Lund University Publications
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Lund University Lund University Publications2000-01-01T00:00+00:001dailyThe α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases
https://lup.lub.lu.se/search/publication/85e7b22c-58cd-436d-a47e-5894ff96e83b
Smith, RubenCapotosti, FrancescaSchain, MartinOhlsson, TomasVokali, EfthymiaMolette, JeromeTouilloux, TanjaHliva, ValerieDimitrakopoulos, Ioannis K.Puschmann, AndreasJögi, JonasSvenningsson, PerAndréasson, MattiasSandiego, ChristineRussell, David S.Miranda-Azpiazu, PatriciaHalldin, ChristerStomrud, ErikHall, SaraBratteby, KlasTampio L’Estrade, ElinaLuthi-Carter, RuthPfeifer, AndreaKosco-Vilbois, MarieStreffer, JohannesHansson, Oskar2023-12A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.https://lup.lub.lu.se/record/85e7b22c-58cd-436d-a47e-5894ff96e83bhttp://dx.doi.org/10.1038/s41467-023-42305-3scopus:85174956785pmid:37891183engNature Communications; 14(1), no 6750 (2023)ISSN: 2041-1723NeurosciencesThe α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseasescontributiontojournal/articleinfo:eu-repo/semantics/articletextMonitoring the interactions between alpha-synuclein and Tau in vitro and in vivo using bimolecular fluorescence complementation
https://lup.lub.lu.se/search/publication/632a07b8-3f33-4b73-b2ca-b11c480f3093
Torres-Garcia, LauraDomingues, Joana M. P.Brandi, EdoardoHaikal, CarolineMudannayake, Janitha M.Brás, Inês C.Gerhardt, EllenLi, WenSvanbergsson, AlexanderOuteiro, Tiago F.Gouras, Gunnar K.Li, Jia Yi2022Parkinson’s disease (PD) and Alzheimer’s disease (AD) are characterized by pathological accumulation and aggregation of different amyloidogenic proteins, α-synuclein (aSyn) in PD, and amyloid-β (Aβ) and Tau in AD. Strikingly, few PD and AD patients’ brains exhibit pure pathology with most cases presenting mixed types of protein deposits in the brain. Bimolecular fluorescence complementation (BiFC) is a technique based on the complementation of two halves of a fluorescent protein, which allows direct visualization of protein–protein interactions. In the present study, we assessed the ability of aSyn and Tau to interact with each other. For in vitro evaluation, HEK293 and human neuroblastoma cells were used, while in vivo studies were performed by AAV6 injection in the substantia nigra pars compacta (SNpc) of mice and rats. We observed that the co-expression of aSyn and Tau led to the emergence of fluorescence, reflecting the interaction of the proteins in cell lines, as well as in mouse and rat SNpc. Thus, our data indicates that aSyn and Tau are able to interact with each other in a biologically relevant context, and that the BiFC assay is an effective tool for studying aSyn-Tau interactions in vitro and in different rodent models in vivo.https://lup.lub.lu.se/record/632a07b8-3f33-4b73-b2ca-b11c480f3093http://dx.doi.org/10.1038/s41598-022-06846-9scopus:85125155172pmid:35194057engScientific Reports; 12, pp 1-11 (2022)ISSN: 2045-2322NeurosciencesMonitoring the interactions between alpha-synuclein and Tau in vitro and in vivo using bimolecular fluorescence complementationcontributiontojournal/articleinfo:eu-repo/semantics/articletextCerebrospinal Fluid Biomarker Levels as Markers for Nursing Home Placement and Survival Time in Alzheimer's Disease
https://lup.lub.lu.se/search/publication/9165161f-5d72-4a1f-8856-2e75c274926a
Wattmo, CarinaBlennow, KajHansson, Oskar2021BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are associated with conversion from mild cognitive impairment to Alzheimer's disease (AD), but their predictive value for later end-points has been less evaluated with inconsistent results.OBJECTIVE: We investigated potential relationships between CSF amyloid-β1-42 (Aβ42), phosphorylated tau (P-tau), and total tau (T-tau) with time to nursing home placement (NHP) and life expectancy after diagnosis.METHODS: This prospective observational study included 129 outpatients clinically diagnosed with mild-to-moderate AD who underwent a lumbar puncture. The CSF biomarkers were analysed with xMAP technology. Dates of institutionalisation and death were recorded.RESULTS: After 20 years of follow-up, 123 patients (95%) were deceased. The participants with abnormal P-tau and T-tau (A+ T+ (N)+) died earlier than those with normal P-tau/abnormal T-tau (A+ T- (N)+) (mean, 80.5 vs. 85.4 years). Linear associations were demonstrated between lower Aβ42 and shorter time to NHP (p = 0.017), and higher P-tau and younger age at death (p = 0.016). No correlations were detected between survival after AD diagnosis and CSF biomarkers. In sex- and-age-adjusted Cox regression models, higher P-tau and T-tau were independent predictors of shorter