| 1. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 2. |
- Walsh, Roddy, et al.
(författare)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 3. |
- Bollack, Ariane, et al.
(författare)
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Evaluation of novel data-driven metrics of amyloid β deposition for longitudinal PET studies
- 2023
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Ingår i: NeuroImage. - 1053-8119. ; 280
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Positron emission tomography (PET) provides in vivo quantification of amyloid-β (Aβ) pathology. Established methods for assessing Aβ burden can be affected by physiological and technical factors. Novel, data-driven metrics have been developed to account for these sources of variability. We aimed to evaluate the performance of four of these amyloid PET metrics against conventional techniques, using a common set of criteria. Methods: Three cohorts were used for evaluation: Insight 46 (N=464, [18F]florbetapir), AIBL (N=277, [18F]flutemetamol), and an independent test-retest data (N=10, [18F]flutemetamol). Established metrics of amyloid tracer uptake included the Centiloid (CL) and where dynamic data was available, the non-displaceable binding potential (BPND). The four data-driven metrics computed were the amyloid load (Aβ load), the Aβ-PET pathology accumulation index (Aβ index), the Centiloid derived from non-negative matrix factorisation (CLNMF), and the amyloid pattern similarity score (AMPSS). These metrics were evaluated using reliability and repeatability in test-retest data, associations with BPND and CL, variability of the rate of change and sample size estimates to detect a 25% slowing in Aβ accumulation. Results: All metrics showed good reliability. Aβ load, Aβ index and CLNMF were strong associated with the BPND. The associations with CL suggest that cross-sectional measures of CLNMF, Aβ index and Aβ load are robust across studies. Sample size estimates for secondary prevention trial scenarios were the lowest for CLNMF and Aβ load compared to the CL. Conclusion: Among the novel data-driven metrics evaluated, the Aβ load, the Aβ index and the CLNMF can provide comparable performance to more established quantification methods of Aβ PET tracer uptake. The CLNMF and Aβ load could offer a more precise alternative to CL, although further studies in larger cohorts should be conducted.
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| 4. |
- Bollack, Ariane, et al.
(författare)
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Investigating reliable amyloid accumulation in Centiloids : Results from the AMYPAD Prognostic and Natural History Study
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:5, s. 3429-3441
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-β (Aβ) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease–Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12–20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.
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| 5. |
- Skillbäck, Tobias, et al.
(författare)
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CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival.
- 2014
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Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 83:21, s. 1945-53
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that CSF neurofilament light (NFL) levels would be elevated in dementias with subcortical involvement, including vascular dementia (VaD), but less elevated in dementias primarily affecting gray matter structures, such as Alzheimer disease (AD), and that elevated CSF NFL would correlate with disease severity and shorter survival time irrespective of clinical diagnosis.
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| 6. |
- Yong, Keir X.X., et al.
(författare)
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Diagnosis and Management of Posterior Cortical Atrophy
- 2023
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Ingår i: Current Treatment Options in Neurology. - : Springer Science and Business Media LLC. - 1092-8480 .- 1534-3138. ; 25:2, s. 23-43
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review: The study aims to provide a summary of recent developments for diagnosing and managing posterior cortical atrophy (PCA). We present current efforts to improve PCA characterisation and recommendations regarding use of clinical, neuropsychological and biomarker methods in PCA diagnosis and management and highlight current knowledge gaps. Recent findings: Recent multi-centre consensus recommendations provide PCA criteria with implications for different management strategies (e.g. targeting clinical features and/or disease). Studies emphasise the preponderance of primary or co-existing Alzheimer’s disease (AD) pathology underpinning PCA. Evidence of approaches to manage PCA symptoms is largely derived from small studies. Summary: PCA diagnosis is frequently delayed, and people are likely to receive misdiagnoses of ocular or psychological conditions. Current treatment of PCA is symptomatic — pharmacological and non-pharmacological — and the use of most treatment options is based on small studies or expert opinion. Recommendations for non-pharmacological approaches include interdisciplinary management tailored to the PCA clinical profile — visual-spatial — rather than memory-led, predominantly young onset — and psychosocial implications. Whilst emerging disease-modifying treatments have not been tested in PCA, an accurate and timely diagnosis of PCA and determining underlying pathology is of increasing importance in the advent of disease-modifying therapies for AD and other albeit rare causes of PCA.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer's disease.
- 2016
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 87:9, s. 1000-1004
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Tidskriftsartikel (refereegranskat)abstract
- Selective vulnerability in the nervous system refers to the fact that subpopulations of neurons in different brain systems may be more or less prone to abnormal function or death in response to specific types of pathological states or injury. The concept has been used extensively as a potential way of explaining differences in degeneration patterns and the clinical presentation of different neurodegenerative diseases. Yet the increasing complexity of molecular histopathology at the cellular level in neurodegenerative disorders frequently appears at odds with phenotyping based on clinically-directed, macroscopic regional brain involvement. While cross-disease comparisons can provide insights into the differential vulnerability of networks and neuronal populations, we focus here on what is known about selective vulnerability-related factors that might explain the differential phenotypic expressions of the same disease-in this case, typical and atypical forms of Alzheimer's disease. Whereas considerable progress has been made in this area, much is yet to be elucidated; further studies comparing different phenotypic variants aimed at identifying both vulnerability and resilience factors may provide valuable insights into disease pathogenesis, and suggest novel targets for therapy.
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| 8. |
- Obrocki, Pawel, et al.
(författare)
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Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course - A joint PhD student course at University College London and University of Gothenburg
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases. In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid β (Aβ) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays. As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring.
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| 9. |
- Skillbäck, Tobias, et al.
(författare)
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Apolipoprotein E genotypes and longevity across dementia disorders
- 2018
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 14:7, s. 895-901
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The ε4 allele of the apolipoprotein E (APOE) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied.METHODS: We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity.RESULTS: The ε4 allele was associated with reduced longevity as ε4 versus ε3 homozygotes lived on average 2.6 years shorter (P = .006). In AD, ε4 carriers lived 1.0 years shorter than noncarriers (P = .028). The ε4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders.DISCUSSION: The APOE ε4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common.
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| 10. |
- Skillbäck, Tobias, et al.
(författare)
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Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia.
- 2015
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 138:Pt 9, s. 2716-31
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Tidskriftsartikel (refereegranskat)abstract
- Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-β1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-β1-42 and amyloid-β1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-β1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-β1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-β1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-β1-42, total tau, phosphorylated tau and the amyloid-β1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-β1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.
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