| 421. |
- Palmqvist, Sebastian, et al.
(författare)
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Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity.
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.
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| 422. |
- Palmqvist, Sebastian, et al.
(författare)
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Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149. ; 76:9, s. 1060-1069
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Tidskriftsartikel (refereegranskat)abstract
- Key PointsQuestionDo plasma levels of beta -amyloid 42, beta -amyloid 40, and tau detect cerebral beta -amyloid status when measured using fully automated immunoassays? FindingsIn 2 cross-sectional studies, plasma beta -amyloid 42 to beta -amyloid 40 ratio, measured using immunoassay, accurately predicted cerebral beta -amyloid status in all stages of Alzheimer disease in the BioFINDER cohort (n=842) and in an independent validation cohort (n=237). The diagnostic accuracy was further increased by analyzing APOE genotype. MeaningBlood-based beta -amyloid 42 and beta -amyloid 40 ratio together with APOE genotype may be used as prescreening tests in primary care and in clinical Alzheimer disease trials to lower the costs and number of positron emission tomography scans and lumbar punctures. This corss-sectional diagnostic study evaluates the accuracy of fully automated plasma assays in measuring plasma beta -amyloid and tau in patients with and without cognitive impairment in the Swedish BioFINDER study and an independent validation cohort. ImportanceAccurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. ObjectiveTo examine the accuracy of plasma beta -amyloid (A beta) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral A beta. Design, Setting, and ParticipantsTwo prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. Main Outcome and MeasuresThe cerebrospinal fluid (CSF) A beta 42/A beta 40 ratio was used as the reference standard for brain A beta status. Plasma A beta 42, A beta 40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of A beta status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. ResultsThe mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma A beta 42 and A beta 40 predicted A beta status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to A beta 42, A beta 40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma A beta 42 and A beta 40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma A beta 42, A beta 40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. Conclusions and RelevancePlasma A beta 42 and A beta 40 measured using Elecsys immunoassays predict A beta status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of A beta positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.
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| 423. |
- Palmqvist, Sebastian, et al.
(författare)
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Practical suggestions on how to differentiate dementia with Lewy bodies from Alzheimer's disease with common cognitive tests.
- 2009
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Ingår i: International Journal of Geriatric Psychiatry. - : Wiley. - 1099-1166 .- 0885-6230. ; 24, s. 1405-1412
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, but it is often underdiagnosed and mistaken for Alzheimer's disease (AD) with sometimes lethal consequences. Over 35 studies have established the differences between DLB and AD in neuropsychological tests, but none have provided easy interpretations of common tests suitable for the clinician. The aim of this study was to suggest practical interpretations of the Mini-Mental State Examination (MMSE), clock drawing, and cube-copying to identify DLB and differentiate it from AD. METHODS: Thirty-three DLB patients were matched according to gender, MMSE, and age with 66 AD patients. The median MMSE score was 24. Easy interpretations of the tests, including the MMSE orientation subscore, were sought for. RESULTS: The identified criteria to separate DLB from AD were (1) the MMSE orientation score x 3 >/= the total MMSE score, (2) an impaired clock drawing, and (3) a non-3D cube-copying. If (1) was fulfilled, the sensitivity and specificity were 100 and 57% in patients with MMSE 21-27. If (1) and (2) were fulfilled in patients with MMSE 21-27, the sensitivity and specificity were 93 and 70%. If at least two of the three criteria were fulfilled, the sensitivity was 85%, and the specificity 75% regardless of MMSE score. CONCLUSION: If the orientation score x 3 >/= the total MMSE score together with an impaired clock drawing and possibly a non-3D cube-copying, the patient should be thoroughly investigated according to the DLB consensus criteria. Copyright (c) 2009 John Wiley & Sons, Ltd.
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| 424. |
- Palmqvist, Sebastian, et al.
(författare)
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Prediction of future Alzheimer's disease dementia using plasma phospho-tau combined with other accessible measures
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27, s. 1034-1042
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Tidskriftsartikel (refereegranskat)abstract
- Plasma P-tau, in combination with clinical measures, predicts future Alzheimer's disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists. A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma A beta 42/A beta 40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, A beta 42/A beta 40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.
