Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage ...marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer's disease (AD) and their clinical utility in predicting disease progression.
pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile.
Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve AUC: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio HR 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005).
pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD.
Cerebrospinal fluid (CSF) Aβ1-42 levels and the Aβ1-42/Aβ1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional ...pathophysiological processes.
To compare Aβ1-42 and the Aβ1-42/Aβ1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression.
We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF Aβ1-42 and Aβ1-42/Aβ1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as "positive" or "negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models.
In the 1791 participants, the agreement between Aβ1-42 and Aβ1-42/Aβ1-40 was 78.3%. The Aβ1-42/Aβ1-40 ratio showed a stronger correlation with tTau and pTau181 than Aβ1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low Aβ1-42/Aβ1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for Aβ1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs.
Although Aβ1-42 and Aβ1-42/Aβ1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the Aβ1-42/Aβ1-40 ratio in clinical laboratories in the context of AD.
Abstract Background Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical ...laboratories, and their performance in clinical practice is unknown. Methods We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aβ 1–42 /Aβ 1–40 ratio. Plasma pTau 217 , pTau 181 , Aβ 1–42 and Aβ 1–40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman’s correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aβ 1–42 /Aβ 1–40 ratio. We analyzed the concordance of pTau 217 with CSF amyloidosis. Results Plasma pTau 217 and pTau 181 concentration were higher in A + than A- while the plasma Aβ 1–42 /Aβ 1–40 ratio was lower in A + compared to A-. pTau 181 and the Aβ 1–42 /Aβ 1–40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92–0.97) for pTau 217 , and 0.88 (95% CI 0.84–0.92) for both pTau 181 and Aβ 1–42 /Aβ 1–40 . Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau 217 had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4–7% misclassification rate. The global accuracy of plasma pTau 217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%. Conclusion The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau 217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit.
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.
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.
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).
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.
Abstract
Background
Cognitive reserve factors may provide protection against the manifestation of symptoms associated with neurodegenerative diseases (Stern, 2012). Although results are mixed, it has ...been observed that bilingualism may contribute to cognitive reserve by delaying the age of onset of symptoms of Alzheimer’s disease (AD) (e.g., Alladi et al., 2013, 2017; Bialystok et al., 2007, 2010; de Leon et al., 2020).
Methods
In the current study, we examined the effects of bilingualism on age of symptom onset in a large cohort of Catalan‐Spanish bilingual speakers (n = 446) with positive Alzheimer’s disease cerebrospinal fluid biomarkers. We conducted a retrospective study in which participants were characterized as bilingual or monolingual based on self‐report at the time of neuropsychological testing. Analyses of covariance (ANCOVA) were conducted to investigate the association between bilingualism and age of symptom onset while controlling for a proxy of disease severity (Mini‐Mental State Exam (Folstein et al., 1975) and education.
Results
The results of our ANCOVA revealed that Catalan‐Spanish bilinguals with AD positive CSF biomarkers present with a significant, approximate two‐year delay in symptom onset relative to monolingual speakers (see Figure 1; bilingual M = 71.41, monolingual M = 69.75).
Conclusion
Although previous reports in the literature indicate that bilingualism may delay the onset of symptoms on the order of 4‐5 years, we observed an approximate 2‐year difference in the onset of symptoms. This finding is consistent with previous literature conducted in Catalan‐Spanish bilinguals (Calabria et al., 2020) and likely reflects that even ‘monolingual’ speakers in this particular sociocultural context are exposed to more than one language and may exhibit a form of passive bilingualism.
Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Cerebrospinal fluid (CSF) Aβ1-42, Aβ1-40, total Tau (t-Tau), and phospho Tau (p-Tau) are important biomarkers ...for the diagnosis, however, they are highly dependent on the pre-analytical conditions. Our aim was to investigate the potential influence of different storage conditions on the simultaneous quantification of these biomarkers in a fully-automated platform to accommodate easier pre-analytical conditions for laboratories.
CSF samples were obtained from 11 consecutive patients. Aβ1-42, Aβ1-40, p-Tau, and t-Tau were quantified using the LUMIPULSE G600II automated platform.
Temperature and storage days significantly influenced Aβ1-42 and Aβ1-40 with concentrations decreasing with days spent at 4 °C. The use of the Aβ1-42/Aβ1-40 ratio could partly compensate it. P-Tau and t-Tau were not affected by any of the tested storage conditions. For conditions involving storage at 4 °C, a correction factor of 1.081 can be applied. Diagnostic agreement was almost perfect in all conditions.
Cutoffs calculated in samples stored at -80 °C can be safely used in samples stored at -20 °C for 15-16 days or up to two days at RT and subsequent freezing at -80 °C. For samples stored at 4 °C, cutoffs would require applying a correction factor, allowing to work with the certainty of reaching the same clinical diagnosis.
Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Recently, blood-based markers (BBM) Aβ1-42, Aβ1-40, and phospho Tau181 (p-Tau181) have demonstrated the ...potential to transform the diagnosis and prognostic assessment of AD. Our aim was to investigate the effect of different storage conditions on the quantification of these BBM and to evaluate the interchangeability of plasma and serum samples.
Forty-two individuals with some degree of cognitive impairment were studied. Thirty further patients were retrospectively selected. Aβ1-42, Aβ1-40, and p-Tau181 were quantified using the LUMIPULSE-G600II automated platform. To assess interchangeability between conditions, correction factors for magnitudes that showed strong correlations were calculated, followed by classification consistency studies.
Storing samples at 4 °C for 8-9 days was associated with a decrease in Aβ fractions but not when stored for 1-2 days. Using the ratio partially attenuated the pre-analytical effects. For p-Tau181, samples stored at 4 °C presented lower concentrations, whereas frozen samples presented higher ones. Concerning classification consistency in comparisons that revealed strong correlations (p-Tau181), the percentage of total agreement was greater than 90 % in a large number of the tested cut-offs values.
Our findings provide relevant information for the standardization of sample collection and storage in the analysis of AD BBM in an automated platform. This knowledge is crucial to ensure their introduction into clinical settings.
Background Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical ...laboratories, and their performance in clinical practice is unknown. Methods We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Abeta.sub.1-42/Abeta.sub.1-40 ratio. Plasma pTau.sub.217, pTau.sub.181, Abeta.sub.1-42 and Abeta.sub.1-40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Abeta.sub.1-42/Abeta.sub.1-40 ratio. We analyzed the concordance of pTau.sub.217 with CSF amyloidosis. Results Plasma pTau.sub.217 and pTau.sub.181 concentration were higher in A + than A- while the plasma Abeta.sub.1-42/Abeta.sub.1-40 ratio was lower in A + compared to A-. pTau.sub.181 and the Abeta.sub.1-42/Abeta.sub.1-40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92-0.97) for pTau.sub.217, and 0.88 (95% CI 0.84-0.92) for both pTau.sub.181 and Abeta.sub.1-42/Abeta.sub.1-40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau.sub.217 had the highest fold change (x 3.2) and showed high predictive capability in discriminating A + from A-, having 4-7% misclassification rate. The global accuracy of plasma pTau.sub.217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%. Conclusion The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau.sub.217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit. Keywords: Plasma, Biomarkers, Alzheimer, Blood, Amyloid, Tau
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