results from the multicenter EVATRISP collaboration study
- 2022
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 13
-
Journal article (peer-reviewed)abstract
- BackgroundPatients with stroke secondary to isolated anterior cerebral artery (ACA) occlusions have poor outcomes. Whether tandem occlusions (TO) of the extracranial internal carotid (ICA) and the ACA carry even worse outcomes that remain unknown. MethodsPatients with TO involving ICA and ACA occlusions were identified from 14 participating centers from the EndoVascular treatment And ThRombolysis in Ischemic Stroke Patients (EVATRISP) project which is a multicenter, observational, cohort study with prospective accrual of data followed by retrospective data analysis. Patients with isolated ACA stroke served as controls. ResultsIncluded were 92 patients with isolated ACA and 16 patients with ICA-ACA TO stroke. On univariate analyses, patients with TO had more severe strokes on admission [median NIHSS (IQR) 13.5 (9-21) vs. 8 (5-12), p = 0.003] and were more often treated with thrombectomy (81 vs. 40%, p = 0.002). Mortality rates were higher among TO patients (31 vs. 11%, p = 0.03). Rates of favorable functional outcomes were numerically lower among TO patients (38 vs. 60%) but the difference was not statistically significant (p = 0.09). On multivariate analyses, the presence of TO did not modify the chances for favorable outcomes. ConclusionTO stroke with ICA and isolated ACA involvement is rare and results in more severe initial neurological deficits and higher mortality compared to those seen in patients with isolated ACA stroke.
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| 17. |
- Orme, T., et al.
(author)
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Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
- 2020
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In: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Journal article (peer-reviewed)abstract
- Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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| 18. |
- Bras, Jose, et al.
(author)
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Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies.
- 2014
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 23:23, s. 6139-6146
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Journal article (peer-reviewed)abstract
- Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
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| 19. |
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| 20. |
- Guerreiro, Rita, et al.
(author)
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Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases.
- 2016
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 38, s. 7-214
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Journal article (peer-reviewed)abstract
- The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.
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| 21. |
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| 22. |
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| 23. |
- Anderson, R. B., et al.
(author)
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Indigenous land rights in Canada : The foundation for development
- 2005
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In: International Journal of Entrepreneurship and Small Business. - : InderScience Publishers. - 1476-1297 .- 1741-8054. ; 2:2, s. 104-133
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Journal article (peer-reviewed)abstract
- Throughout the middle decades of the 20th Century Indigenous people were the target of efforts to assist in economic development. In large part these externally developed, modernisation based efforts failed. In response, a second wave of Indigenous development has emerged; one in which Indigenous peoples are striving to rebuild their 'nations' and improve their lot through economic development 'on their own terms'. Key to this approach is the pursuit by Indigenous people of the recognition of their rights to their traditional lands and resources. This paper examines the emergence of this second wave of Indigenous development in Canada.
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| 24. |
- Anderson, R. B., et al.
(author)
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The Saskatchewan experience
- 2007
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In: International Handbook of Research on Indigenous Entrepreneurship. - Cheltenham : Edward Elgar Publishing. - 9781843768340 ; , s. 352-365
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Book chapter (other academic/artistic)
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| 25. |
- Drori, I., et al.
(author)
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Transnational Entrepreneurship : Toward a unifying theoretical framework
- 2006
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In: Academy of Management 2006 Annual Meeting.
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Conference paper (peer-reviewed)abstract
- This paper seeks to develop a unifying analytical framework to advance the study of Transnational Entrepreneurship (TE), which refers to the processes of creating and growing new business ventures across national boundaries by social actors. We first examine relevant research literatures and theoretical perspectives and identify the limitations of each in analyzing the process of TE. We then introduce a new theoretical lens for studying TE that is grounded in the theory of practice and the concept of "habitus", which refers to aspects of culture that are anchored in the body of daily practices of individuals, groups, societies, and nations. Our proposed analytical framework views TE as a social realm of immigrants who operate in a complex, cross-national habitus, consisting of dual cultural, institutional and economic features from which actors can formulate their entrepreneurial strategies of action. We show how this framework integrates perspectives that focus on actors' motivation and behavior, cultural values and norms, institutional fields, political meaning and consequences, and social capital and network formation. We conclude by developing theoretical propositions and recommendations for future research.
