18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease

Abstract

To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand ¹⁸F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of ¹⁸F-AV-1451, and mainly in demented AD patients. ¹⁸F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal ¹⁸F-AV-1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though ¹⁸F-AV-1451 retention was always increased at this disease stage. We conclude that CSF T-tau and P-tau mainly behave as biomarkers of "disease state", since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, ¹⁸F-AV-1451 is a biomarker of "disease stage", since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.

Keywords: Alzheimer; biomarker; cerebrospinal fluid; positron emission tomography; tau.

Figure EV1. Correlations between CSF T‐tau and P‐tau

CSF P‐tau and T‐tau in different diagnostic groups, with slopes from linear regression models adjusted for age and sex.

Figure 1. Correlations between regional ¹⁸F‐AV‐1451 and CSF tau biomarkers

1. A–L

   Observed data and correlations for CSF T‐tau by regional ¹⁸F‐AV‐1451, and for CSF P‐tau by regional ¹⁸F‐AV‐1451. The y‐axes show ¹⁸F‐AV‐1451 data in the a priori defined tau stage I–II, III, IV, V and VI regions, and in the merged tau stage I–V region. Each symbol represents one person. The fitted lines are from linear regression models adjusted for the interaction between the CSF biomarker and diagnosis, and age, sex and time between lumbar puncture and PET scan. P‐values from these models are shown, extracted for each diagnostic group (CN, controls; Pro AD, prodromal AD; AD dem, AD dementia). Corresponding β‐coefficients are presented in Table EV1.

Figure 2. Voxel‐wise associations of ¹⁸F‐AV‐1451 and CSF tau biomarkers

1. A–D

   Associations of CSF T‐tau (A) and P‐tau (C) on ¹⁸F‐AV‐1451 uptake, adjusted for age, sex, diagnosis and time between lumbar puncture and PET scan. Associations of CSF T‐tau (B) and P‐tau (D) on ¹⁸F‐AV‐1451 uptake when also adjusting for atrophy (using cortical thickness in the “AD‐cortex” region). All results are shown at a statistical significance threshold of P < 0.001 (uncorrected).

Figure 3. Associations between tau biomarkers and neurodegeneration

1. A

   Voxel‐wise association between GM intensity and ¹⁸F‐AV‐1451 uptake in the tau stage I–V composite region, adjusted for age, sex and diagnosis. The model yielded suprathreshold clusters in the posterior lateral temporal lobes, lateral parietal and occipital cortex, as well as the precuneus at a statistical threshold of P < 0.001 (uncorrected).

2. B, C

   Voxel‐wise association between GM intensity and CSF T‐tau or P‐tau, adjusted for age, sex and diagnosis. The model with T‐tau as the independent variable produced small, scattered significant clusters in the precuneus, the middle cingulate gyrus, parietal and left temporal cortex. The model with P‐tau produced a similar pattern, except for the association in precuneus.

Figure EV2. Associations between atrophy and CSF and PET tau, adjusted for the other tau modality

1. A, B

   VBM analyses for ¹⁸F‐AV‐1451 when adjusted for CSF T‐tau or P‐tau.

2. C, D

   VBM analyses for CSF T‐tau and P‐tau when adjusted for ¹⁸F‐AV‐1451.

Figure 4. Associations between tau biomarkers and cognition

1. A–C

   Associations of CSF T‐tau, P‐tau, ¹⁸F‐AV1451 retention in the stage I–V composite region, hippocampal volume and cortical thickness (in the temporal lobe, “AD‐cortex”, see Materials and Methods for details) with the cognitive tests MMSE, ADAS‐cog delayed recall, and AQT colour and form naming. The estimates are β‐coefficients with 95% confidence intervals (error bars) from linear regression models adjusted for age, sex, diagnosis, education and (for hippocampal volume) intracranial volume. All data were scaled and centred. If necessary, the signs were inverted to make a more pathological biomarker associated with greater cognitive impairment. Significant associations are shown in red. In sum, higher ¹⁸F‐AV1451 retention and thinner cortex were associated with worse MMSE, ADAS‐cog delayed recall and AQT; and smaller hippocampal volume was associated with worse ADAS‐cog delayed recall and AQT.

Figure 5. Sensitivity of tau biomarkers for Alzheimer's disease

1. A, B

   The sensitivity of ¹⁸F‐AV‐1451 in different tau stage regions for preclinical AD, prodromal AD and AD dementia, and the sensitivity of ¹⁸F‐AV‐1451 in the tau stage I–V composite region, CSF T‐tau and P‐tau. Cut‐offs were defined using the mean levels plus two standard deviations in Aβ‐negative controls, as explained in the main text.

Figure EV3. Tau PET in preclinical AD

1. A–F

   Regional ¹⁸F‐AV‐1451 by Aβ‐status in controls. The boxplots show medians and interquartile ranges. There were no significant differences between Aβ‐negative and Aβ‐positive controls (tau stage I–II region, P = 0.53; tau stage III region, P = 0.19; tau stage IV region, P = 0.63; tau stage V region, P = 0.30; tau stage VI region, P = 0.72; and tau stage I–V composite region, P = 0.31). Tests were done by linear regression models adjusted for age and sex.

Figure 6. CSF tau biomarkers in preclinical AD

1. A, B

   CSF T‐tau and P‐tau were compared between Aβ‐negative and Aβ‐positive controls. Aβ‐positivity (i.e. preclinical AD) was associated with higher levels of CSF T‐tau and P‐tau, adjusted for age and sex. We also compared CSF T‐tau and P‐tau between Aβ‐negative and Aβ‐positive subjects when including all subjects with a negative ¹⁸F‐AV‐1451 signal in the tau stage I–V tau composite region (30 CN, five prodromal AD and three AD dementia patients). The Aβ‐dependent effects for CSF T‐tau and P‐tau were even greater in this group, with higher CSF T‐tau (β = 222, t = 3.9, P = 0.00048) and P‐tau (β = 22.7, t = 2.9, P = 0.0054) associated with Aβ‐positivity. The boxplots show medians and interquartile ranges.

Figure 7. Concordance between CSF and PET tau biomarkers

1. A–H

   Concordance between CSF T‐tau and ¹⁸F‐AV‐1451, and CSF P‐tau and ¹⁸F‐AV‐1451. Panels (A) and (E) include all subjects, and panels (B–D) and (F–H) include AD patients at different disease stages. The cut‐off for positive CSF T‐tau was > 542 ng/l. The cut‐off for positive CSF P‐tau was > 81 ng/l. For ¹⁸F‐AV‐1451, the cut‐offs were > 1.55, 1.35, 1.57, 1.40 and 1.30 SUVR, for tau stage I–II, III, IV, V and VI regions, respectively, and > 1.41 SUVR for the tau stage I–V composite region. Note that every participant is represented in each category on the x‐axes, since every participant was classified as positive or negative for ¹⁸F‐AV‐1451 in every tau stage region.