Discordant CSF/PET amyloid-β result signals need for follow-up before treatment

medwireNews: An analysis of the ADNI cohort has shown that most people with mild cognitive impairment (MCI) who test positive for amyloid-β according to cerebrospinal fluid (CSF) biomarkers but not positron emission tomography (PET) do not experience cognitive decline over an average 4-year period. They should therefore be followed-up before being recommended for anti-amyloid monoclonal antibody treatment, with measures such as 18F-flurodeoxyglucose or Tau PET, presenter David Knopman, from the Mayo Clinic in Rochester, Minnesota, USA, told delegates at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain. Knopman explained that the question of which assay better predicts cognitive decline arose from neurologists in his clinic feeling uncertain in making therapeutic decisions regarding lecanemab when CSF biomarkers indicated amyloid positivity, but follow-up amyloid PET did not. The researchers assessed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) on 587 patients with MCI and grouped them according to their CSF (phosphorylated (p)-tau181/amyloid-β 42 ratios; abnormal >0.023) and F18 florbetapir PET measures (abnormal ≥25 centiloids). In all, 276 tested both CSF and PET positive (CSF+/PET+) for amyloid-β and 260 tested negative on both (CSF–/PET–). For the remaining patients, 27 were positive on CSF but not PET (CSF+/PET–), while 24 tested CSF negative but PET positive (CSF–/PET+). Knopman pointed out that discordant test results were therefore “uncommon,” with only 5% of patients having a CSF+/PET– result, and so there is no “panic to suggest that CSF is not useful.” The two discordant groups had similar cognition at baseline as patients who tested negative on both assays and better compared with those who tested positive on both. Specifically, the median Rey auditory Verbal Learning Test (AVLT) Sum of Trials 1–6 scores at baseline were 42 points for the CSF+/PET– group, 46 points for the CSF–/PET+ group, and 46 points for the CSF–/PET– group, compared with 35 points for the CSF+/PET+ group. And the odds of patients in the CSF+/PET– and CSF–/PET+ groups having a high Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score were similar compared with the CSF–/PET– group, but lower compared with the CSF+/PET+ group. Focusing on the CSF+/PET– group, as the one causing most uncertainty, the presenter noted that CSF p-tau/amyloid-β ratios were “substantially” lower for these patients than for the CSF+/PET+ group, at a median 0.027 versus 0.049. Over the mean 4 years of follow-up, neither of the discordant groups showed a decline in the AVLT or CDR-SB scores relative to the patients in the CSF–/PET– group, whereas the CSF+/PET+ group did show decline on these measures. Moreover, rates of incident dementia were only elevated in patients who were CSF+/PET+, at a rate of 17.3 per 100 person–years, highlighted Knopman, and there was a “dramatic difference” compared with the rates for the other three groups who “did not really differ from one another,” at rates of 2.7 per 100 person–years for the CSF+/PET– patients, 3.0 per 100 person–years for the CSF–/PET+ patients, and 1.9 per 100 person–years for the CSF–/PET– patients. However, he noted that there were “individual exceptions” and acknowledged that the findings are based on ADNI only and were not replicated. He commented that some patients with discordant CSF+/PET– are in the AD pathway, but some may also have alternative diagnoses, such as isolated cerebral amyloid angiopathy, a disorder of CSF dynamics, or frontotemporal lobar degeneration tauopathy, and a few may just have been misclassified. Concluding, Knopman commented that “it is possible that this will become a moot point as we move to plasma biomarkers, but I think that the discordance between PET and plasma is larger, and I think that is going to be an issue that will have to be dealt with at the time when we have longitudinal data.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group This article was originally published on Journey to a New Era for Alzheimer’s Disease, an independent education program developed by Springer Healthcare IME. This program is supported by an educational grant from Lilly. This content is intended for healthcare professionals outside of the UK. CTAD24; Madrid, Spain: Oct 29–Nov 1

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Discordant CSF/PET amyloid-β result signals need for follow-up before treatment

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