lifespan after diagnosis. In multivariate Cox models, older age and lower baseline cognitive status, but not elevated tau, significantly precipitated both institutionalisation and death.CONCLUSION: These findings suggest that CSF biomarker levels plateau in the dementia phase of AD, which may limit their possible relationships with clinical end-points, such as NHP and survival time. However, the biomarkers reflect the central pathophysiologies of AD. In particular, pathologic tau is associated with more advanced disease, younger age at onset, and earlier death.application/pdfhttps://lup.lub.lu.se/record/9165161f-5d72-4a1f-8856-2e75c274926ahttp://dx.doi.org/10.2174/1567205018666211022164952https://lup.lub.lu.se/search/files/110315068/Wattmo_CSF_biomarkers_NHP_survival.pdfpmid:34719365scopus:85122546321enginfo:eu-repo/semantics/openAccessCurrent Alzheimer Research; 18(7), pp 573-584 (2021)ISSN: 1875-5828NeurologyCerebrospinal Fluid Biomarker Levels as Markers for Nursing Home Placement and Survival Time in Alzheimer's Diseasecontributiontojournal/articleinfo:eu-repo/semantics/articletextDietary amino acids and risk of stroke subtypes : a prospective analysis of 356,000 participants in seven European countries
https://lup.lub.lu.se/search/publication/7f588e82-4889-4248-b643-a4e000643601
Tong, Tammy Y.N.Clarke, RobertSchmidt, Julie A.Huybrechts, IngeNoor, UrwahForouhi, Nita G.Imamura, FumiakiTravis, Ruth C.Weiderpass, ElisabeteAleksandrova, KrasimiraDahm, Christina C.van der Schouw, Yvonne T.Overvad, KimKyrø, CecilieTjønneland, AnneKaaks, RudolfKatzke, VerenaSchiborn, CatarinaSchulze, Matthias B.Mayen-Chacon, Ana LuciaMasala, GiovannaSieri, Sabinade Magistris, Maria SantucciTumino, RosarioSacerdote, CarlottaBoer, Jolanda M.A.Verschuren, W. M.MoniqueBrustad, MagrittNøst, Therese HaugdahlCrous-Bou, MartaPetrova, DafinaAmiano, PilarHuerta, José MaríaMoreno-Iribas, ConchiEngström, GunnarMelander, OlleJohansson, KristinaLindvall, KristinaAglago, Elom K.Heath, Alicia K.Butterworth, Adam S.Danesh, JohnKey, Timothy J.2023Purpose: Previously reported associations of protein-rich foods with stroke subtypes have prompted interest in the assessment of individual amino acids. We examined the associations of dietary amino acids with risks of ischaemic and haemorrhagic stroke in the EPIC study. Methods: We analysed data from 356,142 participants from seven European countries. Dietary intakes of 19 individual amino acids were assessed using validated country-specific dietary questionnaires, calibrated using additional 24-h dietary recalls. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of ischaemic and haemorrhagic stroke in relation to the intake of each amino acid. The role of blood pressure as a potential mechanism was assessed in 267,642 (75%) participants. Results: After a median follow-up of 12.9 years, 4295 participants had an ischaemic stroke and 1375 participants had a haemorrhagic stroke. After correction for multiple testing, a higher intake of proline (as a percent of total protein) was associated with a 12% lower risk of ischaemic stroke (HR per 1 SD higher intake 0.88; 95% CI 0.82, 0.94). The association persisted after mutual adjustment for all other amino acids, systolic and diastolic blood pressure. The inverse associations of isoleucine, leucine, valine, phenylalanine, threonine, tryptophan, glutamic acid, serine and tyrosine with ischaemic stroke were each attenuated with adjustment for proline intake. For haemorrhagic stroke, no statistically significant associations were observed in the continuous analyses after correcting for multiple testing. Conclusion: Higher proline intake may be associated with a lower risk of ischaemic stroke, independent of other dietary amino acids and blood pressure.https://lup.lub.lu.se/record/7f588e82-4889-4248-b643-a4e000643601http://dx.doi.org/10.1007/s00394-023-03251-4scopus:85173723528pmid:37804448engEuropean Journal of Nutrition; (2023)ISSN: 1436-6207Nutrition and DieteticsAmino acidsDietary proteinHaemorrhagic strokeIschaemic strokeNutritional epidemiologyProspective cohortDietary amino acids and risk of stroke subtypes : a prospective analysis of 356,000 participants in seven European countriescontributiontojournal/articleinfo:eu-repo/semantics/articletextInflammation Biomarkers in Huntington’s Disease
https://lup.lub.lu.se/search/publication/64166fd5-3930-46ce-ad91-c7228220dec9
