| 1. |
- Adams, Jenna N., et al.
(författare)
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Reduced repetition suppression in aging is driven by tau-related hyperactivity in medial temporal lobe
- 2021
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Ingår i: The Journal of Neuroscience. - 0270-6474. ; 41:17, s. 3917-3931
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Tidskriftsartikel (refereegranskat)abstract
- Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB) for amyloid-b (Ab). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau1 OA). Low levels of tau (Tau- OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau1 vs Tau- OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Ab. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression.
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| 2. |
- Kristo, Michael J., et al.
(författare)
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The application of radiochronometry during the 4th collaborative materials exercise of the nuclear forensics international technical working group (ITWG)
- 2018
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Ingår i: Journal of Radioanalytical and Nuclear Chemistry. - : Springer Science and Business Media LLC. - 0236-5731 .- 1588-2780. ; 315:2, s. 425-434
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Tidskriftsartikel (refereegranskat)abstract
- In a recent international exercise, 10 international nuclear forensics laboratories successfully performed radiochronometry on three low enriched uranium oxide samples, providing 12 analytical results using three different parent-daughter pairs serving as independent chronometers. The vast majority of the results were consistent with one another and consistent with the known processing history of the materials. In general, for these particular samples, mass spectrometry gave more accurate and more precise analytical results than decay counting measurements. In addition, the concordance of the U-235-Pa-231 and U-234-Th-230 chronometers confirmed the validity of the age dating assumptions, increasing confidence in the resulting conclusions.
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| 3. |
- Maass, Anne, et al.
(författare)
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Alzheimer's pathology targets distinct memory networks in the ageing brain
- 2019
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 142:8, s. 2492-2509
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease researchers have been intrigued by the selective regional vulnerability of the brain to amyloid-β plaques and tau neurofibrillary tangles. Post-mortem studies indicate that in ageing and Alzheimer's disease tau tangles deposit early in the transentorhinal cortex, a region located in the anterior-temporal lobe that is critical for object memory. In contrast, amyloid-β pathology seems to target a posterior-medial network that subserves spatial memory. In the current study, we tested whether anterior-temporal and posterior-medial brain regions are selectively vulnerable to tau and amyloid-β deposition in the progression from ageing to Alzheimer's disease and whether this is reflected in domain-specific behavioural deficits and neural dysfunction. 11C-PiB PET and 18F-flortaucipir uptake was quantified in a sample of 131 cognitively normal adults (age: 20-93 years; 47 amyloid-β-positive) and 20 amyloid-β-positive patients with mild cognitive impairment or Alzheimer's disease dementia (65-95 years). Tau burden was relatively higher in anterior-temporal regions in normal ageing and this difference was further pronounced in the presence of amyloid-β and cognitive impairment, indicating exacerbation of ageing-related processes in Alzheimer's disease. In contrast, amyloid-β deposition dominated in posterior-medial regions. A subsample of 50 cognitively normal older (26 amyloid-β-positive) and 25 young adults performed an object and scene memory task while functional MRI data were acquired. Group comparisons showed that tau-positive (n = 18) compared to tau-negative (n = 32) older adults showed lower mnemonic discrimination of object relative to scene images [t(48) = -3.2, P = 0.002]. In a multiple regression model including regional measures of both pathologies, higher anterior-temporal flortaucipir (tau) was related to relatively worse object performance (P = 0.010, r = -0.376), whereas higher posterior-medial PiB (amyloid-β) was related to worse scene performance (P = 0.037, r = 0.309). The functional MRI data revealed that tau burden (but not amyloid-β) was associated with increased task activation in both systems and a loss of functional specificity, or dedifferentiation, in posterior-medial regions. The loss of functional specificity was related to worse memory. Our study shows a regional dissociation of Alzheimer's disease pathologies to distinct memory networks. While our data are cross-sectional, they indicate that with ageing, tau deposits mainly in the anterior-temporal system, which results in deficits in mnemonic object discrimination. As Alzheimer's disease develops, amyloid-β deposits preferentially in posterior-medial regions additionally compromising scene discrimination and anterior-temporal tau deposition worsens further. Finally, our findings propose that the progression of tau pathology is linked to aberrant activation and dedifferentiation of specialized memory networks that is detrimental to memory function.