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| 425. |
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| 426. |
- Palmqvist, Sebastian, et al.
(författare)
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The usefulness of cube copying for evaluating treatment of Alzheimer's disease.
- 2008
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Ingår i: American Journal of Alzheimers Disease & other Dementias. - : SAGE Publications. - 1938-2731 .- 1533-3175. ; 23:5, s. 439-446
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Cube copying measures visuospatial ability, which is often impaired in Alzheimer's disease (AD). Cube copying was examined as an evaluation of cholinesterase inhibitor (ChEI) treatment in AD. Methods: Eighty-five ChEI-treated AD patients were included. Cube drawings made at prebaseline, baseline, 6 months, and 12 months were assessed. Cube drawings from 56 healthy individuals were also examined. Results: The healthy individuals remained stable in cube copying, whereas untreated AD patients deteriorated during a median period of 6 months. When treatment was given, the deterioration was interrupted. After 12 months, Mini-Mental State Examination (MMSE) had deteriorated compared with baseline whereas cube copying was unchanged.Conclusions: The results indicate that cube copying can be used to evaluate ChEI treatment. It might also show a more long-lasting response to treatment than MMSE. Cube copying only measures a narrow cognitive function and can preferably be used with MMSE, which evaluates visuospatial ability poorly.
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| 427. |
- Pannee, Josef, et al.
(författare)
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A Selected Reaction Monitoring (SRM)-Based Method for Absolute Quantification of A beta(38), A beta(40), and A beta(42) in Cerebrospinal Fluid of Alzheimer's Disease Patients and Healthy Controls
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 33:4, s. 1021-1032
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in research centers, clinical trials, and clinical settings. However, their broad-scale use is hampered by lack of standardization across analytical platforms and by interference from binding of amyloid-beta(A beta) to matrix proteins as well as self-aggregation. Here, we report on a matrix effect-resistant method for the measurement of the AD-associated 42 amino acid species of A beta(A beta(42)), together with A beta(40) and A beta(38) in human CSF based on mass spectrometric quantification using selected reaction monitoring (SRM). Samples were prepared by solid-phase extraction and quantification was performed using stable-isotope labeled A beta peptides as internal standards. The diagnostic performance of the method was evaluated on two independent clinical materials with research volunteers who were cognitively normal and AD patients with mild to moderate dementia. Analytical characteristics of the method include a lower limit of quantification of 62.5 pg/mL for A beta(42) and coefficients of variations below 10%. In a pilot study on AD patients and controls, we verified disease-association with decreased levels of A beta(42) similar to that obtained by ELISA and even better separation was obtained using the A beta(42)/A beta(40) ratio. The developed assay is sensitive and is not influenced by matrix effects, enabling absolute quantification of A beta(42), A beta(40), and A beta(38) in CSF, while it retains the ability to distinguish AD patients from controls. We suggest this SRM-based method for A beta peptide quantification in human CSF valuable for clinical research and trials.
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| 428. |
- Pannee, Josef, 1979, et al.
(författare)
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A selected reaction monitoring (SRM)-based method for absolute quantification of Aβ38, Aβ40, and Aβ42 in cerebrospinal fluid of Alzheimer's Disease patients and healthy controls.
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 33:4, s. 1021-32
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in research centers, clinical trials, and clinical settings. However, their broad-scale use is hampered by lack of standardization across analytical platforms and by interference from binding of amyloid-β (Aβ) to matrix proteins as well as self-aggregation. Here, we report on a matrix effect-resistant method for the measurement of the AD-associated 42 amino acid species of Aβ (Aβ42), together with Aβ40 and Aβ38 in human CSF based on mass spectrometric quantification using selected reaction monitoring (SRM). Samples were prepared by solid-phase extraction and quantification was performed using stable-isotope labeled Aβ peptides as internal standards. The diagnostic performance of the method was evaluated on two independent clinical materials with research volunteers who were cognitively normal and AD patients with mild to moderate dementia. Analytical characteristics of the method include a lower limit of quantification of 62.5 pg/mL for Aβ42 and coefficients of variations below 10%. In a pilot study on AD patients and controls, we verified disease-association with decreased levels of Aβ42 similar to that obtained by ELISA and even better separation was obtained using the Aβ42/Aβ40 ratio. The developed assay is sensitive and is not influenced by matrix effects, enabling absolute quantification of Aβ42, Aβ40, and Aβ38 in CSF, while it retains the ability to distinguish AD patients from controls. We suggest this SRM-based method for Aβ peptide quantification in human CSF valuable for clinical research and trials.
