Preventive Effect of Rifampicin on Alzheimer Disease Needs at Least 450 mg Daily for 1 Year: An FDG-PET Follow-Up Study

Abstract

Background: Rifampicin was reported to inhibit amyloid-β oligomerization and tau hyperphosphorylation in mouse models and could serve as a promising available medicine for the prevention of Alzheimer disease (AD). To examine whether rifampicin has such preventive effects in humans, we retrospectively reviewed ¹⁸F-FDG-PET findings of elderly patients with mycobacterium infection treated with rifampicin.

Methods: Forty nondemented elderly patients treated with rifampicin for mycobacterium infections who showed AD-type hypometabolism were enrolled. The hypometabolic patterns were evaluated with stereotaxic statistical analysis and region of interest analysis.

Results: Before treatment, AD-type hypometa bolism was observed in 12 patients. The FDG uptake in the posterior cingulate cortex (PCC) was improved or stabilized in 6 patients after 12-month therapy (450 mg/day), whereas another 6 patients with 6-month therapy showed a decreased FDG uptake in the PCC. In patients who underwent FDG-PET only after treatment, the metabolic decline in the PCC was significantly milder in patients with ≥12 months of rifampicin treatment than in those with 6 months of treatment. Multiple regression analysis revealed that the dose of rifampicin and treatment duration significantly influenced FDG uptake in the PCC.

Conclusion: The preventive effect of rifampicin depended on the dose and the treatment duration, and the effect needs at least 450 mg daily for 1 year.

Keywords: Alzheimer disease; Amyloid-β; FDG-PET; Oligomer; Preventive therapy; Rifampicin.

Fig. 1

Flow diagram. In Group A, we examined how the AD-type hypometabolism changes by administration of rifampicin. In Group B, we investigated how the Alzheimer disease (AD)-type hypometabolism emerges after therapy and the finding changes during long-term follow-up. CDR, Clinical Dementia Rating.

Fig. 2

Association between Mini-Mental State Examination (MMSE) scores and standardized uptake value ratios (SUVR) in the posterior cingulate cortex (PCC) of rifampicin-treated patients. In rifampicin-treated patients, MMSE scores and SUVR in the PCC at the first and second FDG-PET in Groups A and B were used. Pearson's correlation coefficient of rifampicin-treated patients was 0.680 (p < 0.001).

Fig. 3

The 3D stereotactic surface projection images of hypometabolism before and after therapy in 3 patients in Group A. a The patient was male and 77 years of age at the time of the first FDG-PET examination. He did not have amnesia (Clinical Dementia Rating [CDR]: 0; Mini-Mental State Examination [MMSE] score: 29). After diagnosis of mycobacterium avium complex (MAC), 450 mg/day of rifampicin was administrated for 12 months. The second FDG-PET was performed 24 months after the first FDG. An increase of FDG uptake was observed in the posterior cingulate cortex (PCC) and the parietal association cortex. The CDR and MMSE score of the patient did not change. b The patient was female and 74 years of age at the time of the first FDG-PET examination. She was slightly amnestic but had no problems in daily life (CDR: 0.5; MMSE score: 26). After diagnosis of MAC, she completed 12 months of therapy with 450 mg daily of rifampicin. The second FDG-PET was performed 24 months after the first FDG. An increase of FDG uptake was clearly observed in the PCC and slightly in the parietal association cortex. The CDR of the patient remained 0.5, but the MMSE score increased to 28. c The patient was male and 85 years of age at the time of the first FDG-PET examination. He was slightly amnestic but had no problems in daily life (CDR: 0.5; MMSE score: 25). After diagnosis of MAC, he completed 12 months of rifampicin therapy. The second FDG-PET was performed 36 months after the first FDG. FDG uptake was not changed obviously. The CDR and MMSE score of the patient did not change.

Fig. 4

Metabolic changes in each patient in Group A. The graph shows standardized uptake value ratios (SUVR) in the posterior cingulate cortex (PCC) at the first and second FDG-PET examinations in each patient of Group A. The metabolic change in the PCC between therapy for 12 and 6 months was significantly different in repeated measures ANCOVA (p = 0.009).

Fig. 5

Time course of metabolic decline in patients in Group B. Repeated-measures ANCOVA was applied to assess the metabolic decline during long-term follow-up in patients treated with 450 mg daily of rifampicin for 6 and ≥12 months. The interval of FDG-PET was used as a covariate. The metabolic decline in ≥12-month therapy was significantly milder than that in 6-month therapy (p = 0.013). Regression lines for both ≥12-month (red; R² = 0.741, p < 0.001) and 6-month (blue; R² = 0.772, p < 0.001) therapy are shown. SUVR, standardized uptake value ratio; PCC, posterior cingulate cortex.

Fig. 6

Time course of cognitive decline in patients in Group B. Repeated-measures ANCOVA was applied to assess the cognitive decline during long-term follow-up in patients treated with 450 mg daily of rifampicin for 6 and ≥12 months. The interval of FDG-PET was used as a covariate. The cognitive decline in ≥12-month therapy was significantly milder than that in 6-month therapy (p = 0.045). Regression lines for both ≥12-month (red; R² = 0.420, p < 0.01) and 6-month (black; R² = 0.802, p < 0.001) therapy are shown. MMSE, Mini-Mental State Examination.