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| 26. |
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| 27. |
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| 28. |
- Honig, Benson, et al.
(author)
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The fox in the hen house : A critical examination of plagiarism among members of the academy of management
- 2012
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In: Academy of Management Learning & Education. - : Academy of Management Learning & Education. - 1537-260X .- 1944-9585. ; 11:1, s. 101-123
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Journal article (peer-reviewed)abstract
- Research on academic plagiarism has typically focused on students as the perpetrators of unethical behaviors, and less attention has been paid to academic researchers as likely candidates for such behaviors. We examined 279 papers presented at the International Management division of the 2009 Academy of Management conference for the purpose of studying plagiarism among academics. Results showed that 25% of our sample had some amount of plagiarism, and over 13% exhibited significant plagiarism. This exploratory study raises an alarm regarding the inadequate monitoring of norms and professional activities associated with Academy of Management members.
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| 29. |
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| 30. |
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| 31. |
- Kun-Rodrigues, Celia, et al.
(author)
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A comprehensive screening of copy number variability in dementia with Lewy bodies.
- 2019
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In: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 75
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Journal article (peer-reviewed)abstract
- The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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| 32. |
- Kun-Rodrigues, Celia, et al.
(author)
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Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies
- 2017
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 49
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Journal article (peer-reviewed)abstract
- . C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of . C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of . C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that . C9orf72 repeat expansions are not causally associated with DLB.
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| 33. |
- Odin, Per, et al.
(author)
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Apomorphininjektionstherapie bei Morbus Parkinson
- 2011
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In: Aktuelle Neurologie. - : Georg Thieme Verlag KG. - 0302-4350 .- 1438-9428. ; 38:Suppl. 1, s. 11-16
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Research review (peer-reviewed)abstract
- Apomorphine as subcutaneous injections offers a valuable and effective treatment alternative for Parkinson patients with oral medication-resistant "off' phases. Its efficacy is stable during long-term therapy, with no signs of patient tolerance. Adverse events are usually mild. The best results are obtained with relatively young, active, and cognitively intact patients. Intermittent s.c. apomorphine therapy can improve the patients' possibilities to continue to work and to live a normal social life, by offering increased freedom and self-confidence through a reliable, quick rescue from the disabling medication-resistant off phases.
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| 34. |
- Peredo, A. M., et al.
(author)
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Towards a theory of indigenous entrepreneurship
- 2004
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In: International Journal of Entrepreneurship and Small Business. - : InderScience Publishers. - 1476-1297 .- 1741-8054. ; 1:1-2, s. 1-20
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Journal article (peer-reviewed)abstract
- Indigenous populations throughout the world suffer from chronic poverty, lower education levels, and poor health. The 'second wave' of indigenous development, after direct economic assistance from outside, lies in indigenous efforts to rebuild their 'nations' and improve their lot through entrepreneurial enterprise. This paper suggests that there is a distinguishable kind of activity appropriately called 'indigenous entrepreneurship'. We begin by defining the indigenous population and noting some general facts about their numbers and distribution. In an effort to discern the potential for development on indigenous peoples' own terms, we then explore three frameworks for understanding efforts at development, including indigenous development: modernisation theory, dependency theory and (at somewhat greater length) regulation theory. After distinguishing 'indigenous' from 'ethnic' entrepreneurship, we conclude by identifying a number of lead questions that present themselves at the outset of an enquiry into the nature of indigenous entrepreneurship.
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| 35. |
- Timpka, Jonathan, et al.
(author)
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Improvement of dyskinesias with l-dopa infusion in advanced Parkinson's disease.
- 2015
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In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314.
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Journal article (peer-reviewed)abstract
- We wanted to investigate whether continuous intrajejunal levodopa-carbidopa intestinal gel (LCIG) therapy has an antidyskinetic effect in patients with Parkinson's disease (PD) and troublesome dyskinesias. We also sought to examine the effect of LCIG therapy on motor function and health-related quality of life (HRQoL).
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