Data were obtained from a [¹⁸F] florbetapir positron emission tomography (PET) study carried out as part of the Multidomain Alzheimer Preventive Trial (MAPT), which was a large phase III, multicentre, randomized, placebo-controlled trial (29) (registration: NCT00672685). The trial had a four-arm design comprising a placebo group and three treatment groups; omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation, multidomain intervention (involving nutritional and exercise counseling and cognitive training), and n-3 PUFA supplementation plus multidomain intervention. The trial was designed to assess the efficacy of the interventions in slowing cognitive decline in older adults at risk of dementia (n = 1,680) (29). In the main analysis of MAPT, no significant effects of any of the interventions were found on the composite cognitive score compared to placebo after adjustment for multiple testing (30). Both the MAPT and [¹⁸F] florbetapir PET study were approved by the ethics committee in Toulouse (CPP SOOM II) and written consent was obtained from all participants.

A total of 271 subjects participated in the MAPT-[¹⁸F] florbetapir ancillary study. At inclusion, participants were community-dwelling, men and women without dementia, aged ≥70, and who met at least one of the following criteria: spontaneous memory complaints, limitation in executing ≥1 Instrumental Activity of Daily Living or slow gait speed (<0.8 meters/sec). Two participants were excluded because they developed dementia at the clinical assessment closest to PET [Clinical Dementia Rating (CDR) ≥ 1]. Thus, a total of 269 subjects were included in the analyses described here. The participants of the main MAPT study not assessed for cerebral Aβ load were similar to the participants in the PET sub-study in terms of age at baseline (main MAPT study: 75.9 ± 4.5 years, PET sub-study: 75.2 ± 4.2 years), sex (main MAPT study: 65.6% female, PET sub-study: 60.2% female) and cognition at baseline measured as mini mental state examination test score (main MAPT study: 28.0 ± 1.6, PET sub-study: 28.3 ± 1.5).

PET-scans were performed once during MAPT in volunteers using [¹⁸F] florbetapir as previously described (29, 31). All data acquisitions were begun 50 min after injection of a mean of 4 MBq/kg weight of [¹⁸F]-Florbetapir. Radiochemical purity of [¹⁸F]-Florbetapir was always superior to 99.5%. Standard uptake value ratios (SUVRs) were generated from semi-automated quantitative analysis using the cerebellum as a reference. Cortical-to-cerebellar SUVRs (cortical-SUVRs) were obtained using the mean signal from the following cortical regions: frontal, temporal, parietal, precuneus, anterior cingulate, and posterior cingulate as previously described (32). Other brain regions independently assessed were the: anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex. A quality control based on semi-quantification process was also performed. The median and interquartile range (IQR) for the time interval between baseline and PET-scan assessment was 487.5 days (IQR: 349–728) and 3.7% (10 out of 269) of subjects received a PET-scan at study baseline.

Fatigue was defined according to the following two questions retrieved from the Center for Epidemiological Studies-Depression scale: (a) I felt that everything I did was an effort, (b) I could not get going. The question is asked “How often in the last week did you feel this way?” and subjects score their responses: 0 = rarely or none of the time (<1 day), 1 = some or a little of the time (1–2 days), 2 = a moderate amount of the time (3–4 days), 3 = most of the time. Subjects answering 2 or 3 to either of these questions were designated as fatigued otherwise subjects were classed as non-fatigued. Subjects were classed as having chronic fatigue if answering 2 or 3 to either of the questions at two consecutive visits between study baseline and 1 year (visits were performed at baseline, 6 months, and 1 year after which they were performed annually) otherwise subjects were deemed non-chronically fatigued. The adopted definition of fatigue is commonly used to define the “exhaustion” criterion in the field of frailty (3).

On the basis of data availability and the literature on dementia (33), we selected the following confounders: age at PET-scan assessment, gender, educational level, cognitive status assessed at the clinical visit closest to PET-scan (CDR: scores 0 or 0.5), MAPT group allocation (four groups: placebo, multidomain intervention, n-3 PUFA supplementation and multidomain intervention + n-3 PUFA supplementation), depressive symptoms assessed closed to PET-scan (Geriatric Depression Scale: scores 0–30) and Apolipoprotein E ε4 (ApoE ε4) genotype (carriers of at least one ε4 allele versus non-carriers).

Descriptive statistics are presented as median (IQR) or absolute values/percentages as appropriate. After completing analysis of the primary hypotheses in MAPT (30), we performed post hoc analyses using multiple linear regression models to explore the cross-sectional relationships between fatigue and cerebral Aβ load (measured as SUVR). Clinical and demographic characteristics were compared between the participants deemed as non-fatigued or fatigued (with fatigue assessed at the clinical exam closest to PET-scan) using chi squared tests for categorical variables and Wilcoxon rank sum tests for continuous variables. We ran multiple linear regression analysis to explore the cross-sectional relationship between fatigue at the clinical exam closest to PET-scan and cortical-SUVR and region specific SUVR (13 regions described above) adjusting for all confounders. Sensitivity analysis was performed in subjects with a CDR score of 0.5 as this sub-group represents those more likely to develop AD (34). We also ran multiple linear regression analysis to explore the cross-sectional relationship between chronic fatigue and cortical-SUVR and regional SUVR (13 regions) adjusting for all confounders. There was no correction for multiple comparisons due to the exploratory nature of this study: p < 0.05 was considered statistically significant. All analyses were performed using Stata version 14 (Stata Corp., College Station, TX, USA).

Clinical and demographic characteristics of the study participants are shown in Table 1. The median age of the participants was approximately 75 years and around 60% of the subjects were female and approximately half of the subjects had a CDR score of 0.5. Participants exhibited a high educational level and approximately 30% of the subjects were ApoE ε4 carriers. There were no statistically significant differences between subjects classed as non-fatigued or fatigued (with fatigue assessed at the clinical exam closest to PET-scan). A total of 42 participants out of 269 (15.6%) were classified as fatigued and of these 42.9% (18 out of 42) were Aβ positive using a threshold of mean cortical-SUVR ≥ 1.17 (31, 35). A total of 26 participants out of 269 (9.7%) were classified as having chronic fatigue and of these 38.5% (10 out of 26) were Aβ positive.

There were no statistically significant cross-sectional associations of fatigue at the clinical exam closest to PET-scan with cortical or region specific Aβ load after adjustment for all confounders (Table 2). Sensitivity analysis performed in subjects with a CDR score of 0.5, however, showed a weak positive association between fatigue reported at the clinical exam closest to PET-scan and Aβ load in the hippocampus (Table 3). Chronic fatigue was not significantly associated with cortical Aβ or Aβ found in any other brain region after adjustment for all confounders (Table 4).

Sandrine Andrieu, Christelle Cantet, Nicola Coley.