| 1. |
- Alcolea, D., et al.
(författare)
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Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias
- 2021
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:11, s. 1206-1214
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach. Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination. Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001). Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach. © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
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| 2. |
- Altomare, D., et al.
(författare)
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Plasma biomarkers for Alzheimer's disease: a field-test in a memory clinic
- 2023
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - 0022-3050. ; 94:6
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Tidskriftsartikel (refereegranskat)abstract
- Background The key Alzheimer's disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid A beta 42 and p-tau 181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers. Methods Participants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months. Results Overall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up to r=0.50 (p<0.001) among amyloid, r=0.43 (p=0.002) among tau, and r=-0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers. Conclusion The implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care.
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| 3. |
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| 4. |
- Ayton, Scott, et al.
(författare)
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CSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers
- 2023
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 94:3, s. 211-219
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Tidskriftsartikel (refereegranskat)abstract
- Background: A putative role for iron in driving Alzheimer's disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Methods: Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. Results: In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%-40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. Conclusions: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.
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| 5. |
- Baldvinsdóttir, Bryndís, et al.
(författare)
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Adverse events associated with microsurgial treatment for ruptured intracerebral aneurysms: a prospective nationwide study on subarachnoid haemorrhage in Sweden
- 2023
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 94:7, s. 575-580
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAdverse events (AEs) or complications may arise secondary to the treatment of aneurysmal subarachnoid haemorrhage (SAH). The aim of this study was to identify AEs associated with microsurgical occlusion of ruptured aneurysms, as well as to analyse their risk factors and impact on functional outcome. MethodsPatients with aneurysmal SAH admitted to the neurosurgical centres in Sweden were prospectively registered during a 3.5-year period (2014-2018). AEs were categorised as intraoperative or postoperative. A range of variables from patient history and SAH characteristics were explored as potential risk factors for an AE. Functional outcome was assessed approximately 1 year after the bleeding using the extended Glasgow Outcome Scale. ResultsIn total, 1037 patients were treated for ruptured aneurysms, of which, 322 patients were treated with microsurgery. There were 105 surgical AEs in 97 patients (30%); 94 were intraoperative AEs in 79 patients (25%). Aneurysm rerupture occurred in 43 patients (13%), temporary occlusion of the parent artery >5 min in 26 patients (8%) and adjacent vessel injury in 25 patients (8%). High Fisher grade and brain oedema on CT were related to increased risk of AEs. At follow-up, 38% of patients had unfavourable outcome. Patients suffering AEs were more likely to have unfavourable outcome (OR 2.3, 95% CI 1.10 to 4.69). ConclusionIntraoperative AEs occurred in 25% of patients treated with microsurgery for ruptured intracerebral aneurysm in this nationwide survey. Although most operated patients had favourable outcome, AEs were associated with increased risk of unfavourable outcome.
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| 6. |
- Benussi, Alberto, et al.
(författare)
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Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration.
- 2020
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:9, s. 960-967
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Tidskriftsartikel (refereegranskat)abstract
- To assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181 (p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD).In this retrospective study, performed on 417 participants, we analysed serum NfL and p-Tau181 concentrations with an ultrasensitive single molecule array (Simoa) approach. We assessed the diagnostic values of serum biomarkers in the differential diagnosis between FTLD, Alzheimer's disease (AD) and healthy ageing; their role as markers of disease severity assessing the correlation with clinical variables, cross-sectional brain imaging and neurophysiological data; their role as prognostic markers, considering their ability to predict survival probability in FTLD.We observed significantly higher levels of serum NfL in patients with FTLD syndromes, compared with healthy controls, and lower levels of p-Tau181 compared with patients with AD. Serum NfL concentrations showed a high accuracy in discriminating between FTLD and healthy controls (area under the curve (AUC): 0.86, p<0.001), while serum p-Tau181 showed high accuracy in differentiating FTLD from patients with AD (AUC: 0.93, p<0.001). In FTLD, serum NfL levels correlated with measures of cognitive function, disease severity and behavioural disturbances and were associated with frontotemporal atrophy and indirect measures of GABAergic deficit. Moreover, serum NfL concentrations were identified as the best predictors of survival probability.The assessment of serum NfL and p-Tau181 may provide a comprehensive view of FTLD, aiding in the differential diagnosis, in staging disease severity and in defining survival probability.
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| 7. |
- Butzkueven, H, et al.
(författare)
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Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP)
- 2020
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:6, s. 660-668
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Tidskriftsartikel (refereegranskat)abstract
- The Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients.MethodsThese data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP.ResultsAs of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab’s known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias.ConclusionsSince the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab.Trial registration numberNCT00493298.
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| 8. |
- Chong, J. R., et al.
(författare)
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Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer's disease: a focused review on recent advances
- 2021
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:11, s. 1231-1241
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Forskningsöversikt (refereegranskat)abstract
- Discovery and development of clinically useful biomarkers for Alzheimer's disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-beta (A beta) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring A beta and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish A beta and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of A beta peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.
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| 9. |
- Chouliaras, L., et al.
(författare)
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Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy
- 2022
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 93:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Methods Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Alpha beta)42, A beta 40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-A beta status. Results P-tau181 was elevated in MCI+AD compared with all other groups. A beta 42/40 was lower in MCI+AD compared with controls and FTD. NfL was elevated in all dementias compared with controls while GFAP was elevated in MCI+AD and LBD. Plasma biomarkers could classify between MCI+AD and controls, FTD and PSP with high accuracy but showed limited ability in differentiating MCI+AD from LBD. No differences were detected in the levels of plasma biomarkers when comparing PET-A beta positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern. Conclusion This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change. We confirm that p-tau181 is elevated in MCI+AD, versus controls, FTD and PSP, but is less accurate in the classification between MCI+AD and LBD or detecting amyloid brain pathology in LBD. NfL was elevated in all dementia groups, while GFAP was elevated in MCI+AD and LBD.
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| 10. |
- Convery, RS, et al.
(författare)
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Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in C9orf72 expansion carriers in the GENFI cohort
- 2020
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 91:12, s. 1325-1328
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI).MethodsAbnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception.ResultsAltered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum.ConclusionChanges in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.
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