Twenty-five subjects were clinically unresponsive at baseline with severe end-stage dementia, i.e., ADAS-COG scores greater than 60 points, and were excluded from further analysis to reduce floor effects.
Of the 275 subjects, 161 (59%) fulfilled NINCDS-ADRDA criteria for probable AD and 114 (41%) fulfilled criteria for possible AD. The mean age of the cohort at baseline was 82.7 (SD 7.4) years. Ninety-nine subjects (36%) were men. One hundred seventeen (43%) of the 275 subjects at baseline were taking a cholinesterase inhibitor (CheI), of whom 97 (83%) had been taking the drug for more than 2 months. Eighty-eight subjects (32%) had a history of hypertension, 45 (16%) had a history of hypercholesterolemia, and 19 (7%) had a history of type 2 diabetes. Eighteen subjects (6.5%) had delirium at baseline. shows the type and period prevalence of SIEs at, or retrospectively, in the 2 months preceding, baseline. Thirty-nine subjects (14.2% of all subjects) had a total of 50 SIEs identified at or during the 2 months preceding baseline. Twenty-nine of these 39 subjects had 1 SIE, 9 subjects had 2 SIEs, and 1 subject had 3 SIEs at or preceding baseline assessment. Blood sampling was obtained in 269 of 275 subjects (98%) at baseline. Serum CRP was moderate/high (serum level ≥1 μg/mL) in 192 of all subjects (70%). Serum TNF-α was detectable in all subjects (TNF-α median 3.3 [interquartile range (IQR) 2.4–4.2] pg/mL).
Table 1 Period prevalence of systemic inflammatory events at baseline and during the 6-month follow-up period and effect size on cognitive decline
Baseline cognitive score and systemic inflammation.
At baseline, subjects had a mean ADAS-COG score of 29.6 (SD 13.0) points.
No relationship was found between the presence of low serum CRP and baseline ADAS-COG score (low CRP 28.0 [SE 1.5] pts, c.f. moderate/high CRP 30.7 [SE 0.9] pts; mean difference 2.7 [95% confidence interval (CI) −6.1 to 0.7] pts, t test p = 0.1). Low serum CRP was associated with a younger age (low CRP 81.0 [SE 0.8] years, c.f. moderate/high CRP 83.5 [SE 0.6] years; mean difference 2.5 [95% CI 0.6 to 4.5] years, t test p = 0.01) and with the prescription of a cholinesterase inhibitor (χ2 13.2, p < 0.001) but not sex (χ2 0.7, p = 0.4).
Low baseline serum TNF-α was associated with younger age, lower ADAS-COG scores, and CheI use, but there was no relationship with sex or SIEs preceding baseline ().
Table 2 Baseline serum TNF-α systemic inflammatory markers and demographics
Linear regression analysis with baseline ADAS-COG score as the dependent variable showed that the relationship between baseline ADAS-COG score and low or high serum baseline TNF-α levels remained unchanged (mean difference 4.1 [95% CI 0.5–7.7] pts, t test p = 0.02) after correction for age, CheI use, history of hypertension, type 2 diabetes, hypercholesterolemia, and the presence of delirium at baseline as possible confounders.
Six-month follow-up period.
Two hundred twenty-two (81%) of all subjects had complete clinical and systemic inflammatory marker follow-up at 2, 4, and 6 months. Of the 53 subjects who did not complete the study, 15 subjects died before study completion and 38 subjects declined phlebotomy or further cognitive assessment at some point during the study. A trend relationship was found between study completion and baseline serum levels of TNF-α (completers median level 3.1 [IQR 2.3–4.3] pg/mL, c.f. noncompleters 3.7 [IQR 3.0–4.2] pg/mL, Mann–Whitney U p = 0.07).
Systemic inflammatory events.
One hundred ten (49.5%) of the 222 subjects followed up had a combined total of 150 SIEs (). Eighty-one subjects (36.5%) had clinical evidence of 1 acute SIE, 22 (9.9%) subjects had evidence of 2 SIEs, and 7 (3.2%) had evidence of 3 or more SIEs in the 6 months after baseline assessment.
Subjects with 1 or more SIEs during the 6-month follow-up period had an increase in TNF-α levels compared with subjects with no SIEs over the next 6 months (SIEs absent: TNF-α increased by 0.03 [SE 0.07] pg/mL, c.f. SIEs present: TNF-α increased by 0.32 [SE 0.07] pg/mL; mean difference 0.29 [95% CI 0.08–0.50] pg/mL, t test p = 0.005).
Cognitive decline and systemic inflammation.
The mean change in ADAS-COG score over the 6-month follow-up period was 2.6 (SD 7.0) points.
Change in ADAS-COG score over the 6-month follow-up period showed a low correlation with baseline ADAS-COG score (Pearson correlation 0.14, p = 0.03).
