| 41. |
- Leinonen, Ville, et al.
(författare)
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Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
- 2014
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.
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| 42. |
- Lewczuk, Piotr, et al.
(författare)
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Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.
- 2018
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Ingår i: The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. - : Informa UK Limited. - 1814-1412. ; 19:4, s. 244-328
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Tidskriftsartikel (refereegranskat)abstract
- In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.
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| 43. |
- Li, Yan, et al.
(författare)
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Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques
- 2022
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Ingår i: Neurology. - 0028-3878. ; 98:7, s. 688-699
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.MethodsPlasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.ResultsIn the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ϵ4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ϵ4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals.DiscussionPlasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.Classification of EvidenceThis study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.
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| 44. |
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| 45. |
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| 46. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Diagnostic accuracy of CSF Ab42 and florbetapir PET for Alzheimer's disease.
- 2014
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Ingår i: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 1:8, s. 534-43
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Tidskriftsartikel (refereegranskat)abstract
- Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance.
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| 47. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease.
- 2015
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 138:3, s. 772-783
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Tidskriftsartikel (refereegranskat)abstract
- Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.
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| 48. |
- Mattsson, Niklas, et al.
(författare)
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Plasma tau in Alzheimer disease
- 2016
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 87:17, s. 1827-1835
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism. Methods: This was a study of plasma tau in prospectively followed patients with AD (n 179), patients with mild cognitive impairment (n 195), and cognitive healthy controls (n 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n 61), mild cognitive impairment (n 212), and subjective cognitive decline (n 174) and controls (n 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18 fluorodeoxyglucose-PET, and cognition. Results: Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ 42, but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up. Conclusions: Plasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD.
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| 49. |
- Naylor, Mary D, et al.
(författare)
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Advancing Alzheimer's disease diagnosis, treatment, and care: recommendations from the Ware Invitational Summit.
- 2012
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 8:5, s. 445-52
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Tidskriftsartikel (refereegranskat)abstract
- To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.
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| 50. |
- Nelson, Peter T., et al.
(författare)
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Limbic-predominant age-related TDP-43 encephalopathy (LATE) : consensus working group report
- 2019
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 142, s. 1503-1527
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Forskningsöversikt (refereegranskat)abstract
- We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, similar to 25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-beta plaques and tauopathy. Given that the oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
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