Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study
Abstract Background Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ42 and amyR have different meanings and wh...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-023-01291-w |
| _version_ | 1827724196189306880 |
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| author | Caterina Motta Martina Gaia Di Donna Chiara Giuseppina Bonomi Martina Assogna Agostino Chiaravalloti Nicola Biagio Mercuri Giacomo Koch Alessandro Martorana |
| author_facet | Caterina Motta Martina Gaia Di Donna Chiara Giuseppina Bonomi Martina Assogna Agostino Chiaravalloti Nicola Biagio Mercuri Giacomo Koch Alessandro Martorana |
| author_sort | Caterina Motta |
| collection | DOAJ |
| description | Abstract Background Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods CSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T − = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A − T −). A + T − patients were further stratified into those with normal (CSFAβ42 + /amyR − = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls. Results CSF Aβ40 levels were the lowest in A − T − and in CSFAβ42 + /amyR − , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A − T − (β = 0.58; p < 0.001), CSFAβ42 + /amyR − (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR − (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A − T − . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR − compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + . Conclusions Pathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism. |
| first_indexed | 2024-03-10T22:11:19Z |
| format | Article |
| id | doaj.art-5b1cd006bcd14b99b2fa34881a366471 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-03-10T22:11:19Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-5b1cd006bcd14b99b2fa34881a3664712023-11-19T12:35:58ZengBMCAlzheimer’s Research & Therapy1758-91932023-08-0115111210.1186/s13195-023-01291-wDifferent associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography studyCaterina Motta0Martina Gaia Di Donna1Chiara Giuseppina Bonomi2Martina Assogna3Agostino Chiaravalloti4Nicola Biagio Mercuri5Giacomo Koch6Alessandro Martorana7UOSD Centro Demenze, University of Rome “Tor Vergata”UOSD Centro Demenze, University of Rome “Tor Vergata”UOSD Centro Demenze, University of Rome “Tor Vergata”UOSD Centro Demenze, University of Rome “Tor Vergata”Department of Biomedicine and Prevention, University of Rome Tor VergataUOSD Centro Demenze, University of Rome “Tor Vergata”Experimental Neuropsychophysiology Laboratory, IRCCS Santa Lucia FoundationUOSD Centro Demenze, University of Rome “Tor Vergata”Abstract Background Despite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods CSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T − = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A − T −). A + T − patients were further stratified into those with normal (CSFAβ42 + /amyR − = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls. Results CSF Aβ40 levels were the lowest in A − T − and in CSFAβ42 + /amyR − , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A − T − (β = 0.58; p < 0.001), CSFAβ42 + /amyR − (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR − (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A − T − . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR − compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + . Conclusions Pathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.https://doi.org/10.1186/s13195-023-01291-wAlzheimer’s diseaseCerebrospinal fluid biomarkersAmyloid beta 40Amyloid beta 42Amyloid beta 42/40 ratioPhosphorylated-tau |
| spellingShingle | Caterina Motta Martina Gaia Di Donna Chiara Giuseppina Bonomi Martina Assogna Agostino Chiaravalloti Nicola Biagio Mercuri Giacomo Koch Alessandro Martorana Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study Alzheimer’s Research & Therapy Alzheimer’s disease Cerebrospinal fluid biomarkers Amyloid beta 40 Amyloid beta 42 Amyloid beta 42/40 ratio Phosphorylated-tau |
| title | Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study |
| title_full | Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study |
| title_fullStr | Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study |
| title_full_unstemmed | Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study |
| title_short | Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study |
| title_sort | different associations between amyloid βeta 42 amyloid βeta 40 and amyloid βeta 42 40 with soluble phosphorylated tau and disease burden in alzheimer s disease a cerebrospinal fluid and fluorodeoxyglucose positron emission tomography study |
| topic | Alzheimer’s disease Cerebrospinal fluid biomarkers Amyloid beta 40 Amyloid beta 42 Amyloid beta 42/40 ratio Phosphorylated-tau |
| url | https://doi.org/10.1186/s13195-023-01291-w |
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