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| 429. |
- Pannee, Josef, 1979, et al.
(författare)
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Reference measurement procedure for CSF amyloid beta (Aβ)1–42 and the CSF Aβ1–42/Aβ1–40 ratio – a cross-validation study against amyloid PET
- 2016
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 139:4, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- A clinical diagnosis of Alzheimer's disease is currently made on the basis of results from cognitive tests in combination with medical history and general clinical evaluation, but the peptide amyloid-beta (Aβ) in cerebrospinal fluid (CSF) is increasingly used as a biomarker for amyloid pathology in clinical trials and in recently proposed revised clinical criteria for Alzheimer's disease. Recent analytical developments have resulted in mass spectrometry (MS) reference measurement procedures for absolute quantification of Aβ1–42 in CSF. The CSF Aβ1–42/Aβ1–40 ratio has been suggested to improve the detection of cerebral amyloid deposition, by compensating for inter-individual variations in total Aβ production. Our aim was to cross-validate the reference measurement procedure as well as the Aβ1–42/Aβ1–40 and Aβ1–42/Aβ1–38 ratios in CSF, measured by high-resolution MS, with the cortical level of Aβ fibrils as measured by amyloid (18F-flutemetamol) positron emission tomography (PET). We included 100 non-demented patients with cognitive symptoms from the Swedish BioFINDER study, all of whom had undergone both lumbar puncture and 18F-flutemetamol PET. Comparing CSF Aβ1–42 concentrations with 18F-flutemetamol PET showed high concordance with an area under the receiver operating characteristic curve of 0.85 and a sensitivity and specificity of 82% and 81%, respectively. The ratio of Aβ1–42/Aβ1–40 or Aβ1–42/Aβ1–38 significantly improved concordance with an area under the receiver operating characteristic curve of 0.95 and a sensitivity and specificity of 96% and 91%, respectively. These results show that the CSF Aβ1–42/Aβ1–40 and Aβ1–42/Aβ1–38 ratios using the described MS method are strongly associated with cortical Aβ fibrils measured by 18F-flutemetamol PET. (Figure presented.).
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| 430. |
- Parnetti, Lucilla, et al.
(författare)
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CSF and blood biomarkers for Parkinson's disease.
- 2019
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Ingår i: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 18:6, s. 573-586
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Tidskriftsartikel (refereegranskat)abstract
- In the management of Parkinson's disease, reliable diagnostic and prognostic biomarkers are urgently needed. The diagnosis of Parkinson's disease mostly relies on clinical symptoms, which hampers the detection of the earliest phases of the disease-the time at which treatment with forthcoming disease-modifying drugs could have the greatest therapeutic effect. Reliable prognostic markers could help in predicting the response to treatments. Evidence suggests potential diagnostic and prognostic value of CSF and blood biomarkers closely reflecting the pathophysiology of Parkinson's disease, such as α-synuclein species, lysosomal enzymes, markers of amyloid and tau pathology, and neurofilament light chain. A combination of multiple CSF biomarkers has emerged as an accurate diagnostic and prognostic model. With respect to early diagnosis, the measurement of CSF α-synuclein aggregates is providing encouraging preliminary results. Blood α-synuclein species and neurofilament light chain are also under investigation because they would provide a non-invasive tool, both for early and differential diagnosis of Parkinson's disease versus atypical parkinsonian disorders, and for disease monitoring. In view of adopting CSF and blood biomarkers for improving Parkinson's disease diagnostic and prognostic accuracy, further validation in large independent cohorts is needed.
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