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| 4. |
- Mozes, Ferenc E., et al.
(författare)
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Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis
- 2023
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Ingår i: The Lancet Gastroenterology & Hepatology. - : ELSEVIER INC. - 2468-1253. ; 8:8, s. 704-713
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Tidskriftsartikel (refereegranskat)abstract
- Background Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score >= 15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs >= 20 kPa; FIB-4: <1<middle dot>3 vs 1<middle dot>3 to <= 2<middle dot>67 vs >2<middle dot>67; NFS: <-1<middle dot>455 vs -1<middle dot>455 to <= 0<middle dot>676 vs >0<middle dot>676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.Findings Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44<middle dot>7%] were female, median age was 54 years [IQR 44-63), and 1161 [46<middle dot>1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5<middle dot>8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0<middle dot>0001 for all comparisons). The tAUC at 5 years were 0<middle dot>72 (95% CI 0<middle dot>62-0<middle dot>81) for histology, 0<middle dot>76 (0<middle dot>70-0<middle dot>83) for LSM-VCTE, 0<middle dot>74 (0<middle dot>64-0<middle dot>82) for FIB-4, and 0<middle dot>70 (0<middle dot>63-0<middle dot>80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.Interpretation Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases.
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| 5. |
- Olofsson, Jonas K., et al.
(författare)
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A cortical pathway to olfactory naming : evidence from primary progressive aphasia
- 2013
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 136, s. 1245-1259
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Tidskriftsartikel (refereegranskat)abstract
- It is notoriously difficult to name odours. Without the benefit of non-olfactory information, even common household smells elude our ability to name them. The neuroscientific basis for this olfactory language 'deficit' is poorly understood, and even basic models to explain how odour inputs gain access to transmodal representations required for naming have not been put forward. This study used patients with primary progressive aphasia, a clinical dementia syndrome characterized by primary deficits in language, to investigate the interactions between olfactory inputs and lexical access by assessing behavioural performance of olfactory knowledge and its relationship to brain atrophy. We specifically hypothesized that the temporal pole would play a key role in linking odour object representations to transmodal networks, given its anatomical proximity to olfactory and visual object processing areas. Behaviourally, patients with primary progressive aphasia with non-semantic subtypes were severely impaired on an odour naming task, in comparison with an age-matched control group. However, with the availability of picture cues or word cues, odour matching performance approached control levels, demonstrating an inability to retrieve but not to recognize the name and nature of the odorant. The magnitude of cortical thinning in the temporal pole was found to correlate with reductions in odour familiarity and odour matching to visual cues, whereas the inferior frontal gyrus correlated with both odour naming and matching. Volumetric changes in the mediodorsal thalamus correlated with the proportion of categorical mismatch errors, indicating a possible role of this region in error-signal monitoring to optimize recognition of associations linked to the odour. A complementary analysis of patients with the semantic subtype of primary progressive aphasia, which is associated with marked temporopolar atrophy, revealed much more pronounced impairments of odour naming and matching. In identifying the critical role of the temporal pole and inferior frontal gyrus in transmodal linking and verbalization of olfactory objects, our findings provide a new neurobiological foundation for understanding why even common odours are hard to name.
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| 6. |
- Pavlides, Michael, et al.
(författare)
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Liver investigation: Testing marker utility in steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol
- 2023
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Ingår i: Contemporary Clinical Trials. - : ELSEVIER SCIENCE INC. - 1551-7144 .- 1559-2030. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721
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| 7. |
- Pereira, Joana B., et al.
(författare)
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Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults
- 2020
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-β (Aβ), APOE, sex, and longitudinal cognitive decline. Methods: We included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aβ status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread. Results: We found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aβ-positive compared with Aβ-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas. Conclusions: These findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aβ, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.
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| 8. |
- Selvaraj, Emmanuel Anandraj, et al.
(författare)
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Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD : a systematic review and meta-analysis
- 2021
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:4, s. 770-785
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND AND AIMS: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), two-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) are proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH).METHODS: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model.RESULTS: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and four 2DSWE studies, and for diagnosing NASH in four MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs.CONCLUSIONS: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking.LAY SUMMARY: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy in assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring.
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