There was no difference in change in ADAS-COG score over the 6-month follow-up period in those subjects with low CRP levels at baseline compared with subjects with moderate/high CRP levels at baseline (low CRP 1.9 [SE 0.7] pts, c.f. moderate/high CRP 3.0 [SE 0.6] pts; mean difference 1.1 [95% CI −3.1 to 1.0] pts, t test p = 0.3). However, change in ADAS-COG score over the 6-month follow-up period was greater in those subjects with high TNF-α levels at baseline compared with subjects with low TNF-α levels at baseline (low TNF-α 0.8 [SE 0.8] pts, c.f. high TNF-α 3.2 [SE 0.6] pts; mean difference 2.4 [95% CI 0.3–4.5] pts, t test p = 0.02).
Subjects with 1 or more SIEs during the 6-month follow-up period had a faster rate of cognitive decline from baseline to 6 months compared with those with no recorded SIEs (SIE absent ADAS-COG change 1.6 [SE 0.6] pts, c.f. SIE present 3.5 [SE 0.8] pts; mean difference 2.0 [95% CI 0.1–3.8] pts, t test p = 0.04) (). There was a trend for patients with more than 1 SIE to have an increased rate of cognitive decline (SIEs absent ADAS-COG change 1.6 [SE 0.6] pts, 1 SIE ADAS-COG change 3.3 [SE 0.9] pts, 2 or more SIEs ADAS-COG change 4.3 [SE 1.6] pts; ANOVA F 2.4, p = 0.09). Effect sizes for individual SIEs varied ().
Figure 1 Presence or absence of systemic inflammatory events and mean change in cognitive score from baseline
Change in ADAS-COG score had a low correlation with the change in serum TNF-α levels over the 6-month follow-up period (Pearson correlation 0.20, p = 0.004).
Linear regression analysis was performed with change in ADAS-COG as the dependent variable and age, baseline ADAS-COG, the presence or absence of an SIE through the 6-month follow-up period, presence of low or high TNF-α level at baseline, change in TNF-α, and CheI use as independent variables. This analysis showed a change in the relationship between change in ADAS-COG and baseline ADAS-COG score (adjusted mean difference 0.06 [95% CI −0.02 to 0.14] pts, p = 0.1) and the presence or absence of SIEs (adjusted mean difference 1.2 [95% CI −0.7 to 3.2] pts, p = 0.2). However, there was little change in the relationship between change in ADAS-COG and either baseline TNF-α level (adjusted mean difference 2.5 [95% CI 0.3–4.7] pts, p = 0.03) or change in serum TNF-α (adjusted mean difference 1.8 [95% CI 0.6–3.0] pts, p = 0.003). Correction for the presence of a history of hypertension, hypercholesterolemia, and type 2 diabetes did not alter these relationships.
Delirium was identified in 25 subjects during the 6-month follow-up period and was more frequent in subjects with increased serum TNF-α at baseline (χ2 7.4, p = 0.007) but was not related to the presence of SIEs (χ2 0.7, p = 0.2). Correcting for the presence of delirium altered the relationship between change in ADAS-COG and baseline TNF-α level (adjusted mean difference 1.6 [95% CI −0.6 to 3.7] pts, p = 0.1), but no difference was found between change in ADAS-COG score and change in serum TNF-α (adjusted mean difference 1.8 [95% CI 0.6–2.9] pts, p = 0.002).
Allocating subjects to 1 of 4 groups based on low or high levels of TNF-α at baseline and the presence or absence of SIEs in the 6-month follow-up period showed a difference in rates of cognitive decline at 6 months between groups (ANOVA F 3.3, p = 0.02) (). There was no interaction effect between low or high levels of TNF-α at baseline and the presence or absence of SIEs in the 6-month follow-up period (ANOVA F 0.5, p = 0.5).
Figure 2 Rate of cognitive decline at 6 months by presence of incident systemic inflammatory events and baseline serum TNF-α levels
In total, 27 of the 83 subjects at baseline with low serum CRP levels had low levels throughout the 6-month follow-up period. Examination of those 27 subjects showed no differences in their rate of cognitive decline compared with those with moderate/high CRP levels (low CRP 1.9 [SE 1.3] pts, c.f. moderate/high CRP 2.6 [SE 0.5] pts; mean difference 0.7 [95% CI −3.7 to 2.1] pts, p = 0.6).
In total, 34 of the 59 subjects at baseline with low serum TNF-α levels had serum TNF-α levels that remained at less than 2.4 pg/mL during the 6-month follow-up. Examination of those 34 subjects with low TNF-α throughout the course of the study showed them to have a markedly lower rate of cognitive decline compared with those with high TNF-α (low TNF-α −0.3 [SE 1.2] pts, c.f. high TNF-α 3.1 [SE 0.5] pts; mean difference 3.4 [95% CI 0.7–5.9] pts, p = 0.01) ().
Figure 3 Rate of cognitive decline by mean serum TNF-α levels during the follow-up period