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Sökning: WFRF:(Santillo Alexander) > Lunds universitet

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  • Ashton, Nicholas J., et al. (författare)
  • A multicentre validation study of the diagnostic value of plasma neurofilament light
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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  • Degerman Gunnarsson, Malin, et al. (författare)
  • Re-Evaluation of Clinical Dementia Diagnoses with Pittsburgh Compound B Positron Emission Tomography
  • 2013
  • Ingår i: Dementia and Geriatric Cognitive Disorders Extra. - Basel : S. Karger. - 1664-5464. ; 3:1, s. 472-481
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimer's disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [18F]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET). Methods: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting. Results: The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up. Conclusions: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.
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  • Ducharme, Simon, et al. (författare)
  • Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders
  • 2020
  • Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:6, s. 1632-1650
  • Tidskriftsartikel (refereegranskat)abstract
    • The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.
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  • Eratne, Dhamidhu, et al. (författare)
  • Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from non-progressors
  • 2022
  • Ingår i: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X. ; 442
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative ‘non-progressor’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Methods: Cerebrospinal fluid (CSF) NfL, amyloid beta 1–42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow-up information, patients were categorised as Progressors or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes). Results: Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses. Conclusion: This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.
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8.
  • Eratne, D., et al. (författare)
  • Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings
  • 2022
  • Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:11, s. 2218-2233
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. Methods Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). Results A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. Discussion We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
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9.
  • Eratne, D., et al. (författare)
  • Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives
  • 2022
  • Ingår i: Australian and New Zealand Journal of Psychiatry. - : SAGE Publications. - 0004-8674 .- 1440-1614. ; 56:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. Methods: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59). Results: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]). Conclusion: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
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10.
  • Eratne, D., et al. (författare)
  • Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders
  • 2023
  • Ingår i: Australian and New Zealand Journal of Psychiatry. - 0004-8674. ; 58:1, s. 70-81
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. Methods: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). Results: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. Conclusions: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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