Björkqvist, Maria2023Neurodegenerative diseases share many features, such as inflammation. Accumulating evidence support the role of neuroinflammation in the pathogenesis and treatment of neurodegenerative diseases, and inflammatory markers are suggested important tools to identify disease risk, diagnose disease, monitor disease progression or treatment response, as well as predict clinical outcomes. In Huntington’s disease (HD) inflammatory processes, both centrally and peripherally, are suggested to contribute to pathology, and modulating the immune system may be a potential therapeutic strategy. Neuroinflammation has been shown to be an important factor and microglial activation can be detected before onset of clinical features. Central inflammatory processes are mirrored peripherally, and a peripheral low-grade immune response has been demonstrated in premanifest HD. Both direct and in-direct effects of mutant huntingtin within inflammatory cells have been demonstrated. As circulating markers of inflammation has been shown to mirror brain inflammatory changes in HD, this has raised the possibility that these markers could be useful as markers of disease features. This chapter aims to summarize current knowledge on biofluid immune markers and discuss how these markers may assist in understanding of HD pathology and aid in detection of new therapeutic targets.https://lup.lub.lu.se/record/64166fd5-3930-46ce-ad91-c7228220dec9http://dx.doi.org/10.1007/978-3-031-32815-2_11scopus:85175188109engContemporary Clinical Neuroscience; Part F1569, pp 277-304 (2023)ISSN: 2627-5341ISSN: 2627-535XNeurosciencesIL-6Innate immune responseNeuroinflammationPeripheral low grade immune responseInflammation Biomarkers in Huntington’s Diseasecontributiontobookanthology/chapterinfo:eu-repo/semantics/bookParttextCortical microvascular raspberries and ageing : an independent but not exclusive relationship
https://lup.lub.lu.se/search/publication/77ffd2fe-2c8c-4836-8518-39f79066d39a
Ek Olofsson, HenricÖsterling Delshammar, TheaEnglund, Elisabet2023-12Introduction: Raspberries are cerebral microvascular formations of unknown origin, defined as three or more transversally sectioned vascular lumina surrounded by a common perivascular space. We have previously demonstrated an increased raspberry density in the cortex of patients with vascular dementia and cerebral atherosclerosis, while studies by other authors on overlapping and synonymously defined vascular entities mainly associate them with advancing age. The aim of the present study was to examine the relationship between raspberries and age in a large study sample while including multiple potential confounding factors in the analysis.Materials and methods: Our study sample consisted of 263 individuals aged 20–97 years who had undergone a clinical autopsy including a neuropathological examination. The cortical raspberry density had either been quantified as part of a previous study or was examined de novo in a uniform manner on haematoxylin- and eosin-stained tissue sections from the frontal lobe. The medical records and autopsy reports were assessed regarding neurodegeneration, cerebral infarcts, cerebral atherosclerosis and small vessel disease, cardiac hypertrophy, nephrosclerosis, hypertension, and diabetes mellitus. With the patients grouped according to 10-year age interval, non-parametric tests (the Kruskal–Wallis test, followed by pairwise testing with Bonferroni-corrected P values) and multiple linear regression models (not corrected for multiple tests) were performed.Results: The average raspberry density increased with advancing age. The non-parametric tests demonstrated statistically significant differences in raspberry density when comparing the groups aged 60–99 years and 70–99 years to those aged 20–29 years (P < 0.012) and 30–59 years (P < 0.011), respectively. The multiple linear regression models demonstrated positive associations with age interval (P < 0.001), cerebral atherosclerosis (P = 0.024), cardiac hypertrophy (P = 0.021), hypertension subgrouped for organ damage (P = 0.006), and female sex (P = 0.004), and a tendency towards a negative association with Alzheimer’s disease neuropathologic change (P = 0.048).Conclusion: The raspberry density of the frontal cortex increases with advancing age, but our results also indicate associations with acquired pathologies. Awareness of the biological and pathological context where raspberries occur can guide further research on their origin.https://lup.lub.lu.se/record/77ffd2fe-2c8c-4836-8518-39f79066d39ahttp://dx.doi.org/10.1186/s40478-023-01700-zpmid:38087325scopus:85179344066engActa Neuropathologica Communications; 11, no 195 (2023)ISSN: 2051-5960NeurologyAgingAtherosclerosisBrain ischemiaCardiac hypertrophyCerebral angiogenesisCerebral neovascularizationCerebrovascular diseaseHypertensionSmall vessel diseaseCortical microvascular raspberries and ageing : an independent but not exclusive relationshipcontributiontojournal/articleinfo:eu-repo/semantics/articletext