Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease

Abstract

Objective: To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression.

Methods: A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ]₄₂, phosphorylated tau₁₈₁, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity.

Results: CSF Aβ₄₂ and PiB PET showed maximal correlation when collected within 6 years of each other (R ≈ -0.5). CSF phosphorylated tau₁₈₁ and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET (R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval (R _avg ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval (R _avg < -0.2).

Conclusions: CSF Aβ₄₂ and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.

Figure 1. Correlation of Amyloid Biomarkers

Biomarkers of amyloid showed reasonably good correlation for a wide range of time bins (A). For individuals classified as amyloid-positive with a PET scan using Pittsburgh compound B (PiB), the greatest inverse correlation between CSF β-amyloid (Aβ)₄₂ and PET PiB was when the lumbar puncture (LP) was performed 4–8 years prior to the PET (B). The timeframes with the greatest correlation for all participants (C), as well as those for participants with Alzheimer disease pathologic change (D), are shown.

Figure 2. Correlation of Tau Biomarkers

Biomarkers of tau show reasonably good correlation when the lumbar puncture (LP) was performed several years prior to the PET scan (A). For individuals classified as amyloid-positive using a PET amyloid (Pittsburgh compound B) scan, correlation between CSF (phosphorylated tau [p-tau]) and flortaucipir PET was highest when the LP was performed 4–8 years prior to the PET (B). The timeframes with greatest measurement correlation for all participants (C), as well as those for participants with documented Alzheimer disease pathology (D), are shown.

Figure 3. Correlation of Neurodegeneration Biomarkers

Biomarkers of neurodegeneration (Alzheimer disease [AD] cortical thickness and CSF neurofilament light [NfL]) showed relatively poor correlation, regardless of the time bin (A). For individuals classified as amyloid-positive with a PET amyloid (Pittsburgh compound B) scan, correlation between cortical thickness and CSF NfL increased with age. The greatest correlation occurred when the lumbar puncture (LP) was performed 0–2 years after the structural MRI (B). For all participants, the greatest correlation between CSF NfL and structural MRI occurred when the LP was performed 2–4 years prior to the MRI (C). However, for participants with documented AD pathology, the greatest correlation was observed when the LP was performed 0–2 years after the MRI (D).