Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography

Abstract

Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer's disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET during preclinical stages of Alzheimer's disease. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) study. All underwent (18)F-florbetapir positron emission tomography and cerebrospinal fluid amyloid-β42 analysis at baseline and at least one additional positron emission tomography after a mean follow-up of 2.1 years (range 1.1-4.4 years). Group classifications were based on normal and abnormal cerebrospinal fluid and positron emission tomography results at baseline. We found that cases with isolated abnormal cerebrospinal fluid amyloid-β and normal positron emission tomography at baseline accumulated amyloid with a mean rate of 1.2%/year, which was similar to the rate in cases with both abnormal cerebrospinal fluid and positron emission tomography (1.2%/year, P = 0.86). The mean accumulation rate of those with isolated abnormal cerebrospinal fluid was more than three times that of those with both normal cerebrospinal fluid and positron emission tomography (0.35%/year, P = 0.018). The group differences were similar when analysing yearly change in standardized uptake value ratio of florbetapir instead of percentage change. Those with both abnormal cerebrospinal fluid and positron emission tomography deteriorated more in memory and hippocampal volume compared with the other groups (P < 0.001), indicating that they were closer to Alzheimer's disease dementia. The results were replicated after adjustments of different factors and when using different cut-offs for amyloid-β abnormality including a positron emission tomography classification based on the florbetapir uptake in regions where the initial amyloid-β accumulation occurs in Alzheimer's disease. This is the first study to show that individuals who have abnormal cerebrospinal amyloid-β42 but normal amyloid-β positron emission tomography have an increased cortical amyloid-β accumulation rate similar to those with both abnormal cerebrospinal fluid and positron emission tomography and higher rate than subjects where both modalities are normal. The results indicate that cerebrospinal fluid amyloid-β42 becomes abnormal in the earliest stages of Alzheimer's disease, before amyloid positron emission tomography and before neurodegeneration starts.

Keywords: Alzheimer’s disease; CSF Aβ42; PET; amyloid-β; florbetapir.

See Rabinovici (doi: 10.1093/brain/aww025 ) for a scientific commentary on this article. The success of disease-modifying therapies in Alzheimer’s disease may depend on detecting the earliest signs of abnormal amyloid-β load. Palmqvist et al . show that CSF amyloid-β ₄₂ becomes abnormal before amyloid PET and before neurodegeneration onset in preclinical Alzheimer’s disease. This may have implications for risk factor interventions and future therapies.

Figure 1

CSF amyloid-β42 levels versus global amyloid PET SUVR relative to the composite region . Solid lines represent the predefined thresholds for CSF amyloid-β ₄₂ (<192 ng/l) and florbetapir PET (>0.79 SUVR). Dashed lines represent a ± 5% interval from the thresholds, which was used in the final classification to exclude borderlines cases. Aβ42 ₌ amyloid-β ₄₂ .

Figure 2

Boxplots of the amyloid-β accumulation rate (% SUVR change/year) for the different groups. Group comparisons were analysed with Mann-Whitney. There were no CSF–/PET+ individuals in A and only one in B and C . Therefore, this group is not shown. ( A ) Amyloid-β accumulation rate in the global neocortical region. Group classifications were based on the a priori cut-offs for amyloid-β ₄₂ (CSF+<182.4 ng/l, CSF– >201.6 ng/l) and the global neocortical amyloid-β SUVR relative a composite reference region (PET+>0.8295, PET − <0.7505). ( B ) Amyloid-β accumulation rate in the global neocortical region using a PET classification (+/–) based on abnormal/normal amyloid-β in brain regions affected in early amyloid-β deposition (the medial and lateral orbitofrontal cortex and the frontal pole; ‘the early amyloid-β region’). Cut-offs were established with mixture modelling (PET+>0.8579 SUVR, PET– <0.7762 SUVR). The CSF classification was the same as in ( A ). ( C ) Amyloid-β accumulation rate in the ‘early amyloid-β region’ using the same CSF/PET classification as in ( B ). Aβ = amyloid-β.

Figure 3

The annual rate of amyloid-β accumulation (%) as a function of CSF amyloid-β ₄₂ levels in PET− and PET+ individuals. The local regression line was fitted using the partial least square criterion (‘LOESS’) and illustrates the increase in accumulation rate with decreasing amyloid-β ₄₂ levels as seen in CSF+/PET+ subjects and at lower amyloid-β ₄₂ levels in CSF−/PET− subjects ( A ). The gap between CSF−/PET− and CSF+/PET− is caused by the exclusion of borderline cases. In B , the local regression line shows an accumulation rate that has plateaued and does not increase with decreasing CSF amyloid-β ₄₂ levels.

Figure 4

Longitudinal changes in memory and hippocampal atrophy. ( A ) Illustration of the linear slopes in composite memory score for the three groups. The coefficients were calculated from scores at the ADNI baseline and the 12, 24, 36, 48 and 60-month visits. The CSF+/PET+ group deteriorated significantly in memory function, but no deterioration was seen in the other groups. The difference between CSF+/PET+ and the other groups was significant. ( B ) The coefficient of the hippocampal volume was calculated based on all available data at all ADNI visits. CSF+/PET+ progressed significantly more than the other groups. Supplementary Fig. 1A and B shows the individual trajectories of the composite memory score and the hippocampal volume.