| 1. |
- Paterson, Ross W, et al.
(author)
-
Cerebrospinal fluid in the differential diagnosis of Alzheimer's disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic
- 2018
-
In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10, s. 1-11
-
Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n = 156), DLB (n = 20), behavioural variant frontotemporal dementia (bvFTD; n = 45), progressive non-fluent aphasia (PNFA; n = 17), and semantic dementia (SD; n = 7); approximately 10% were pathology/genetically confirmed (n = 26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n = 104), DLB (n = 5), bvFTD (n = 12), PNFA (n = 3), SD (n = 9), and controls (n = 10).There were significant global differences in Aβ1-42, T-tau, T-tau/Aβ1-42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1-42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1-42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity > 50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.CSF AβX-42/X-40 and T-tau/Aβ1-42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.
|
|
| 2. |
- Banerjee, Gargi, et al.
(author)
-
Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.
- 2020
-
In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:4, s. 1189-1201
-
Journal article (peer-reviewed)abstract
- There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile.CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.
|
|
| 3. |
- Paterson, Ross W, et al.
(author)
-
Dissecting IWG-2 typical and atypical Alzheimer's disease: insights from cerebrospinal fluid analysis.
- 2015
-
In: Journal of neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 262, s. 2722-2730
-
Journal article (peer-reviewed)abstract
- Pathobiological factors underlying phenotypic diversity in Alzheimer's disease (AD) are incompletely understood. We used an extended cerebrospinal fluid (CSF) panel to explore differences between "typical" with "atypical" AD and between amnestic, posterior cortical atrophy, logopenic aphasia and frontal variants. We included 97 subjects fulfilling International Working Group-2 research criteria for AD of whom 61 had "typical" AD and 36 "atypical" syndromes, and 30 controls. CSF biomarkers included total tau (T-tau), phosphorylated tau (P-tau), amyloid β1-42, amyloid βX-38/40/42, YKL-40, neurofilament light (NFL), and amyloid precursor proteins α and β. The typical and atypical groups were matched for age, sex, severity and rate of cognitive decline and had similar biomarker profiles, with the exception of NFL which was higher in the atypical group (p = 0.03). Sub-classifying the atypical group into its constituent clinical syndromes, posterior cortical atrophy was associated with the lowest T-tau [604.4 (436.8-675.8) pg/mL], P-tau (79.8 ± 21.8 pg/L), T-tau/Aβ1-42 ratio [2.3 (1.4-2.6)], AβX-40/X-42 ratio (22.1 ± 5.8) and rate of cognitive decline [1.9 (0.75-4.25) MMSE points/year]. Conversely, the frontal variant group had the highest levels of T-tau [1185.4 (591.7-1329.3) pg/mL], P-tau (116.4 ± 45.4 pg/L), T-tau/Aβ1-42 ratio [5.2 (3.3-6.9)] and AβX-40/X-42 ratio (27.9 ± 7.5), and rate of cognitive decline. Whilst on a group level IWG-2 "typical" and "atypical" AD share similar CSF profiles, which are very different from controls, atypical AD is a heterogeneous entity with evidence for subtle differences in amyloid processing and neurodegeneration between different clinical syndromes. These findings also have practical implications for the interpretation of clinical CSF biomarker results.
|
|
| 4. |
- Paterson, Ross W, et al.
(author)
-
Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes.
- 2021
-
In: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 3:3
-
Journal article (peer-reviewed)abstract
- Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS (n = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with (n = 94) and without (n = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.
|
|
| 5. |
- Toombs, Jamie, et al.
(author)
-
Identification of an important potential confound in CSF AD studies: aliquot volume.
- 2013
-
In: Clinical chemistry and laboratory medicine : CCLM / FESCC. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 51:12
-
Journal article (peer-reviewed)abstract
- Abstract Background: Cerebrospinal fluid (CSF) amyloid beta 1-42 (Aβ1-42), total tau (T-tau) and phosphorylated tau181 (P-tau) are finding increasing utility as biomarkers of Alzheimer's disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by aliquot storage volume and whether addition of detergent-containing buffer mitigates any observed effects. Methods: AD and control CSF was distributed into polypropylene tubes in aliquots of different volumes (50-1500 μL). Aβ1-42, T-tau and P-tau were measured with and without addition of Tween 20 (0.05%). Results: Measured concentrations of Aβ1-42 increased two-fold with aliquot storage volume. A volume increase of 10 µL caused an Aβ1-42 increase of 0.95 pg/mL [95% confidence interval (CI) 0.36-1.50, p=0.02] in controls, and 0.60 pg/mL (CI 0.23-0.98 pg/mL, p=0.003) in AD samples. Following addition of Tween 20, the positive relationship between Aβ1-42 and aliquot volume disappeared. T-tau and P-tau were not significantly affected. Conclusions: CSF aliquot storage volume has a significant impact on the measured concentration of Aβ1-42. The introduction of a buffer detergent at the initial aliquoting stage may be an effective solution to this problem.
|
|
| 6. |
- Cunningham, Emma L, et al.
(author)
-
CSF Beta-amyloid 1-42 Concentration Predicts Delirium Following Elective Arthroplasty Surgery in an Observational Cohort Study.
- 2019
-
In: Annals of surgery. - 1528-1140. ; 269:6, s. 1200-1205
-
Journal article (peer-reviewed)abstract
- To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aβ42, T-tau and P-tau would independently predict the risk of postoperative delirium.Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium.This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium.Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aβ42 (P < 0.01) were independent predictors of postoperative delirium.This study is the first to show an independent association between CSF Aβ42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.
|
|
| 7. |
- Weston, Philip S J, et al.
(author)
-
Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid?
- 2016
-
In: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 54:4, s. 1297-1302
-
Journal article (peer-reviewed)abstract
- Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer's disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist's working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains.
|
|
